Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer’s disease mouse model
Open accessAbstract
Macrophages accumulate lipid droplets (LDs) under stress and inflammatory conditions. Despite the presence of LD-loaded macrophages in many tissues, including the brain, their contribution to neurodegenerative disorders remains elusive. This study investigated the role of lipid metabolism in Alzheimer’s disease (AD) by assessing the contribution of LD-loaded brain macrophages, including microglia and border-associated macrophages (BAMs), in an AD mouse model. Particularly, BAMs and activated CD11c + microglia localized near β amyloid (Aβ) plaques exhibited a pronounced lipid-associated gene signature and a high LD load. Having observed that elevated intracellular LD content correlated inversely with microglial phagocytic activities, we subsequently inhibited LD formation specifically in CX3CR1 + brain macrophages using an inducible APP-KI/ Fit2 i Δ M φ transgenic mouse model. We demonstrated that reducing LD content in microglia and CX3CR1 + BAMs remarkably improved their phagocytic ability. Furthermore, lowering microglial LDs consistently enhanced their efferocytosis capacities and notably reduced Aβ deposition in the brain parenchyma. Therefore, mitigating LD accumulation in brain macrophages provides perspectives for AD treatment.
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TL;DR
In an Alzheimer’s disease mouse model, lipid-droplet load in brain macrophages increases with age and disease and is highest in plaque-associated CD11c+ microglia and CD206+ BAMs. Inducible FIT2 depletion in CX3CR1+ brain macrophages lowers lipid droplets, enhances phagocytosis and efferocytosis, and reduces Aβ deposition.
Key findings
- Lipid-droplet accumulation in microglia increased with age and AD: LD+ microglia rose from 5% at 2 months to 35% at 6 months in WT mice and from about 10% to 50% in APP-KI mice; with HFD, LD+ microglia reached 60% at 6 months in APP-KI mice. About 65% of lipid-droplet-accumulating microglia were localized near Aβ plaques.
- scRNA-seq showed that the CD11c+ activated-response microglia cluster was the most abundant in AD brains and was enriched for foam-cell/lipid-associated genes including Plin2, Apoe, Trem2, Lpl, and Cd9; CD206+ BAMs also expressed lipid-metabolism genes such as Plin2, Apoe, Trem2, and Cd36. CD11c+ microglia had higher neutral lipid accumulation than CD11c− microglia.
- FIT2 depletion in CX3CR1+ brain macrophages reduced the microglial LD area by ~30%, lowered triglyceride levels, increased phagocytosis of E. coli bioparticles and Aβ oligomers in CD11c− and CD11c+ microglia and in MHCIIhi/int BAMs, enhanced efferocytosis of apoptotic N2A cells, and reduced Aβ plaque deposition in cortex and hippocampus. It also reduced pro-inflammatory molecules including Tnfa, Il6, Ccl2, and Ccl4.
Methods
- Mice: APP-KI AD model crossed with an inducible CX3CR1+ macrophage-specific FIT2-deficient strain (Fit2iΔMφ); FIT2 depletion induced with 4 mg tamoxifen/day for four consecutive days at 2 months of age. Mice were male and fed normal chow or high-fat diet.
- Data and assays: flow cytometry and cell sorting; BODIPY/LipidSpot lipid-droplet staining; immunofluorescence for Iba-1, Aβ, CD206, and thioflavin S; LC-MS lipidomics; scRNA-seq; qPCR; in vitro phagocytosis with pHrodo E. coli or Aβ oligomers; in vivo methoxy-XO4 Aβ uptake; efferocytosis with apoptotic N2A cells.
- Analysis: Student’s t test, one-way or two-way ANOVA, with P < 0.05 considered significant.
Limitations
- The paper states that FIT2-deficient microglia were not entirely devoid of LDs, likely because sterol esters can still contribute to LD formation, and cholesterol ester levels were not markedly affected.
- The paper states that APP-KI mice show a relatively mild behavioral phenotype, making it difficult to assess behavioral significance; it also notes ongoing debate about Aβ’s role in AD progression and that tau deposition or other misfolded proteins were not tested.
- The paper states that further studies are needed to identify effective pharmacological interventions targeting LD metabolism and to test clinical implications. Evident from the text: only male mice were used, and investigators were not blind to treatment group.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
76 of 89 cited sources checked · 47 supported · 2 flagged · accuracy not yet measured
- Premisecitation
Lipid-droplet accumulating microglia (LDAM) have been identified in aged brains of mice.
“Lipid-droplet accumulating microglia (LDAM) have been identified in aged brains of mice and classified as dysfunctional cells as they exhibit defective phagocytic activity and show increased production of pro-inflammatory cytokines and reactive oxygen species (ROS) (11)”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [11] J. Marschallinger, T. Iram, M. Zardeneta, S. E. Lee, B. Lehallier, M. S. Haney, J. V. Pluvinage, V. Mathur, O. Hahn, D. W. Morgens, J. Kim, J. Tevini, T. K. Felder, H. Wolinski, C. R. Bertozzi, M. C. Bassik, L. Aigner, T. Wyss-Coray, Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nat. Neurosci. 23, 194– 208 (2020). 31959936 PMC7595134 source
- Premisecitation
Excessive lipid droplet accumulation within microglia leads to a decline in their phagocytic activity.
“However, we and others (11, 13, 39) have observed that excessive LD accumulation within microglia led to a decline in their phagocytic activity, potentially reducing the efficiency of Aβ clearance in the AD brain.”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [11] J. Marschallinger, T. Iram, M. Zardeneta, S. E. Lee, B. Lehallier, M. S. Haney, J. V. Pluvinage, V. Mathur, O. Hahn, D. W. Morgens, J. Kim, J. Tevini, T. K. Felder, H. Wolinski, C. R. Bertozzi, M. C. Bassik, L. Aigner, T. Wyss-Coray, Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nat. Neurosci. 23, 194– 208 (2020). 31959936 PMC7595134 source
The Results section (‘LDAM have phagocytosis deficits’) reports significantly less Zymosan uptake in lipid-droplet-rich cells. But the Discussion (‘Role of lipid droplets in the LDAM functional phenotype’) says impaired phagocytosis could be a cause or consequence of droplet accumulation, or an independent co-occurring effect. The paper therefore supports the observed association, not the unqualified claim that accumulation leads to the decline; the suggested effect on Aβ clearance in AD is not established by these passages. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [13] M. Arbaizar-Rovirosa, J. Pedragosa, J. J. Lozano, C. Casal, A. Pol, M. Gallizioli, A. M. Planas, Aged lipid-laden microglia display impaired responses to stroke. EMBO Mol. Med. 15, e17175 (2023). 36541061 PMC9906381 source
- cites [39] P. Prakash, P. Manchanda, E. Paouri, K. Bisht, K. Sharma, P. R. Wijewardhane, C. E. Randolph, M. G. Clark, J. Fine, E. A. Thayer, A. Crockett, N. Gasmi, S. Stanko, R. A. Prayson, C. Zhang, D. Davalos, G. Chopra, Amyloid β induces lipid droplet-mediated microglial dysfunction in Alzheimer’s disease. bioRxiv 543525 [Preprint]. 6 June 2023. 10.1101/2023.06.04.543525. source
- Premisecitation
Microglia play a crucial role in clearing Aβ plaques in the brain during Alzheimer's disease progression.
“Microglia play a crucial role in clearing Aβ plaques in the brain during AD progression (25, 26).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [25] Z. Yin, D. Raj, N. Saiepour, D. Van Dam, N. Brouwer, I. R. Holtman, B. J. L. Eggen, T. Moller, J. A. Tamm, A. Abdourahman, E. M. Hol, W. Kamphuis, T. A. Bayer, P. P. De Deyn, E. Boddeke, Immune hyperreactivity of Aβ plaque-associated microglia in Alzheimer’s disease. Neurobiol. Aging 55, 115– 122 (2017). 28434692 source
- cites [26] S. Hellwig, A. Masuch, S. Nestel, N. Katzmarski, M. Meyer-Luehmann, K. Biber, Forebrain microglia from wild-type but not adult 5xFAD mice prevent amyloid-β plaque formation in organotypic hippocampal slice cultures. Sci. Rep. 5, 14624 (2015). 26416689 PMC4586757 source
The Results section reports that microglia ingest and digest Aβ in organotypic hippocampal slice cultures, and the Discussion describes a beneficial role in clearing Aβ. The paper supports a role in limiting plaque formation in that model, but does not establish that microglia clear existing plaques in the brain during AD progression; its Abstract notes that microglial depletion did not affect plaque load in two in vivo mouse models. (LLM, conf=0.85)
Experimental — accuracy not yet measured
- Findingcitation
LDAM numbers increase with age.
“For instance, we confirmed the findings of Marschallinger et al. by showing that LDAM numbers increased with age (11).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [11] J. Marschallinger, T. Iram, M. Zardeneta, S. E. Lee, B. Lehallier, M. S. Haney, J. V. Pluvinage, V. Mathur, O. Hahn, D. W. Morgens, J. Kim, J. Tevini, T. K. Felder, H. Wolinski, C. R. Bertozzi, M. C. Bassik, L. Aigner, T. Wyss-Coray, Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nat. Neurosci. 23, 194– 208 (2020). 31959936 PMC7595134 source
- Premisecitation
Many studies have demonstrated a phagocytosis defect associated with LD accumulation in microglia.
“Many studies have demonstrated a phagocytosis defect associated with LD accumulation in microglia (11, 13).”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [11] J. Marschallinger, T. Iram, M. Zardeneta, S. E. Lee, B. Lehallier, M. S. Haney, J. V. Pluvinage, V. Mathur, O. Hahn, D. W. Morgens, J. Kim, J. Tevini, T. K. Felder, H. Wolinski, C. R. Bertozzi, M. C. Bassik, L. Aigner, T. Wyss-Coray, Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nat. Neurosci. 23, 194– 208 (2020). 31959936 PMC7595134 source
- cites [13] M. Arbaizar-Rovirosa, J. Pedragosa, J. J. Lozano, C. Casal, A. Pol, M. Gallizioli, A. M. Planas, Aged lipid-laden microglia display impaired responses to stroke. EMBO Mol. Med. 15, e17175 (2023). 36541061 PMC9906381 source
- Findingown data
In AD brain microglia, mRNA of proteins involved in extracellular lipid uptake such as TREM2 and LPL are highly expressed.
“In our study, a series of proteins involved in extracellular lipid uptake, such as TREM2 and LPL (35), were highly expressed in mRNA in microglia obtained from the AD brain.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [35] B. A. Loving, K. D. Bruce, Lipid and lipoprotein metabolism in Microglia. Front. Physiol. 11, 393 (2020). 32411016 PMC7198855 source
- Premisecitation
Inflammatory activation of microglia triggers their metabolic reprogramming.
“The inflammatory activation of microglia triggers their metabolic reprogramming (43).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [43] C. Lauro, C. Limatola, Metabolic reprograming of microglia in the regulation of the innate inflammatory response. Front. Immunol. 11, 493 (2020). 32265936 PMC7099404 source
- Premisecitation
Lipid droplet overload can induce lysosomal defects leading to phagocytosis impairment.
“LD overload could also induce lysosomal defects (49), ultimately leading to phagocytosis impairment.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [49] F. Cabrera-Reyes, C. Parra-Ruiz, M. I. Yuseff, S. Zanlungo, Alterations in lysosome homeostasis in lipid-related disorders: Impact on metabolic tissues and immune cells. Front. Cell Dev. Biol. 9, 790568 (2021). 34957117 PMC8703004 source
The Figure 1 caption says lipid overload induces lysosomal membrane permeabilization in adipose and liver tissues, supporting the lysosomal-defects part of the cited clause. The paper does not specifically identify lipid-droplet overload as the cause. The sentence places the citation before its separate statement about phagocytosis impairment. (LLM, conf=0.78)
Experimental — accuracy not yet measured
- Premisecitation
Microglia participating in Aβ phagocytosis express higher levels of MHCII-related genes.
“Similarly, microglia participating in Aβ phagocytosis expressed higher levels of MHCII-related genes (61).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [61] A. Grubman, X. Y. Choo, G. Chew, J. F. Ouyang, G. Sun, N. P. Croft, F. J. Rossello, R. Simmons, S. Buckberry, D. V. Landin, J. Pflueger, T. H. Vandekolk, Z. Abay, Y. Zhou, X. Liu, J. Chen, M. Larcombe, J. M. Haynes, C. McLean, S. Williams, S. Y. Chai, T. Wilson, R. Lister, C. W. Pouton, A. W. Purcell, O. J. L. Rackham, E. Petretto, J. M. Polo, Transcriptional signature in microglia associated with Aβ plaque phagocytosis. Nat. Commun. 12, 3015 (2021). 34021136 PMC8140091 source
The Results section identifies XO4+ microglia as actively phagocytosing Aβ plaques and reports antigen-presentation enrichment in human microglial clusters resembling the XO4+ signature. The Discussion reports upregulation of MHC class II genes in AD, but does not establish that those genes are expressed at higher levels specifically in the Aβ-phagocytosing cells than in non-phagocytosing microglia. The indexed passages provide no page numbers. (LLM, conf=0.82)
Experimental — accuracy not yet measured
- Premisecitation
MHCII+ microglia have higher phagocytosis rates than MHCII− microglia in 5xFAD mice.
“MHCII+ microglia exhibited higher rates of phagocytosis than their MHCII− counterparts in 5xFAD mice (60).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [60] K. Mittal, E. Eremenko, O. Berner, Y. Elyahu, I. Strominger, D. Apelblat, A. Nemirovsky, I. Spiegel, A. Monsonego, CD4 T cells induce a subset of MHCII-expressing microglia that attenuates Alzheimer pathology. iScience 16, 298– 311 (2019). 31203186 PMC6581663 source
The Results (Figure 2B; page not available in our copy) report greater Aβ co-localization and engulfment by MHCII+ than MHCII− cells, which the authors interpret as presumably indicating greater phagocytic activity. The comparison was made in 5XFAD mice injected with Aβ-specific Th1 cells, and the paper measured co-localization rather than phagocytosis rates directly; the citing sentence omits those qualifications. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Premisecitation
APP-KI mice display a relatively mild behavioral phenotype compared to other transgenic mouse models.
“Second, although the APP-KI mouse model can offer some advantages over the transgenic mouse models that overexpress APP protein, they appeared to display a relatively mild behavioral phenotype (70) than other transgenic mouse models, which makes it challenging to assess the significance of this microglial functional restoration in the behavior of APP-KI mice.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [70] A. Latif-Hernandez, D. Shah, K. Craessaerts, T. Saido, T. Saito, B. De Strooper, A. Van der Linden, R. D’Hooge, Subtle behavioral changes and increased prefrontal-hippocampal network synchronicity in APPNL-G-F mice before prominent plaque deposition. Behav. Brain Res. 364, 431– 441 (2019). 29158112 source
- Findingown data
BAMs and activated CD11c+ microglia localized near Aβ plaques exhibited a pronounced lipid-associated gene signature and a high LD load.
“Particularly, BAMs and activated CD11c+ microglia localized near β amyloid (Aβ) plaques exhibited a pronounced lipid-associated gene signature and a high LD load.”
Quote in the paperSubstantial claim - Findingown data
The LD area within microglia increased significantly with age, particularly in the AD model mice.
“Similarly, the LD area within the microglia increased significantly with age, particularly in the AD model mice (Fig. 1D and fig. S2).”
Quote in the paperSubstantial claim - Findingown data
FIT2 deficiency induced subtle yet significant perturbations in the expression of lipid-related genes, such as Plin2 and Apoe, within CD11c+ microglia.
“Our results showed that FIT2 deficiency induced subtle yet significant perturbations in the expression of lipid-related genes (e.g., Plin2 and Apoe) within the CD11c+ microglia (Fig. 5D).”
Quote in the paperNot a substantial claim - Findingown data
Approximately 65% of LDAM were localized near Aβ plaques.
“Approximately 65% of LDAM were localized near the Aβ plaques (Fig. 1I), emphasizing a spatial association between the LDs and Aβ plaques in the AD brain.”
Quote in the paperNot a substantial claim - Findingown data
The LD area in microglia decreased by approximately 30% in the absence of FIT2.
“The LD area in microglia decreased by ~30% in the absence of FIT2 (Fig. 4, B and C).”
Quote in the paperSubstantial claim - Findingown data
Reducing LD content in microglia and CX3CR1+ BAMs improved their phagocytic ability.
“We demonstrated that reducing LD content in microglia and CX3CR1+ BAMs remarkably improved their phagocytic ability.”
Quote in the paperSubstantial claim - Findingown data
Flow cytometry validated an increase in E. coli+ cells in both CD11c− and CD11c+ microglial subsets from FIT2-deficient mice.
“Microscopy revealed an increase in the percentage of E. coli+ cells in the FIT2-deficient bulk microglial population (Fig. 6, B and C); this observation was validated by flow cytometry for both the CD11c− and CD11c+ microglial subsets (Fig. 6, D and E).”
Quote in the paperSubstantial claim - Findingown data
The levels of glycerolipids increased markedly in the microglia of APP-KI mice.
“The levels of glycerolipids increased markedly in the microglia of APP-KI mice (Fig. 2C).”
Quote in the paperSubstantial claim - Findingown data
Fit2 mRNA expression is increased in microglia isolated from the brains of AD versus healthy mice.
“We observed increased Fit2 mRNA expression in microglia isolated from the brains of AD versus healthy mice (fig. S4A).”
Quote in the paperSubstantial claim - Findingown data
In FIT2-deficient APP-KI mice, key pro-inflammatory molecules including Tnfa, Il6, Ccl2, and Ccl4 are reduced.
“Our results revealed a reduction in key pro-inflammatory molecules, including Tnfa, Il6, Ccl2, and Ccl4, in FIT2-deficient APP-KI mice (fig. S7).”
Quote in the paperSubstantial claim - Findingown data
CD11c+ microglia have higher accumulation of neutral lipids than CD11c− microglia.
“Our analysis revealed a higher accumulation of neutral lipids within the CD11c+ fraction than their CD11c− counterparts (Fig. 3, F and G).”
Quote in the paperSubstantial claim - Findingown data
The lipid profiles of FIT2-depleted and WT microglia of APP-KI mice are clearly distinct by 3D PCA.
“The three-dimensional (3D) PCA plot revealed clear distinctions between the lipid profiles of these two groups (Fig. 5A).”
Quote in the paperNot a substantial claim - Findingown data
Phagocytosis assay with Aβ oligomers showed a significant increase in Aβ+ CD11c− and CD11c+ microglia in the FIT2-deficient group.
“Phagocytosis assay conducted with Aβ oligomers showed a similar trend, with a significant increase in Aβ+ CD11c− and CD11c+ microglia observed in the FIT2-deficient group (Fig. 6, F and G).”
Quote in the paperSubstantial claim - Findingown data
The CD11c+ ARM cluster showed enrichment in foam cell-associated genes implicated in lipid metabolism, including Plin2, Apoe, Trem2, Lpl, and Cd9.
“The results revealed enrichment in foam cell–associated genes implicated in lipid metabolism, including Plin2, Apoe, Trem2, Lpl, and Cd9, within the CD11c+ ARM cluster (Fig. 3, D and E).”
Quote in the paperSubstantial claim - Findingown data
Aβ plaque deposition was significantly lower in the hippocampus and cortex of FIT2-deficient versus WT groups of mice.
“Analysis of several brain sections from distinct TAM-treated and untreated mice revealed significantly lower levels of Aβ plaque deposition in the hippocampus and cortex of the FIT2-deficient versus WT groups of mice (Fig. 7, F and G).”
Quote in the paperSubstantial claim- Rests on an assumption: The APP-KI mouse model recapitulates Alzheimer's disease sufficiently for conclusions about AD progression and Aβ pathology to apply.
- Findingown data
FIT2-depleted CD11c+ microglia were slightly enriched in the lysosomal and phagosomal pathways.
“Given the professional phagocytic nature of microglia, we next performed gene set enrichment analysis and found that the FIT2-depleted CD11c+ microglia were slightly enriched in the lysosomal and phagosomal pathways, indicating that these cells had a higher phagocytic potential than their WT counterparts (Fig. 5H).”
Quote in the paperNot a substantial claim - Findingown data
The LD area of CD206+ BAMs was reduced after FIT2 depletion.
“As most CD206+ BAMs express high levels of CX3CR1, their LD area was also reduced after FIT2 depletion (Fig. 4, F and G).”
Quote in the paperSubstantial claim - Findingown data
Among CD206+ BAMs from TAM-treated APP-KI/Fit2iΔMφ mice, only the two subsets with highest CX3CR1 expression (CD206+MHCIIhi and CD206+MHCIIint) exhibited superior phagocytic activity after FIT2 depletion.
“In the case of CD206+ BAMs obtained from TAM-treated APP-KI/Fit2iΔMφ, only the two subsets showing the highest levels of CX3CR1 expression (i.e., CD206+MHCIIhi and CD206+MHCIIint; fig. S4B) exhibited superior phagocytic activity after FIT2 depletion (Fig. 6, H to K).”
Quote in the paperSubstantial claim - Findingown data
CX3CR1 is highly expressed in microglia and BAMs.
“Given the high expression of CX3CR1 in microglia and BAMs (fig. S4B)”
Quote in the paperSubstantial claim - Findingown data
Microscopy revealed an increase in the percentage of E. coli+ cells in the FIT2-deficient bulk microglial population.
“Microscopy revealed an increase in the percentage of E. coli+ cells in the FIT2-deficient bulk microglial population (Fig. 6, B and C); this observation was validated by flow cytometry for both the CD11c− and CD11c+ microglial subsets (Fig. 6, D and E).”
Quote in the paperSubstantial claim - Findingown data
Both CD11c− and CD11c+ microglia from TAM-treated APP-KI/Fit2iΔMφ mice show increased efferocytic capacity compared to untreated controls.
“The results showed that although both CD11c− microglia and CD11c+ microglia ingested apoptotic N2A cells, their efferocytic capacity increased after TAM treatment, indicating that FIT2 deficiency promoted efferocytosis (fig. S9, B and C).”
Quote in the paperSubstantial claim - Findingown data
Microglial FIT2 deficiency reduces Aβ load in the AD brain.
“Fig. 7. Microglial FIT2 deficiency reduces Aβ load in the AD brain.”
Quote in the paperSubstantial claim - Findingown data
Microglial lipid droplet content is considerably accelerated during AD development in a diet-independent manner.
“In addition, we demonstrate that microglial LD content not only was slightly enhanced under obese conditions, but was considerably accelerated during AD development in a diet-independent manner.”
Quote in the paperSubstantial claim - Findingown data
TG levels were lower in microglia from TAM-treated than untreated APP-KI/Fit2iΔMφ mice.
“Notably, TG levels were lower in the microglia on TAM-treated than untreated APP-KI/Fit2iΔMφ mice (Fig. 5B and fig. S6).”
Quote in the paperSubstantial claim - Findingown data
The levels of TGs typically abundant in AD brains, such as those containing 46, 48, or 50 carbon atoms, were reduced after TAM administration.
“Specifically, the levels of TGs that are typically abundant in the microglia of AD brains (e.g., those containing 46, 48, or 50 carbon atoms) were reduced after TAM administration (Fig. 5C).”
Quote in the paperSubstantial claim - Findingown data
Microglia isolated from age-matched WT and APP-KI mice show an inverse correlation between LD content and phagocytic activity.
“We observed a similar inverse correlation between LD content and phagocytic activity when comparing microglia isolated from age-matched WT and APP-KI mice (fig. S3, A to F).”
Quote in the paperSubstantial claim - Findingown data
FIT2-depleted microglia from TAM-treated mice had significantly lower LD levels than WT counterparts.
“Notably, the FIT2-depleted microglia of the TAM-treated mice had significantly lower LDs levels than the WT counterparts.”
Quote in the paperSubstantial claim - Findingown data
Microglial lipid droplet content is slightly enhanced under obese conditions.
“In addition, we demonstrate that microglial LD content not only was slightly enhanced under obese conditions, but was considerably accelerated during AD development in a diet-independent manner.”
Quote in the paperNot a substantial claim - Findingcitation
BAMs have elevated expression of lipid-related genes.
“In addition, we confirmed previous findings of elevated expression of lipid-related genes in BAMs (31) and observed an increase in LD content within these cells over time and during disease progression.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [31] H. Van Hove, L. Martens, I. Scheyltjens, K. De Vlaminck, A. R. Pombo Antunes, S. De Prijck, N. Vandamme, S. De Schepper, G. Van Isterdael, C. L. Scott, J. Aerts, G. Berx, G. E. Boeckxstaens, R. E. Vandenbroucke, L. Vereecke, D. Moechars, M. Guilliams, J. A. Van Ginderachter, Y. Saeys, K. Movahedi, A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment. Nat. Neurosci. 22, 1021– 1035 (2019). 31061494 source
- Findingown data
There was a noticeable reduction in LDAM in the brain tissue of TAM-treated versus untreated APP-KI/Fit2iΔMφ mice.
“Consistent with the BODIPY staining results, there was a noticeable reduction in LDAM in the brain tissue of the TAM-treated versus untreated groups (Fig. 4, D and E), indicating that FIT2 deficiency in microglia disrupts their ability to form LDs.”
Quote in the paperSubstantial claim - Findingown data
Elevated intracellular LD content correlated inversely with microglial phagocytic activities.
“Having observed that elevated intracellular LD content correlated inversely with microglial phagocytic activities”
Quote in the paperSubstantial claim - Findingown data
There was an increase in the rate of Aβ uptake and phagocytosis by microglia, especially the CD11c+ subset, after the FIT2-associated reduction in LD load.
“We observed an increase in the rate of Aβ uptake and phagocytosis by microglia (especially the CD11c+ subset) after the FIT2-associated reduction in LD load (Fig. 7, B and C).”
Quote in the paperSubstantial claim- Rests on an assumption: The APP-KI mouse model recapitulates Alzheimer's disease sufficiently for conclusions about AD progression and Aβ pathology to apply.
- Findingown data
LDs were detected within CD206+ BAMs of the dura mater and subdural meninges.
“Notably, LDs were also detected within CD206+ BAMs of the dura mater and subdural meninges (Fig. 1J).”
Quote in the paperNot a substantial claim - Findingown data
CD206+ BAMs exhibited expression of key genes associated with lipid metabolism, including Plin2, Apoe, Trem2, and Cd36.
“Notably, CD206+ BAMs also exhibited expression of key genes associated with lipid metabolism (e.g., Plin2, Apoe, Trem2, and Cd36) (Fig. 3E), further suggesting their role in lipid storage and metabolism.”
Quote in the paperNot a substantial claim - Findingown data
Lipid droplet content within BAMs increases over time and during disease progression.
“In addition, we confirmed previous findings of elevated expression of lipid-related genes in BAMs (31) and observed an increase in LD content within these cells over time and during disease progression.”
Quote in the paperSubstantial claim - Findingown data
Microglia from 6-month-old WT and APP-KI mice have distinct lipid profiles by principal component analysis.
“Principal component analysis (PCA) revealed the distinct lipid profiles of the microglia in each group, implying that the lipid composition of these subsets was altered during disease progression (Fig. 2B).”
Quote in the paperSubstantial claim - Findingown data
The primary up-regulated lipid metabolites in microglia of APP-KI mice were triglycerides and cholesterol esters, the main components of LDs.
“Specifically, the primary up-regulated lipid metabolites were triglycerides (TGs) and cholesterol esters (CEs) (Fig. 2D), the main components of LDs.”
Quote in the paperSubstantial claim - Findingown data
AD progression was associated with the expansion of distinct clusters of reactive microglia, such as activated response CD11c+ microglia (ARM), Nlrp3+ inflammasome-related microglia, and Tnfhi microglia.
“The results showed that AD progression was associated with the expansion of distinct clusters of reactive microglia, such as activated response CD11c+ microglia (ARM), Nlrp3+ inflammasome–related microglia, and Tnfhi microglia (Fig. 3C); of these, the CD11c+ ARM cluster was the most abundant in the brains of AD model mice.”
Quote in the paperNot a substantial claim- Rests on an assumption: The APP-KI mouse model recapitulates Alzheimer's disease sufficiently for conclusions about AD progression and Aβ pathology to apply.
- Findingown data
CD11c+ microglia located near Aβ plaques in the AD brain progressively accumulate more lipid droplets.
“Specifically, we showed that CD11c+ microglia located near Aβ plaques in the AD brain progressively accumulated more LDs.”
Quote in the paperSubstantial claim - Findingown data
The CD11c+ ARM cluster was the most abundant microglial cluster in the brains of AD model mice.
“The results showed that AD progression was associated with the expansion of distinct clusters of reactive microglia, such as activated response CD11c+ microglia (ARM), Nlrp3+ inflammasome–related microglia, and Tnfhi microglia (Fig. 3C); of these, the CD11c+ ARM cluster was the most abundant in the brains of AD model mice.”
Quote in the paperNot a substantial claim- Rests on an assumption: The APP-KI mouse model recapitulates Alzheimer's disease sufficiently for conclusions about AD progression and Aβ pathology to apply.
- Findingown data
Genes encoding Toll-like receptors such as Tlr2 are up-regulated in CD11c+ microglia.
“Moreover, we found that genes encoding Toll-like receptors (TLRs) such as Tlr2, which participates in Aβ recognition in the brains of AD model mice (40, 41), were up-regulated in the CD11c+ microglia.”
Quote in the paperNot a substantial claim - Findingown data
LDAM accumulate around Aβ plaques in the AD brain.
“In addition, we demonstrated the accumulation of LDAM around Aβ plaques in the AD brain.”
Quote in the paperSubstantial claim - Findingnone given
Lipid droplet accumulation is associated with increased triglycerides and cholesteryl esters.
“The accumulation of LDs is associated with changes in the lipid profile, particularly an increase in TGs and CEs.”
Quote in the paperNot a substantial claim - Findingown data
Up-regulation of lysosomal and phagosomal pathways occurs in FIT2-depleted CD11c+ microglia.
“This was accompanied by the up-regulation of lysosomal and phagosomal pathways, particularly in the FIT2-depleted CD11c+ microglial subset.”
Quote in the paperSubstantial claim - Findingown data
LDAM around Aβ plaques have an elevated lipid droplet load.
“These LDAM had an elevated LD load and overexpressed genes related to lipid metabolism.”
Quote in the paperSubstantial claim - Findingown data
LDAM around Aβ plaques overexpress genes related to lipid metabolism.
“These LDAM had an elevated LD load and overexpressed genes related to lipid metabolism.”
Quote in the paperSubstantial claim - Findingown data
Sphingosine is reduced in diseased microglia.
“In contrast, sphingolipids, particularly sphingosine, were found to be reduced in the diseased microglia.”
Quote in the paperNot a substantial claim - Findingown data
CD206+ BAMs located in the dura mater and subdural meninges accumulate lipid droplets.
“In situ LipidSpot staining showed that the CD206+ BAMs located in the dura mater and subdural meninges of the brain were also capable of accumulating LDs.”
Quote in the paperNot a substantial claim - Findingown data
Augmented microglial phagocytosis significantly reduced Aβ in brain tissue.
“Third, our study demonstrated that the augmented microglial phagocytosis significantly reduced Aβ in the brain tissue.”
Quote in the paperSubstantial claim - Interpretationown data
Microglia accumulate LDs over time and during Alzheimer's disease progression, especially under HFD conditions.
“These results indicate that microglia accumulate LDs over time and during AD progression, especially under HFD conditions.”
Quote in the paperSubstantial claim- Rests on an assumption: The APP-KI mouse model recapitulates Alzheimer's disease sufficiently for conclusions about AD progression and Aβ pathology to apply.
- Study design and conductown data
The phagocytic activity of CX3CR1− neutrophils was not significantly different between TAM-treated and untreated APP-KI/Fit2iΔMφ mice.
“As a control, we also showed that the phagocytic activity of CX3CR1− neutrophils was not significantly different between the TAM-treated and untreated groups of APP-KI/Fit2iΔMφ mice (fig. S8).”
Quote in the paperNot a substantial claim - Interpretationown data
Reduction in lipid droplet levels within microglia positively correlates with their efferocytic activity.
“These findings suggest that the reduction in LD levels within microglia positively correlates with their efferocytic activity, emphasizing the potential impact of lipid metabolism on the microglial function that is critical for maintaining brain homeostasis.”
Quote in the paperSubstantial claim - Interpretationown data
Alzheimer's disease progression is associated with profound remodeling of microglial lipid composition, with enrichment in triglycerides and cholesterol esters.
“This observation highlights a profound remodeling of microglial lipid composition during AD progression, with enrichment in TGs and CEs.”
Quote in the paperSubstantial claim- Rests on an assumption: The APP-KI mouse model recapitulates Alzheimer's disease sufficiently for conclusions about AD progression and Aβ pathology to apply.
- Interpretationreasoning
Microglial lipid droplet load correlates with Aβ plaque accumulation.
“These results suggest a correlation between microglial LD load and Aβ plaque accumulation, implying that modulating the microglial function could be a potential strategy for mitigating Aβ pathology and neuroinflammation in AD.”
Quote in the paperSubstantial claim - Interpretationown data
FIT2-depleted CD11c+ microglia have a higher phagocytic potential than WT counterparts.
“Given the professional phagocytic nature of microglia, we next performed gene set enrichment analysis and found that the FIT2-depleted CD11c+ microglia were slightly enriched in the lysosomal and phagosomal pathways, indicating that these cells had a higher phagocytic potential than their WT counterparts (Fig. 5H).”
Quote in the paperSubstantial claim - Interpretationcitation
There is a close relationship between lipid metabolism and microglial activation.
“Recent scRNA-seq studies have identified distinct states of microglial activation in brains affected by neurogenerative disease; some of these activation states were characterized by the enrichment in genes involved in lipid and lipoprotein metabolism (14, 32), indicating a close relationship between lipid metabolism and microglial activation.”
Quote in the paperSubstantial claim - Interpretationown data
The lipid composition of microglia is altered during Alzheimer's disease progression.
“Principal component analysis (PCA) revealed the distinct lipid profiles of the microglia in each group, implying that the lipid composition of these subsets was altered during disease progression (Fig. 2B).”
Quote in the paperSubstantial claim- Rests on an assumption: The APP-KI mouse model recapitulates Alzheimer's disease sufficiently for conclusions about AD progression and Aβ pathology to apply.
- Interpretationown data
FIT2 deficiency disrupts microglial lipid metabolism.
“These findings further support the notion that FIT2 deficiency disrupts microglial lipid metabolism.”
Quote in the paperSubstantial claim - Interpretationown data
FIT2 deficiency in microglia disrupts their ability to form LDs.
“Consistent with the BODIPY staining results, there was a noticeable reduction in LDAM in the brain tissue of the TAM-treated versus untreated groups (Fig. 4, D and E), indicating that FIT2 deficiency in microglia disrupts their ability to form LDs.”
Quote in the paperSubstantial claim - Study design and conductown data
Other enzymes involved in lipid biogenesis (Lpin1, DGAT1, and DGAT2) were not altered after CX3CR1-mediated FIT2 depletion.
“Other enzymes involved in lipid biogenesis (e.g., Lpin1, DGAT1, and DGAT2) were not altered after CX3CR1-mediated FIT2 depletion (fig. S4E).”
Quote in the paperNot a substantial claim - Interpretationown data
FIT2 deficiency promotes microglial efferocytosis.
“The results showed that although both CD11c− microglia and CD11c+ microglia ingested apoptotic N2A cells, their efferocytic capacity increased after TAM treatment, indicating that FIT2 deficiency promoted efferocytosis (fig. S9, B and C).”
Quote in the paperSubstantial claim - Interpretationreasoning
Reducing microglial lipid droplet load via FIT2 depletion or other pharmacological interventions is a feasible therapeutic strategy for boosting phagocytic activity to mitigate Aβ deposition in the brain.
“Our findings suggest that reducing microglial LD load via FIT2 depletion or other pharmacological interventions is a feasible therapeutic strategy for boosting the phagocytic activity of these cells to mitigate Aβ deposition in the brain.”
Quote in the paperSubstantial claim - Interpretationreasoning
Aβ-induced microglial activation contributes to lipid droplet accumulation.
“These reports further imply that Aβ-induced microglial activation also contributes to LD accumulation.”
Quote in the paperSubstantial claim - Interpretationnone given
In our study, lipid droplet accumulation within microglia was induced by chronic inflammation.
“Unlike in ischemic stroke, where the accumulation of microglial LDs is induced by an acute pro-inflammatory microenvironment, the accumulation of LDs within microglia reported in our study was induced by chronic inflammation.”
Quote in the paperNot a substantial claim - Interpretationown data
Targeting FIT2 is sufficient to perturb lipid droplet formation within microglia.
“In our study, we found that microglia lacking FIT2 had fewer LDs and lower TG levels, suggesting that targeting FIT2 was sufficient to perturb LD formation within microglia.”
Quote in the paperSubstantial claim - Interpretationown data
Lipid droplet formation or accumulation could be targeted to regulate BAM functions.
“In our study, FIT2 depletion effectively impaired LD formation in BAMs and increased their phagocytic activity, suggesting that LD formation/accumulation could be targeted to regulate the functions of BAMs in addition to those of microglia.”
Quote in the paperSubstantial claim - Interpretationown data
Lipid droplets are a promising target for rewiring microglial phagocytic and efferocytic abilities.
“Last, our data suggest that LD is a promising target for rewiring microglia phagocytic and efferocytic abilities.”
Quote in the paperSubstantial claim - Interpretationown data
Strategies aimed at reducing microglial or macrophage lipid droplet load hold promise for rewiring their functionality and bolstering their resilience in neurodegenerative disorders.
“Our findings suggest that strategies aimed at reducing microglial/macrophage LD load hold promise in rewiring their functionality and bolstering their resilience in the context of neurogenerative disorders.”
Quote in the paperNot a substantial claim
- May combine two claims. 36
- Classified as probably not a substantial claim. 46
May combine two claims.
PremisecitationTREM2 mutations impair microglial activation and reduce their ability to accumulate lipid droplets in the AD brain.
“Mutations affecting the TREM2 function impair microglial activation (37) and reduce their ability to accumulate LDs in the AD brain (38).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [37] T. K. Ulland, M. Colonna, TREM2 — A key player in microglial biology and Alzheimer disease. Nat. Rev. Neurol. 14, 667– 675 (2018). 30266932 source
- cites [38] C. Claes, E. P. Danhash, J. Hasselmann, J. P. Chadarevian, S. K. Shabestari, W. E. England, T. E. Lim, J. L. S. Hidalgo, R. C. Spitale, H. Davtyan, M. Blurton-Jones, Plaque-associated human microglia accumulate lipid droplets in a chimeric model of Alzheimer’s disease. Mol. Neurodegener. 16, 50 (2021). 34301296 PMC8305935 source
The Findings section (page unavailable) reports less total lipid-droplet area in TREM2-R47H microglia in chimeric AD mice, but explicitly says this reflects fewer plaque-associated microglia, not a reduced ability to form lipid droplets. It found no significant difference in the proportion of nearby microglia positive for the lipid-droplet marker PLIN2. (LLM, conf=0.89)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIn ischemic brain injury, lipid droplets mitigate the microglial pro-inflammatory response, decrease infarct volume, and improve neurobehavioral performance.
“In ischemic brain injury, for instance, LDs mitigate the microglial pro-inflammatory response, decrease infarct volume, and improve their neurobehavioral performance (63, 64).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [63] W. Wei, L. Zhang, W. Xin, Y. Pan, L. Tatenhorst, Z. Hao, S. T. Gerner, S. Huber, M. Juenemann, M. Butz, H. B. Huttner, M. Bahr, D. Fitzner, F. Jia, T. R. Doeppner, TREM2 regulates microglial lipid droplet formation and represses post-ischemic brain injury. Biomed. Pharmacother. 170, 115962 (2024). 38042110 source
The Discussion (page unavailable) says that lipid-droplet accumulation after ischemia may promote neuronal death and inflammatory responses—the opposite of the claimed anti-inflammatory effect. It also links lipid-rich microglia after TREM2 knockdown to severe neurological deficits. The paper attributes protection to TREM2, not to lipid droplets. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured - cites [64] H. Li, P. Liu, S. Deng, L. Zhu, X. Cao, X. Bao, S. Xia, Y. Xu, B. Zhang, Pharmacological upregulation of microglial lipid droplet alleviates neuroinflammation and acute ischemic brain injury. Inflammation 46, 1832– 1848 (2023). 37450211 PMC10567859 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMicroglia form a protective barrier around Aβ plaques to safeguard the brain from their neurotoxic effects.
“Microglia form a protective barrier around these Aβ plaques to safeguard the brain from their neurotoxic effects (15, 16).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [15] P. Yuan, C. Condello, C. D. Keene, Y. Wang, T. D. Bird, S. M. Paul, W. Luo, M. Colonna, D. Baddeley, J. Grutzendler, TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron 90, 724– 739 (2016). 27196974 PMC4898967 source
- cites [16] C. Condello, P. Yuan, A. Schain, J. Grutzendler, Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques. Nat. Commun. 6, 6176 (2015). 25630253 PMC4311408 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe gradual appearance of a highly metabolically active subpopulation of CD11c+ microglia around plaques correlates with Alzheimer's disease progression.
“The gradual appearance of a highly metabolically active subpopulation of CD11c+ microglia around the plaques correlates with AD progression (14).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [14] H. Keren-Shaul, A. Spinrad, A. Weiner, O. Matcovitch-Natan, R. Dvir-Szternfeld, T. K. Ulland, E. David, K. Baruch, D. Lara-Astaiso, B. Toth, S. Itzkovitz, M. Colonna, M. Schwartz, I. Amit, A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276– 1290.e17 (2017). 28602351 source
May combine two claims.
PremisecitationLDAM exhibit defective phagocytic activity and increased production of pro-inflammatory cytokines and reactive oxygen species.
“Lipid-droplet accumulating microglia (LDAM) have been identified in aged brains of mice and classified as dysfunctional cells as they exhibit defective phagocytic activity and show increased production of pro-inflammatory cytokines and reactive oxygen species (ROS) (11)”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [11] J. Marschallinger, T. Iram, M. Zardeneta, S. E. Lee, B. Lehallier, M. S. Haney, J. V. Pluvinage, V. Mathur, O. Hahn, D. W. Morgens, J. Kim, J. Tevini, T. K. Felder, H. Wolinski, C. R. Bertozzi, M. C. Bassik, L. Aigner, T. Wyss-Coray, Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nat. Neurosci. 23, 194– 208 (2020). 31959936 PMC7595134 source
Classified as probably not a substantial claim.
PremisecitationMicroglia in neurodegenerative diseases such as Alzheimer's disease express diverse genes associated with lipid homeostasis and LD accumulation, including Apoe, Lpl, and Trem2.
“The microglia expressed diverse genes associated with lipid homeostasis and LD accumulation, including apolipoprotein E (Apoe), lipoprotein lipase (Lpl), and triggering receptor expressed on myeloid cells 2 (Trem2) (14).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [14] H. Keren-Shaul, A. Spinrad, A. Weiner, O. Matcovitch-Natan, R. Dvir-Szternfeld, T. K. Ulland, E. David, K. Baruch, D. Lara-Astaiso, B. Toth, S. Itzkovitz, M. Colonna, M. Schwartz, I. Amit, A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276– 1290.e17 (2017). 28602351 source
The Results report that Apoe, Lpl, and Trem2 expression increases as microglia transition toward a disease-associated state in an Alzheimer’s mouse model; the Discussion links that state to lipid-metabolism pathways. Our copy does not establish that these genes are associated with lipid-droplet (LD) accumulation. (LLM, conf=0.88)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationPerturbations in microglial activity, often associated with aging, can affect the effective clearance of neuron-derived Aβ fibrils, leading to increased plaque formation and progression of cognitive and behavioral impairments.
“However, perturbations in microglial activity, often associated with aging, can affect the effective clearance of these neuron-derived Aβ fibrils, leading to increased plaque formation and the progression of cognitive and behavioral impairments (17–20).”
Quote in the paperSubstantial claim4 of 4 sources checked- cites [17] C. Gao, J. Jiang, Y. Tan, S. Chen, Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets. Signal Transduct. Target Ther. 8, 359 (2023). 37735487 PMC10514343 source
In “Effect of microglia on Aβ pathology” (page unavailable), the review says aging-related increases in microglial NgR impair Aβ clearance, while NgR-deficient AD mice have lower amyloid burden and improved cognition. This supports the main relationship, but the passage does not identify the cleared Aβ as neuron-derived fibrils or establish progression of behavioral impairments. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [18] K. I. Mosher, T. Wyss-Coray, Microglial dysfunction in brain aging and Alzheimer’s disease. Biochem. Pharmacol. 88, 594– 604 (2014). 24445162 PMC3972294 source
Section 4.5 (Phagocytosis; page unavailable) reports that aged microglia take up less Aβ and that microglial clearance becomes less efficient in later disease stages. But section 4.6 (Proteostasis; page unavailable) treats protection through Aβ clearance as an assumption and cites a mouse study in which microglial ablation did not change plaque deposition. The paper does not establish the claimed chain from impaired clearance of neuron-derived Aβ fibrils to increased plaques and progressive cognitive and behavioral impairments. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [19] G. Krabbe, A. Halle, V. Matyash, J. L. Rinnenthal, G. D. Eom, U. Bernhardt, K. R. Miller, S. Prokop, H. Kettenmann, F. L. Heppner, Functional impairment of microglia coincides with beta-amyloid deposition in mice with Alzheimer-like pathology. PLOS ONE 8, e60921 (2013). 23577177 PMC3620049 source
The Introduction says microglia can take up fibrillar Aβ, and the Results show that impaired phagocytosis coincides with plaque deposition in Alzheimer-like mice. But the paper does not establish that impaired clearance causes increased plaque formation or cognitive and behavioral decline. Its Discussion also argues against aging-related microglial senescence as the main cause of the dysfunction observed here. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [20] E. G. Njie, E. Boelen, F. R. Stassen, H. W. M. Steinbusch, D. R. Borchelt, W. J. Streit, Ex vivo cultures of microglia from young and aged rodent brain reveal age-related changes in microglial function. Neurobiol. Aging 33, 195.e1– 195.e12 (2012). PMC4162517 20580465 source
The Results and Discussion (pages not specified in our copy) report that aged microglia internalize less Aβ42 and propose that this could leave more Aβ available for plaque formation. The tested Aβ42 preparation contained several forms, including likely fibrils; the paper does not establish reduced clearance of fibrils specifically or link the proposed plaque increase to progression of cognitive and behavioral impairments. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationLD accumulation in macrophages is associated with inflammatory conditions, infectious diseases, and cancer.
“LD accumulation in macrophages is associated with several inflammatory conditions (e.g., atherosclerosis) (4, 5), infectious diseases (e.g., mycobacterial infections) (6, 7), and cancer (8, 9).”
Quote in the paperNot a substantial claim5 of 6 sources checked- cites [4] Y. Gui, H. Zheng, R. Y. Cao, Foam cells in atherosclerosis: Novel insights into its origins, consequences, and molecular mechanisms. Front. Cardiovasc. Med. 9, 845942 (2022). 35498045 PMC9043520 source
- cites [5] C. Cochain, E. Vafadarnejad, P. Arampatzi, J. Pelisek, H. Winkels, K. Ley, D. Wolf, A. E. Saliba, A. Zernecke, Single-cell RNA-seq reveals the transcriptional landscape and heterogeneity of aortic macrophages in murine atherosclerosis. Circ. Res. 122, 1661– 1674 (2018). 29545365 source
- cites [6] D. Shim, H. Kim, S. J. Shin, Mycobacterium tuberculosis infection-driven foamy macrophages and their implications in tuberculosis control as targets for host-directed therapy. Front. Immunol. 11, 910 (2020). 32477367 PMC7235167 source
- cites [7] M. J. Kim, H. C. Wainwright, M. Locketz, L. G. Bekker, G. B. Walther, C. Dittrich, A. Visser, W. Wang, F. F. Hsu, U. Wiehart, L. Tsenova, G. Kaplan, D. G. Russell, Caseation of human tuberculosis granulomas correlates with elevated host lipid metabolism. EMBO Mol. Med. 2, 258– 274 (2010). 20597103 PMC2913288 source
- cites [8] X. Zheng, S. Mansouri, A. Krager, F. Grimminger, W. Seeger, S. S. Pullamsetti, C. E. Wheelock, R. Savai, Metabolism in tumour-associated macrophages: A quid pro quo with the tumour microenvironment. Eur. Respir. Rev. 29, 200134 (2020). 33004525 PMC9488699 source
- cites [9] G. Marelli, N. Morina, F. Portale, M. Pandini, M. Iovino, G. D. Conza, P.-C. Ho, D. D. Mitri, Lipid-loaded macrophages as new therapeutic target in cancer. J. Immunother. Cancer 10, e004584 (2022). 35798535 PMC9263925 source
Classified as probably not a substantial claim.
PremisecitationFIT2 plays a key role in LD biogenesis by facilitating LD formation from the endoplasmic reticulum.
“FIT2, a ubiquitously expressed protein, plays a key role in LD biogenesis by facilitating LD formation from the endoplasmic reticulum (1).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [1] J. A. Olzmann, P. Carvalho, Dynamics and functions of lipid droplets. Nat. Rev. Mol. Cell Biol. 20, 137– 155 (2019). 30523332 PMC6746329 source
The Lipid droplet budding section (page unavailable) identifies FIT2 as an ER membrane protein and says FIT proteins facilitate lipid-droplet budding from the ER; FIT2 mutants also fail to restore proper budding. The copy does not establish the citing sentence’s additional description of FIT2 as ubiquitously expressed. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSome microglial activation states in neurodegenerative disease are enriched in genes involved in lipid and lipoprotein metabolism.
“Recent scRNA-seq studies have identified distinct states of microglial activation in brains affected by neurogenerative disease; some of these activation states were characterized by the enrichment in genes involved in lipid and lipoprotein metabolism (14, 32), indicating a close relationship between lipid metabolism and microglial activation.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [14] H. Keren-Shaul, A. Spinrad, A. Weiner, O. Matcovitch-Natan, R. Dvir-Szternfeld, T. K. Ulland, E. David, K. Baruch, D. Lara-Astaiso, B. Toth, S. Itzkovitz, M. Colonna, M. Schwartz, I. Amit, A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276– 1290.e17 (2017). 28602351 source
- cites [32] C. Sala Frigerio, L. Wolfs, N. Fattorelli, N. Thrupp, I. Voytyuk, I. Schmidt, R. Mancuso, W.-T. Chen, M. E. Woodbury, G. Srivastava, T. Moller, E. Hudry, S. Das, T. Saido, E. Karran, B. Hyman, V. H. Perry, M. Fiers, B. De Strooper, The major risk factors for Alzheimer’s disease: Age, sex, and genes modulate the microglia response to Aβ plaques. Cell Rep. 27, 1293– 1306.e6 (2019). 31018141 PMC7340153 source
The Discussion (page unavailable) reports that activated-response microglia (ARMs) induce Apoe expression up to 27-fold, supporting a link between this activation state and an apolipoprotein gene. The Results identify distinct microglial states, but our copy does not report enrichment of lipid- and lipoprotein-metabolism gene sets in those states. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
PremisecitationBrain microglia can increase their intracellular lipid content by assimilating lipids from their environment.
“Brain microglia can increase their intracellular lipid content (33) by assimilating lipids (e.g., myelin debris) from their environment (34).”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [33] L. Cantuti-Castelvetri, D. Fitzner, M. Bosch-Queralt, M. T. Weil, M. Su, P. Sen, T. Ruhwedel, M. Mitkovski, G. Trendelenburg, D. Lutjohann, W. Mobius, M. Simons, Defective cholesterol clearance limits remyelination in the aged central nervous system. Science 359, 684– 688 (2018). 29301957 source
- cites [34] E. N. Santos, R. D. Fields, Regulation of myelination by microglia. Sci. Adv. 7, eabk1131 (2021). 34890221 PMC8664250 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMicroglial efferocytosis relies on features of phagocytosis such as recognition, engulfment, digestion, and disposal of apoptotic cells and waste.
“Microglial efferocytosis relies on many features of phagocytosis such as the ability to recognize, engulf, digest, and dispose of apoptotic cells and other cellular waste materials (29).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [29] C. Romero-Molina, F. Garretti, S. J. Andrews, E. Marcora, A. M. Goate, Microglial efferocytosis: Diving into the Alzheimer’s disease gene pool. Neuron 110, 3513– 3533 (2022). 36327897 PMC13175419 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationMicroglia clear apoptotic cells via efferocytosis, contributing to brain homeostasis.
“Microglia also contribute to the maintenance of brain homeostasis by clearing apoptotic cells in the brain via efferocytosis (27–29).”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [27] J. L. Marin-Teva, I. Dusart, C. Colin, A. Gervais, N. van Rooijen, M. Mallat, Microglia promote the death of developing Purkinje cells. Neuron 41, 535– 547 (2004). 14980203 source
- cites [28] M. Colonna, O. Butovsky, Microglia function in the central nervous system during health and neurodegeneration. Annu. Rev. Immunol. 35, 441– 468 (2017). 28226226 PMC8167938 source
- cites [29] C. Romero-Molina, F. Garretti, S. J. Andrews, E. Marcora, A. M. Goate, Microglial efferocytosis: Diving into the Alzheimer’s disease gene pool. Neuron 110, 3513– 3533 (2022). 36327897 PMC13175419 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMicroglia contribute crucially to brain homeostasis during aging and neurodegeneration.
“Numerous studies have highlighted the crucial contribution of microglia to brain homeostasis during aging and neurodegeneration (17, 18, 28, 30).”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [17] C. Gao, J. Jiang, Y. Tan, S. Chen, Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets. Signal Transduct. Target Ther. 8, 359 (2023). 37735487 PMC10514343 source
- cites [18] K. I. Mosher, T. Wyss-Coray, Microglial dysfunction in brain aging and Alzheimer’s disease. Biochem. Pharmacol. 88, 594– 604 (2014). 24445162 PMC3972294 source
- cites [28] M. Colonna, O. Butovsky, Microglia function in the central nervous system during health and neurodegeneration. Annu. Rev. Immunol. 35, 441– 468 (2017). 28226226 PMC8167938 source
May combine two claims.
PremisecitationPhagocytosis is the major mechanism for Aβ aggregate clearance in the brain, with microglia as the main effector cells for engulfing and degrading Aβ.
“Phagocytosis is the major mechanism contributing to Aβ aggregate clearance in the brain, with microglia serving as the main effector cells for engulfing and degrading Aβ (30).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [30] J. Miao, H. Ma, Y. Yang, Y. Liao, C. Lin, J. Zheng, M. Yu, J. Lan, Microglia in Alzheimer’s disease: Pathogenesis, mechanisms, and therapeutic potentials. Front. Aging Neurosci. 15, 1201982 (2023). 37396657 PMC10309009 source
Section 4 says microglial phagocytosis is essential for clearing Aβ deposits and describes microglia engulfing Aβ. Section 4.4 also describes other clearance routes and cells, but does not establish that phagocytosis is the major clearance mechanism or that microglia are the main effector cells. Page numbers were not available in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationMicroglia near Aβ plaques remove Aβ aggregates via TREM2 and other phagocytic receptors, providing a protective barrier that limits plaque formation.
“By removing Aβ aggregates via TREM2 and other phagocytic receptors (e.g., AXL), the microglia located near Aβ plaques provide a protective barrier that limits plaque formation (14).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [14] H. Keren-Shaul, A. Spinrad, A. Weiner, O. Matcovitch-Natan, R. Dvir-Szternfeld, T. K. Ulland, E. David, K. Baruch, D. Lara-Astaiso, B. Toth, S. Itzkovitz, M. Colonna, M. Schwartz, I. Amit, A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276– 1290.e17 (2017). 28602351 source
The Results report Aβ-containing phagocytic microglia clustered near plaques, and the Discussion says full activation of their phagocytic program depends on TREM2. The paper describes these cells as potentially protective, but our copy does not establish that they form a barrier that limits plaque formation or that AXL mediates the claimed removal. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationLipopolysaccharide-induced innate responses are linked to lipid droplet formation within microglia.
“Comparable innate responses induced by lipopolysaccharide have been strongly linked to LD formation within microglia (11).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [11] J. Marschallinger, T. Iram, M. Zardeneta, S. E. Lee, B. Lehallier, M. S. Haney, J. V. Pluvinage, V. Mathur, O. Hahn, D. W. Morgens, J. Kim, J. Tevini, T. K. Felder, H. Wolinski, C. R. Bertozzi, M. C. Bassik, L. Aigner, T. Wyss-Coray, Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nat. Neurosci. 23, 194– 208 (2020). 31959936 PMC7595134 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationLipid droplet accumulation in macrophages occurs in lipid-rich microenvironments in the periphery.
“LD accumulation in macrophages has also been documented in lipid-rich microenvironments in the peripheral, such as atherosclerosis plaques (5), white adipose tissue (10), and tumors (9).”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [5] C. Cochain, E. Vafadarnejad, P. Arampatzi, J. Pelisek, H. Winkels, K. Ley, D. Wolf, A. E. Saliba, A. Zernecke, Single-cell RNA-seq reveals the transcriptional landscape and heterogeneity of aortic macrophages in murine atherosclerosis. Circ. Res. 122, 1661– 1674 (2018). 29545365 source
- cites [10] Q. Chen, S. M. Lai, S. Xu, Y. Tan, K. Leong, D. Liu, J. C. Tan, R. R. Naik, A. M. Barron, S. S. Adav, J. Chen, S. Z. Chong, L. G. Ng, C. Ruedl, Resident macrophages restrain pathological adipose tissue remodeling and protect vascular integrity in obese mice. EMBO Rep. 22, e52835 (2021). 34196465 PMC8339675 source
- cites [9] G. Marelli, N. Morina, F. Portale, M. Pandini, M. Iovino, G. D. Conza, P.-C. Ho, D. D. Mitri, Lipid-loaded macrophages as new therapeutic target in cancer. J. Immunother. Cancer 10, e004584 (2022). 35798535 PMC9263925 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIntracellular lipid droplets within macrophages are transported to lysosomes for enzymatic degradation via lipophagy.
“Intracellular LDs within macrophages are transported to lysosomes for enzymatic degradation in a process called lipophagy (48).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [48] K. Liu, M. J. Czaja, Regulation of lipid stores and metabolism by lipophagy. Cell Death Differ. 20, 3– 11 (2013). 22595754 PMC3524634 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAbnormal sphingolipid levels are linked to neuroinflammatory disorders.
“These abnormal changes in sphingolipid levels have been closely linked to neuroinflammatory disorders, as they play a crucial role in cell signaling and are, therefore, frequently discussed as potential therapeutic targets (45, 46).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [45] X. Wang, H. Li, Y. Sheng, B. He, Z. Liu, W. Li, S. Yu, J. Wang, Y. Zhang, J. Chen, L. Qin, X. Meng, The function of sphingolipids in different pathogenesis of Alzheimer’s disease: A comprehensive review. Biomed. Pharmacother. 171, 116071 (2024). 38183741 source
- cites [46] J. Y. Lee, H. K. Jin, J. S. Bae, Sphingolipids in neuroinflammation: A potential target for diagnosis and therapy. BMB Rep. 53, 28– 34 (2020). 31818364 PMC6999823 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationAged and diseased microglia have more gangliosides, while macroglia in ischemic stroke are characterized by high cholesterol levels.
“In relation to LD content, we and others have revealed the presence of more GLs in aged and diseased microglia (11), while the macroglia encountered in ischemic stroke are characterized by high cholesterol levels (63).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [11] J. Marschallinger, T. Iram, M. Zardeneta, S. E. Lee, B. Lehallier, M. S. Haney, J. V. Pluvinage, V. Mathur, O. Hahn, D. W. Morgens, J. Kim, J. Tevini, T. K. Felder, H. Wolinski, C. R. Bertozzi, M. C. Bassik, L. Aigner, T. Wyss-Coray, Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nat. Neurosci. 23, 194– 208 (2020). 31959936 PMC7595134 source
The Results section, “Microglia accumulate lipid droplets in the aging brain” (page unavailable), reports more lipid droplets in aged microglia and identifies glycerolipids as their main component. The paper also reports lipid-droplet accumulation in a mouse model of neurodegeneration, but it does not establish that aged or diseased microglia have more gangliosides. Citation (11) is attached to the microglia clause; the ischemic-stroke clause cites a different source. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [63] W. Wei, L. Zhang, W. Xin, Y. Pan, L. Tatenhorst, Z. Hao, S. T. Gerner, S. Huber, M. Juenemann, M. Butz, H. B. Huttner, M. Bahr, D. Fitzner, F. Jia, T. R. Doeppner, TREM2 regulates microglial lipid droplet formation and represses post-ischemic brain injury. Biomed. Pharmacother. 170, 115962 (2024). 38042110 source
The Discussion reports increased cholesterol in mouse brains after ischemia with TREM2 knockdown and impaired cholesterol clearance in microglia. Citation (63) is attached only to the cholesterol clause, not the earlier ganglioside claim. The source studies microglia, not macroglia, and does not establish high cholesterol as a general characteristic of macroglia in ischemic stroke. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S2 (checkable).
PremisecitationRestoring microglial phagocytosis is therapeutically important.
“Many studies have underscored the therapeutic importance of restoring microglial phagocytosis (54–56).”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [54] Y. Yoo, G. Neumayer, Y. Shibuya, M. M.-D. Mader, M. Wernig, A cell therapy approach to restore microglial Trem2 function in a mouse model of Alzheimer’s disease. Cell Stem Cell 30, 1043– 1053.e6 (2023). 37541210 source
- cites [55] K. Biber, Reestablishing microglia function: Good news for Alzheimer’s therapy? EMBO J. 36, 565– 567 (2017). 28213481 PMC5331753 source
- cites [56] M. R. P. Elmore, L. A. Hohsfield, E. A. Kramar, L. Soreq, R. J. Lee, S. T. Pham, A. R. Najafi, E. E. Spangenberg, M. A. Wood, B. L. West, K. N. Green, Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice. Aging Cell 17, e12832 (2018). 30276955 PMC6260908 source
The Introduction (page unavailable) describes impaired phagocytosis as an age-related microglial change and suggests that microglial replacement may benefit impaired brain function. The Results (page unavailable) report improved spatial memory after replacement in aged mice, but do not show that phagocytosis was restored or that its restoration produced the benefit. The paper therefore supports the therapeutic potential of microglial replacement, not the specific claim about restoring phagocytosis. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTlr2 participates in Aβ recognition in the brains of AD model mice.
“Moreover, we found that genes encoding Toll-like receptors (TLRs) such as Tlr2, which participates in Aβ recognition in the brains of AD model mice (40, 41), were up-regulated in the CD11c+ microglia.”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [40] C. L. McDonald, E. Hennessy, A. Rubio-Araiz, B. Keogh, W. McCormack, P. McGuirk, M. Reilly, M. A. Lynch, Inhibiting TLR2 activation attenuates amyloid accumulation and glial activation in a mouse model of Alzheimer’s disease. Brain Behav. Immun. 58, 191– 200 (2016). 27422717 source
- cites [41] C. Hughes, M. L. Choi, J. H. Yi, S. C. Kim, A. Drews, P. S. George-Hyslop, C. Bryant, S. Gandhi, K. Cho, D. Klenerman, Beta amyloid aggregates induce sensitised TLR4 signalling causing long-term potentiation deficit and rat neuronal cell death. Commun. Biol. 3, 79 (2020). 32071389 PMC7028984 source
The Introduction describes TLR2 as a pattern-recognition receptor in a discussion of Aβ-induced inflammation, but does not establish that it recognizes Aβ in AD-model mouse brains. In Results (Fig. 1), Aβ-induced cytokine responses persisted in TLR2-knockout macrophages but not TLR4-knockout macrophages. The cited paper therefore does not support the claim’s specific setting or demonstrate the proposed TLR2 role there. (LLM, conf=0.79)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationDGAT2 inhibitors attenuate triglyceride formation and lipid droplet accumulation and increase Aβ phagocytosis in microglia.
“A similar increase in Aβ phagocytosis was observed in microglia treated with DGAT2 inhibitors, which attenuate TG formation and LD accumulation (39).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [39] P. Prakash, P. Manchanda, E. Paouri, K. Bisht, K. Sharma, P. R. Wijewardhane, C. E. Randolph, M. G. Clark, J. Fine, E. A. Thayer, A. Crockett, N. Gasmi, S. Stanko, R. A. Prayson, C. Zhang, D. Davalos, G. Chopra, Amyloid β induces lipid droplet-mediated microglial dysfunction in Alzheimer’s disease. bioRxiv 543525 [Preprint]. 6 June 2023. 10.1101/2023.06.04.543525. source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPrimary microglia undergo profound lipidome perturbations to promote lipid droplet formation upon exposure to Aβ aggregates.
“A recent study demonstrated that primary microglia undergo profound lipidome perturbations to promote LD formation upon exposure to Aβ aggregates (39).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [39] P. Prakash, P. Manchanda, E. Paouri, K. Bisht, K. Sharma, P. R. Wijewardhane, C. E. Randolph, M. G. Clark, J. Fine, E. A. Thayer, A. Crockett, N. Gasmi, S. Stanko, R. A. Prayson, C. Zhang, D. Davalos, G. Chopra, Amyloid β induces lipid droplet-mediated microglial dysfunction in Alzheimer’s disease. bioRxiv 543525 [Preprint]. 6 June 2023. 10.1101/2023.06.04.543525. source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTLR2 inhibition mitigates lipopolysaccharide-induced lipid accumulation in hepatic cells.
“In accordance, TLR2 inhibition has been shown to markedly mitigate lipopolysaccharide-induced lipid accumulation in hepatic cells (42).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [42] L. Zhang, Z. Xie, H. Yu, H. Du, X. Wang, J. Cai, Y. Qiu, R. Chen, X. Jiang, Z. Liu, Y. Li, T. Chen, TLR2 inhibition ameliorates the amplification effect of LPS on lipid accumulation and lipotoxicity in hepatic cells. Ann. Transl. Med. 9, 1429 (2021). 34733981 PMC8506759 source
The Results section reports that TLR2 inhibition markedly reduced lipid accumulation in palmitic-acid-treated L02 hepatic cells when LPS amplified that accumulation. The claim omits the palmitic-acid condition and can imply an effect on LPS-induced accumulation alone; the Results found no significant effect of TLR2 inhibition in cells treated with LPS alone. No page number is available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn LDAM, lysosomes might be used for lipophagy rather than the degradation of phagocytosed material.
“A recent study highlighted close contact between LDs and lysosomes within microglia, suggesting that, in LDAM, lysosomes might be used for lipophagy rather than the degradation of phagocytosed material (11).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [11] J. Marschallinger, T. Iram, M. Zardeneta, S. E. Lee, B. Lehallier, M. S. Haney, J. V. Pluvinage, V. Mathur, O. Hahn, D. W. Morgens, J. Kim, J. Tevini, T. K. Felder, H. Wolinski, C. R. Bertozzi, M. C. Bassik, L. Aigner, T. Wyss-Coray, Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nat. Neurosci. 23, 194– 208 (2020). 31959936 PMC7595134 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationBAMs may adopt harmful activation profiles with aging and worsening amyloidosis or tauopathy, contributing to excessive synaptic pruning and neuronal dysfunction.
“However, as aging progresses and amyloidosis and/or tauopathy worsen, BAMs may adopt harmful activation profiles that exacerbate microglial overactivation, contributing to excessive synaptic pruning and neuronal dysfunction (65).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [65] S. De Schepper, J. Z. Ge, G. Crowley, L. S. S. Ferreira, D. Garceau, C. E. Toomey, D. Sokolova, J. Rueda-Carrasco, S. H. Shin, J. S. Kim, T. Childs, T. Lashley, J. J. Burden, M. Sasner, C. Sala Frigerio, S. Jung, S. Hong, Perivascular cells induce microglial phagocytic states and synaptic engulfment via SPP1 in mouse models of Alzheimer’s disease. Nat. Neurosci. 26, 406– 415 (2023). 36747024 PMC9991912 source
The Results section ('SPP1 drives microglial engulfment of synapses in AD context'; page unavailable) links perivascular SPP1 to microglial synaptic engulfment and synapse loss in amyloid-model mice. The cited passages do not establish that BAMs broadly adopt harmful profiles as aging or tauopathy progresses, or demonstrate the claimed neuronal dysfunction. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe initial neuroprotective effect of lipid droplets after injury may gradually become detrimental over time.
“Moreover, the initial neuroprotective effect of LDs after injury may gradually become detrimental over time (13).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [13] M. Arbaizar-Rovirosa, J. Pedragosa, J. J. Lozano, C. Casal, A. Pol, M. Gallizioli, A. M. Planas, Aged lipid-laden microglia display impaired responses to stroke. EMBO Mol. Med. 15, e17175 (2023). 36541061 PMC9906381 source
May combine two claims.
InterpretationcitationIn the AD brain, chronic and Aβ-induced inflammation promotes a sustained metabolic shift from mitochondrial oxidative phosphorylation to glycolysis, resulting in excessive lipid droplet formation and accumulation within microglia.
“Thus, in the AD brain, chronic and Aβ-induced inflammation could promote a sustained metabolic shift from mitochondrial oxidative phosphorylation to glycolysis (44), resulting in the excessive formation and accumulation of LDs within microglia.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [44] L. H. Fairley, J. H. Wong, A. M. Barron, Mitochondrial regulation of microglial immunometabolism in Alzheimer’s disease. Front. Immunol. 12, 624538 (2021). 33717134 PMC7947196 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTREM2 binds to various lipid ligands to mediate lipid sensing and uptake.
“TREM2 binds to various lipid ligands, such as APOE particles (main cholesterol carriers in the brain) and myelin debris, to mediate lipid sensing and uptake (36).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [36] R. Y. Li, Q. Qin, H. C. Yang, Y. Y. Wang, Y. X. Mi, Y. S. Yin, M. Wang, C. J. Yu, Y. Tang, TREM2 in the pathogenesis of AD: A lipid metabolism regulator and potential metabolic therapeutic target. Mol. Neurodegener. 17, 40 (2022). 35658903 PMC9166437 source
May combine two claims.
PremisecitationDepletion of brain and leptomeningeal BAMs in 5xFAD mice compromises glymphatic function and increases Aβ burden, suggesting a protective role of BAMs.
“Depletion of brain and leptomeningeal BAMs in 5xFAD mice has been shown to compromise the glymphatic function and increase Aβ burden in the brain (23), suggesting a protective role of BAMs in maintaining brain functions induced by Aβ accumulation and deposition.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [23] A. Drieu, S. Du, S. E. Storck, J. Rustenhoven, Z. Papadopoulos, T. Dykstra, F. Zhong, K. Kim, S. Blackburn, T. Mamuladze, O. Harari, C. M. Karch, R. J. Bateman, R. Perrin, M. Farlow, J. Chhatwal, Dominantly Inherited Alzheimer Network, S. Hu, G. J. Randolph, I. Smirnov, J. Kipnis, Parenchymal border macrophages regulate the flow dynamics of the cerebrospinal fluid. Nature 611, 585– 593 (2022). 36352225 PMC9899827 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn vivo loss of FIT2 in adipocytes and pancreatic β cells results in failed lipid droplet formation.
“The in vivo loss of FIT2 in adipocytes and pancreatic β cells also resulted in failed LD formation (24, 59).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [24] D. A. Miranda, J.-H. Kim, L. N. Nguyen, W. Cheng, B. C. Tan, V. J. Goh, J. S. Y. Tan, J. Yaligar, B. P. Kn, S. S. Velan, H. Wang, D. L. Silver, Fat storage-inducing transmembrane protein 2 is required for normal fat storage in adipose tissue. J. Biol. Chem. 289, 9560– 9572 (2014). 24519944 PMC3975007 source
- cites [59] X. Zheng, Q. W. C. Ho, M. Chua, O. Stelmashenko, X. Y. Yeo, S. Muralidharan, F. Torta, E. G. Y. Chew, M. M. Lian, J. N. Foo, S. Jung, S. H. Wong, N. S. Tan, N. Tong, G. A. Rutter, M. R. Wenk, D. L. Silver, P.-O. Berggren, Y. Ali, Destabilization of β Cell FIT2 by saturated fatty acids alter lipid droplet numbers and contribute to ER stress and diabetes. Proc. Natl. Acad. Sci. U.S.A. 119, e2113074119 (2022). 35254894 PMC8931238 source
The Results section (“Palmitate and Stearate Reduce β Cell FIT2 Protein Levels”; page not provided) reports that β-cell-specific FIT2 deletion in mice significantly reduced lipid droplet numbers in islets. It does not show that droplet formation failed altogether. The adipocyte portion of the sentence has another citation; this paper’s experiment concerns β cells. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationFIT2 overexpression promotes lipid droplet accumulation in HEK293 cells, while FIT2 knockdown reduces triglyceride levels and lipid droplet accumulation in mouse adipocytes.
“For instance, in vitro FIT2 overexpression promoted LD accumulation in human embryonic kidney 293 cells, while FIT2 knockdown reduced TG levels and LD accumulation in mouse adipocytes (58).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [58] B. Kadereit, P. Kumar, W. J. Wang, D. Miranda, E. L. Snapp, N. Severina, I. Torregroza, T. Evans, D. L. Silver, Evolutionarily conserved gene family important for fat storage. Proc. Natl. Acad. Sci. U.S.A. 105, 94– 99 (2008). 18160536 PMC2224239 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationReversing the lipid-laden phenotype of tumoral macrophages suppresses gastric cancer development.
“In line with this proposed strategy, reversing the lipid-laden phenotype of tumoral macrophages has already been successfully used to suppress the development of gastric cancer (62).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [62] Q. Luo, N. Zheng, L. Jiang, T. Wang, P. Zhang, Y. Liu, P. Zheng, W. Wang, G. Xie, L. Chen, D. Li, P. Dong, X. Yuan, L. Shen, Lipid accumulation in macrophages confers protumorigenic polarization and immunity in gastric cancer. Cancer Sci. 111, 4000– 4011 (2020). 32798273 PMC7648032 source
The Results section reports that PI3K-γ inhibition reduced lipid accumulation in tumor-associated macrophages and significantly delayed tumor growth in an MFC gastric cancer mouse model. This supports a preclinical effect, but the citing sentence's suggestion that the strategy has already been successfully used to suppress gastric cancer development is broader than the demonstrated mouse-model result; the Discussion describes clinical use as a future prospect. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationBAMs control the neurovasculature by mediating arterial motion and driving cerebrospinal fluid flow.
“In addition, BAMs control the neurovasculature, for instance, by mediating arterial motion and driving the flow of cerebrospinal fluid (23).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [23] A. Drieu, S. Du, S. E. Storck, J. Rustenhoven, Z. Papadopoulos, T. Dykstra, F. Zhong, K. Kim, S. Blackburn, T. Mamuladze, O. Harari, C. M. Karch, R. J. Bateman, R. Perrin, M. Farlow, J. Chhatwal, Dominantly Inherited Alzheimer Network, S. Hu, G. J. Randolph, I. Smirnov, J. Kipnis, Parenchymal border macrophages regulate the flow dynamics of the cerebrospinal fluid. Nature 611, 585– 593 (2022). 36352225 PMC9899827 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductcitationCells with gene counts above the 99th percentile or with unique genes below the first percentile are more likely to be dead cells or doublets, respectively, and were therefore excluded from further analysis.
“Cells with gene counts above the 99th percentile or with unique genes below the first percentile are more likely to be dead cells or doublets, respectively, and were therefore excluded from further analysis (80).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [80] A. S. Bais, D. Kostka, scds: Computational annotation of doublets in single-cell RNA sequencing data. Bioinformatics 36, 1150– 1158 (2020). 31501871 PMC7703774 source
The Methods (§2.4) describe filtering barcodes by experimental doublet annotations, while the Discussion (§4) describes using doublet scores as one factor in deciding which cells to exclude. Searches for the 99th and first percentiles, dead cells, and high or low per-cell gene counts found no passage supporting the claimed thresholds or their stated associations. (LLM, conf=0.76)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe dura mater is the epicenter of immune surveillance in the brain, where macrophages present antigens to T cells to induce immune responses.
“The dura mater is considered the epicenter of immune surveillance in the brain, where macrophages present antigens to T cells to induce immune responses (66).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [66] J. Rustenhoven, A. Drieu, T. Mamuladze, K. A. de Lima, T. Dykstra, M. Wall, Z. Papadopoulos, M. Kanamori, A. F. Salvador, W. Baker, M. Lemieux, S. D. Mesquita, A. Cugurra, J. Fitzpatrick, S. Sviben, R. Kossina, P. Bayguinov, R. R. Townsend, Q. Zhang, P. Erdmann-Gilmore, I. Smirnov, M.-B. Lopes, J. Herz, J. Kipnis, Functional characterization of the dural sinuses as a neuroimmune interface. Cell 184, 1000– 1016.e27 (2021). 33508229 PMC8487654 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationFIT2 is primarily involved in triglyceride-mediated lipid droplet development.
“Since FIT2 is primarily involved in TG-mediated LD development (58), sterol esters might still contribute to LD formation without this FIT isoform.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [58] B. Kadereit, P. Kumar, W. J. Wang, D. Miranda, E. L. Snapp, N. Severina, I. Torregroza, T. Evans, D. L. Silver, Evolutionarily conserved gene family important for fat storage. Proc. Natl. Acad. Sci. U.S.A. 105, 94– 99 (2008). 18160536 PMC2224239 source
May combine two claims.
PremisecitationLipid droplet accumulation in macrophages elevates ROS production, promoting neurovascular dysfunction.
“LD accumulation in macrophages can elevate their ROS production (9, 11), promoting neurovascular dysfunction (67).”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [9] G. Marelli, N. Morina, F. Portale, M. Pandini, M. Iovino, G. D. Conza, P.-C. Ho, D. D. Mitri, Lipid-loaded macrophages as new therapeutic target in cancer. J. Immunother. Cancer 10, e004584 (2022). 35798535 PMC9263925 source
The 'Lipid accumulation in tumor-associated macrophages' section describes lipid droplets in macrophages but does not link them to increased ROS production. The ROS passage in Figure 2 concerns CD4+ T cells, not macrophages. I searched for ROS, reactive oxygen species, and lipid droplets in macrophages; neurovascular dysfunction is attached to a different citation in the citing sentence. (LLM, conf=0.72)
Experimental — accuracy not yet measured - cites [11] J. Marschallinger, T. Iram, M. Zardeneta, S. E. Lee, B. Lehallier, M. S. Haney, J. V. Pluvinage, V. Mathur, O. Hahn, D. W. Morgens, J. Kim, J. Tevini, T. K. Felder, H. Wolinski, C. R. Bertozzi, M. C. Bassik, L. Aigner, T. Wyss-Coray, Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nat. Neurosci. 23, 194– 208 (2020). 31959936 PMC7595134 source
The Results section (‘LDAM produce high levels of ROS’; page unavailable) reports higher ROS in lipid-droplet-rich microglia, and the Discussion says inhibiting droplet formation prevented ROS generation in BV2 cells. The paper does not directly establish that lipid droplets elevate ROS in macrophages generally. The neurovascular-dysfunction clause has a separate citation (67), so it is not assessed against this source. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [67] G. Faraco, Y. Sugiyama, D. Lane, L. Garcia-Bonilla, H. Chang, M. M. Santisteban, G. Racchumi, M. Murphy, N. Van Rooijen, J. Anrather, C. Iadecola, Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension. J. Clin. Invest. 126, 4674– 4689 (2016). 27841763 PMC5127678 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationExcessive lipid droplet accumulation in macrophages weakens their antigen-presenting activity.
“Excessive LD accumulation within macrophages has been reported to weaken their antigen-presenting activity (43), which could result in the dysregulation of brain homeostasis.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [43] C. Lauro, C. Limatola, Metabolic reprograming of microglia in the regulation of the innate inflammatory response. Front. Immunol. 11, 493 (2020). 32265936 PMC7099404 source
The Introduction section “Microglia Phenotypes and Metabolic States” mentions lipid droplets only in glucose-deprived microglia, as a possible sign of alternative fuel use. Searches for lipid droplets, lipid accumulation, and antigen presentation found no passage linking excessive lipid droplets in macrophages to weakened antigen-presenting activity. Page numbers were unavailable in our copy. (LLM, conf=0.75)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationLipid droplet-mediated impairment of BAM phagocytosis may lead to insufficient waste clearance, causing excessive deposition of debris such as Aβ.
“Moreover, the LD-mediated impairment of BAM phagocytosis may also lead to insufficient waste clearance at the brain interface and in the perivascular space, causing the excessive deposition of debris, such as Aβ (68, 69).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [68] C. A. Hawkes, J. McLaurin, Selective targeting of perivascular macrophages for clearance of β-amyloid in cerebral amyloid angiopathy. Proc. Natl. Acad. Sci. U.S.A. 106, 1261– 1266 (2009). 19164591 PMC2633563 source
- cites [69] K. Uekawa, Y. Hattori, S. J. Ahn, J. Seo, N. Casey, A. Anfray, P. Zhou, W. Luo, J. Anrather, L. Park, C. Iadecola, Border-associated macrophages promote cerebral amyloid angiopathy and cognitive impairment through vascular oxidative stress. Mol. Neurodegener. 18, 73 (2023). 37789345 PMC10548599 source
The Discussion (page unavailable) links BAM-generated oxidative stress and neurovascular dysfunction to impaired perivascular Aβ clearance and accumulation. The Methods describe BAM phagocytosis of dextran, but the paper does not link lipid droplets or impaired BAM phagocytosis to Aβ deposition; it proposes a vascular mechanism instead. (LLM, conf=0.87)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataHFD slightly exacerbated the age-related increase in LD accumulation, particularly in APP-KI mice, with LD+ microglial frequency reaching 60% at 6 months.
“Notably, HFD slightly exacerbated the age-related increase in LD accumulation, particularly in the APP-KI mice, as the LD+ microglial frequency reached 60% at 6 months in these animals (Fig. 1C and fig. S2).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataLowering microglial LDs enhanced their efferocytosis capacities and reduced Aβ deposition in the brain parenchyma.
“Furthermore, lowering microglial LDs consistently enhanced their efferocytosis capacities and notably reduced Aβ deposition in the brain parenchyma.”
Quote in the paperSubstantial claim- Rests on an assumption: The APP-KI mouse model recapitulates Alzheimer's disease sufficiently for conclusions about AD progression and Aβ pathology to apply.
May combine two claims.
Findingown dataGenes associated with MHCII presentation, such as Cd74, H2-Aa, and H2-Eb1, were markedly up-regulated in FIT2-deficient CD11c+ microglia, and this result was validated by flow cytometry.
“In addition, genes associated with MHCII presentation, such as Cd74, H2-Aa, and H2-Eb1, were markedly up-regulated in the FIT2-deficient CD11c+ microglia (Fig. 5E); this result was further validated using flow cytometry (Fig. 5, F and G).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe percentage of LD+ BAMs and the LD area significantly increased by 6 months of age in both WT and APP-KI groups.
“The percentage of LD+ BAMs and the LD area significantly increased by 6 months of age in both WT and APP-KI groups (Fig. 1, F and G, and fig. S2).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe proportion of LD+ microglia significantly increased from 5% at 2 months to 35% at 6 months in WT mice and from about 10% at 2 months to 50% at 6 months in age-matched APP-KI mice.
“Specifically, the proportion of LD+ microglia significantly increased from 5% (at 2 months) to 35% (at 6 months) in WT mice and from about 10% (2 months) to 50% (at 6 months) in age-matched APP-KI mice (Fig. 1C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCD206+ BAMs have a pronounced lipid-related transcriptomic signature and display several lipid-accumulating phenotypes.
“We demonstrated that CD206+ BAMs had a pronounced lipid-related transcriptomic signature and displayed several lipid-accumulating phenotypes.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataFIT2-deficient bulk and CD11c+ microglia show increased phagocytosis of E. coli bioparticles, Aβ, and apoptotic cells.
“We observed increased rates of E. coli bioparticle, Aβ, and apoptotic cell phagocytosis in both the FIT2-deficient bulk and CD11c+ microglia.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMicroglia lacking FIT2 have fewer lipid droplets and lower triglyceride levels.
“In our study, we found that microglia lacking FIT2 had fewer LDs and lower TG levels, suggesting that targeting FIT2 was sufficient to perturb LD formation within microglia.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataFIT2 depletion impairs lipid droplet formation in BAMs and increases their phagocytic activity.
“In our study, FIT2 depletion effectively impaired LD formation in BAMs and increased their phagocytic activity, suggesting that LD formation/accumulation could be targeted to regulate the functions of BAMs in addition to those of microglia.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataFIT2-deficient microglia have reduced lipid droplet content but are not entirely devoid of lipid droplets.
“First, while we demonstrated that FIT2-deficient microglia exhibited reduced LD content, they were not entirely devoid of LDs.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
FindingreasoningCholesteryl ester levels were not markedly affected in FIT2-deficient microglia.
“This may explain why CE levels were not markedly affected in the FIT2-deficient microglia.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationLDs are present in immune cells, in particular macrophages, where they supply energy for the formation and maturation of phagosomes.
“LDs are also present in immune cells, in particular macrophages, where they supply energy for the formation and maturation of phagosomes (3).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [3] R. C. N. Melo, D. L. Fabrino, F. F. Dias, G. G. Parreira, Lipid bodies: Structural markers of inflammatory macrophages in innate immunity. Inflamm. Res. 55, 342– 348 (2006). 16977381 source
May combine two claims.
Interpretationown dataFIT2 depletion promotes the phagocytic capacity of CD11c− microglia, CD11c+ microglia, and CD206+ MHCIIhi/int BAMs.
“These in vitro findings collectively indicate that FIT2 depletion promotes the phagocytic capacity of CD11c− microglia, CD11c+ microglia, and CD206+ MHCIIhi/int BAMs.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataFIT2 depletion induces a shift in the lipidomic and transcriptomic profiles of microglia, which may also be associated with alterations in their function.
“Together, these results suggest that FIT2 depletion induces a shift in the lipidomic and transcriptomic profiles of microglia, which may also be associated with alterations in their function.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductown dataNo LD differences were found in microglia isolated from TAM-treated control Fit2wt/wt Cx3cr1CreERT2APP-KI mice, excluding TAM-related interference.
“No LD differences were found in microglia isolated from TAM-treated control Fit2wt/wt Cx3cr1CreERT2APP-KI mice, which excluded any TAM-related interference (fig. S5).”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationDecreased phagocytic activity results in insufficient clearance of apoptotic cells, leading to secondary necrosis and inflammation.
“The decreased phagocytic activity also results in the insufficient clearance of apoptotic cells (efferocytosis) in the brain; the release of intracellular content from dead and dying cells, in turn, induces secondary necrosis and inflammation, which exacerbates disease pathology (47).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [47] F. Taheri, E. Taghizadeh, J. G. Navashenaq, M. Rezaee, S. M. Gheibihayat, The role of efferocytosis in neuro-degenerative diseases. Neurol. Sci. 43, 1593– 1603 (2022). 35059903 source
May combine two claims.
PremisecitationSmall lipid droplets interfere with structural filaments, leading to cytoskeletal dysfunction and reduced phagocytic activity.
“Furthermore, in microglia, small LDs can interfere with structural filaments, leading to cytoskeletal dysfunction and reduced phagocytic activity (53).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [53] M. P. Tobin, I. L. Ivanovska, D. E. Discher, Small fat droplets interact with structural filaments in macrophages with cytoskeletal dysfunction contributing to perturbed phagocytosis and migration. Biophys. J. 122, 409a (2023). source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenEach experiment, except scRNA-seq and lipidomic analyses, was repeated at least three times to ensure the reliability of the results.
“Each experiment, except scRNA-seq and lipidomic analyses, was repeated at least three times to ensure the reliability of the results.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenNo values were excluded from the analysis.
“In the experimental design, animals were randomized into different treatment groups to minimize bias; investigators were not blind to the treatment group, and no values were excluded from the analysis.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll samples were analyzed at random.
“All samples were analyzed at random.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenβ-Actin was used as the housekeeping gene for qPCR.
“β-Actin was used as the housekeeping gene.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataInvestigators were not blind to the treatment group.
“In the experimental design, animals were randomized into different treatment groups to minimize bias; investigators were not blind to the treatment group, and no values were excluded from the analysis.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenAll qPCR reactions were run in duplicate with at least three samples in each group.
“All qPCR reactions were run in duplicate with at least three samples in each group.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenSix quality control samples were analyzed alongside test samples in each batch to ensure the reliability of the method and the stability of the instrument.
“The six quality control samples were analyzed alongside the test samples in each batch to ensure the reliability of the method and the stability of the instrument.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenRaw peak areas for lipid species were normalized to the internal standard for each lipid class.
“Raw peak areas for the lipid species detected were integrated using SCIEX OS software (version 1.4, AB Sciex Corporation, Framingham, MA) and normalized to the internal standard for each lipid class.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataFIT2 depletion reduces lipid droplet accumulation in both microglia and CD206+ BAMs, improving their phagocytic activity in the AD brain.
“In summary, our study underscores the potential of FIT2 depletion in reducing LD accumulation within both microglia and CD206+ BAMs to improve their phagocytic activity in the AD brain.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenGene expression levels were ranked in reverse Bonferroni-adjusted P value order.
“The gene expression levels were ranked in reverse Bonferroni-adjusted P value order.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAnimal studies were approved by the Institutional Animal Care and Use Committee of Nanyang Technological University.
“All animal studies were carried out according to the recommendations of the National Advisory Committee for Laboratory Animal Research, and the A19093 protocol was approved by the Institutional Animal Care and Use Committee of the Nanyang Technological University.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAnimals were randomized into different treatment groups to minimize bias.
“In the experimental design, animals were randomized into different treatment groups to minimize bias; investigators were not blind to the treatment group, and no values were excluded from the analysis.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductreasoningThe threshold cycle (Ct) values of all genes were normalized to the Ct value of β-actin.
“The threshold cycle (Ct) values of all the genes were normalized to the Ct value of β-actin.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
The APP-KI mouse model recapitulates Alzheimer's disease sufficiently for conclusions about AD progression and Aβ pathology to apply.
“we isolated bulk microglia and CD206+ BAMs from 2- and 6-month-old healthy wild-type (WT) and APPNL-G-F (APP-KI) mice”
“To study the role of LDAM in the context of AD, we also crossed the Fit2iΔMφ strain with the APP-KI strain.”
Cites
Comprehensive Integration of Single-Cell Data
Stuart, T., Butler, A., Hoffman, P., Hafemeister, C., Papalexi, E., Mauck, W. M., Hao, Y., Stoeckius, M., Smibert, P., & Satija, R. (2019) · Cell · doi:10.1016/j.cell.2019.05.031 · Cited by 15,453 · see citing works
Integrating single-cell transcriptomic data across different conditions, technologies, and species
Butler, A., Hoffman, P., Smibert, P., Papalexi, E., & Satija, R. (2018) · Nature Biotechnology · doi:10.1038/nbt.4096 · Cited by 13,174 · see citing works
Massively parallel digital transcriptional profiling of single cells
Zheng, G. X. Y., Terry, J. M., Belgrader, P., Ryvkin, P., Bent, Z. W., Wilson, R., Ziraldo, S. B., Wheeler, T. D., McDermott, G. P., Zhu, J., et al. (2017) · Nature Communications · doi:10.1038/ncomms14049 · Cited by 7,353 · see citing works
A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease
Keren-Shaul, H., Spinrad, A., Weiner, A., Matcovitch-Natan, O., Dvir-Szternfeld, R., Ulland, T. K., David, E., Baruch, K., Lara-Astaiso, D., Toth, B., et al. (2017) · Cell · doi:10.1016/j.cell.2017.05.018 · Cited by 5,493 · see citing works
Microglia Function in the Central Nervous System During Health and Neurodegeneration
Colonna, M., & Butovsky, O. (2017) · Annual Review of Immunology · doi:10.1146/annurev-immunol-051116-052358 · Cited by 2,894 · cited 1× · see citing works
“Numerous studies have highlighted the crucial contribution of microglia to brain homeostasis during aging and neurodegeneration ( 17 , 18 , 28 , 30 ).”
Dynamics and functions of lipid droplets
Olzmann, J. A., & Carvalho, P. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0085-z · Cited by 2,740 · see citing works
Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets
Gao, C., Jiang, J., Tan, Y., & Chen, S. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01588-0 · Cited by 1,616 · cited 2× · see citing works
“However, perturbations in microglial activity, often associated with aging, can affect the effective clearance of these neuron-derived A β fibrils, leading to increased plaque formation and the progression of cognitive and behavioral impairments ( 17 – 20 ).”
Single App knock-in mouse models of Alzheimer’s disease
Saito, T., Matsuba, Y., Mihira, N., Takano, J., Nilsson, P., Itohara, S., Iwata, N., & Saido, T. C. (2014) · Nature Neuroscience · doi:10.1038/nn.3697 · Cited by 1,447 · cited 1× · see citing works
“The App NL- G-F (APP-KI) mouse model is a knockin mouse line coex-pressing the Swedish (KM670/671 NL), Beyreuther/Iberian [/Iberian (I716F)], and Arctic (E693G) mutations, effectively mimicking AD-associated pathologies such as amyloid plaques, synaptic loss, and microgliosis ( 74 ).”
Marschallinger, J., Iram, T., Zardeneta, M., Lee, S. E., Lehallier, B., Haney, M. S., Pluvinage, J. V., Mathur, V., Hahn, O., Morgens, D. W., et al. (2020) · Nature Neuroscience · doi:10.1038/s41593-019-0566-1 · Cited by 1,384 · cited 9× · see citing works
“…(LDAM) have been identified in aged brains of mice and classified as dysfunctional cells as they exhibit defective phagocytic activity and show increased production of pro-inflammatory cytokines and reactive oxygen species (ROS) ( 11 ) where they contribute to an impaired response of stroke ( 13 ).”
InfluentialLipid-associated macrophages control metabolic homeostasis in a Trem2-dependent manner
Jaitin, D. A., Adlung, L., Thaiss, C. A., Weiner, A., Li, B., Descamps, H., Lundgren, P., Bleriot, C., Liu, Z., Deczkowska, A., et al. (2019) · Cell · doi:10.1016/j.cell.2019.05.054 · Cited by 1,377 · cited 1× · see citing works
“These lipid-associated macrophages potentially play an essential function in controlling tissue-level lipid homeostasis ( 12 ).”
Van Hove, H., Martens, L., Scheyltjens, I., De Vlaminck, K., Pombo Antunes, A. R., De Prijck, S., Vandamme, N., De Schepper, S., Van Isterdael, G., Scott, C. L., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0393-4 · Cited by 1,160 · cited 1× · see citing works
“In addition, we confirmed previous findings of elevated expression of lipid-related genes in BAMs ( 31 ) and observed an increase in LD content within these cells over time and during disease progression.”
Sala Frigerio, C., Wolfs, L., Fattorelli, N., Thrupp, N., Voytyuk, I., Schmidt, I., Mancuso, R., Chen, W.-T., Woodbury, M. E., Srivastava, G., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.03.099 · Cited by 926 · cited 1× · see citing works
“…states of microglial activation in brains affected by neurogenerative disease; some of these activation states were characterized by the enrichment in genes involved in lipid and lipoprotein metabolism ( 14 , 32 ), indicating a close relationship between lipid metabolism and microglial activation.”
Cochain, C., Vafadarnejad, E., Arampatzi, P., Pelisek, J., Winkels, H., Ley, K., Wolf, D., Saliba, A.-E., & Zernecke, A. (2018) · Circulation Research · doi:10.1161/circresaha.117.312509 · Cited by 894 · see citing works
Yuan, P., Condello, C., Keene, C. D., Wang, Y., Bird, T. D., Paul, S. M., Luo, W., Colonna, M., Baddeley, D., & Grutzendler, J. (2016) · Neuron · doi:10.1016/j.neuron.2016.05.003 · Cited by 817 · cited 1× · see citing works
“Microglia form a protective barrier around these A β plaques to safeguard the brain from their neurotoxic effects ( 15 , 16 ).”
Self-citationWalther, T. C., Chung, J., & Farese, R. V. (2017) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-100616-060608 · Cited by 772 · see citing works
Microglia Promote the Death of Developing Purkinje Cells
Marı́n-Teva, J. L., Dusart, I., Colin, C., Gervais, A., van Rooijen, N., & Mallat, M. (2004) · Neuron · doi:10.1016/s0896-6273(04)00069-8 · Cited by 757 · cited 1× · see citing works
“Microglia also contribute to the maintenance of brain homeostasis by clearing apoptotic cells in the brain via efferocytosis ( 27 – 29 ).”
TREM2 — a key player in microglial biology and Alzheimer disease
Ulland, T. K., & Colonna, M. (2018) · Nature Reviews Neurology · doi:10.1038/s41582-018-0072-1 · Cited by 735 · cited 1× · see citing works
“Mutations affecting the TREM2 function impair microglial activation ( 37 ) and reduce their ability to accumulate LDs in the AD brain ( 38 ).”
Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques
Condello, C., Yuan, P., Schain, A., & Grutzendler, J. (2015) · Nature Communications · doi:10.1038/ncomms7176 · Cited by 718 · see citing works
Functional characterization of the dural sinuses as a neuroimmune interface
Rustenhoven, J., Drieu, A., Mamuladze, T., de Lima, K. A., Dykstra, T., Wall, M., Papadopoulos, Z., Kanamori, M., Salvador, A. F., Baker, W., et al. (2021) · Cell · doi:10.1016/j.cell.2020.12.040 · Cited by 685 · cited 1× · see citing works
“The dura mater is considered the epicenter of immune surveillance in the brain, where macrophages present antigens to T cells to induce immune responses ( 66 ).”
Microglial dysfunction in brain aging and Alzheimer's disease
Mosher, K. I., & Wyss-Coray, T. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2014.01.008 · Cited by 618 · cited 1× · see citing works
“Numerous studies have highlighted the crucial contribution of microglia to brain homeostasis during aging and neurodegeneration ( 17 , 18 , 28 , 30 ).”
Defective cholesterol clearance limits remyelination in the aged central nervous system
Cantuti-Castelvetri, L., Fitzner, D., Bosch-Queralt, M., Weil, M.-T., Su, M., Sen, P., Ruhwedel, T., Mitkovski, M., Trendelenburg, G., Lütjohann, D., et al. (2018) · Science · doi:10.1126/science.aan4183 · Cited by 586 · cited 1× · see citing works
“Brain microglia can increase their intracellular lipid content ( 33 ) by assimi-lating lipids (e.g., myelin debris) from their environment ( 34 ).”
Regulation of lipid stores and metabolism by lipophagy
Liu, K., & Czaja, M. J. (2013) · Cell Death & Differentiation · doi:10.1038/cdd.2012.63 · Cited by 542 · cited 1× · see citing works
“Intracellular LDs within macrophages are transported to lysosomes for enzymatic degradation in a process called lipophagy ( 48 ).”
Wang, J., Xia, Y., Grundke, I., & Iqbal, K. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-129031 · Cited by 532 · cited 2× · see citing works
“…is involved in AD progression and cognitive decline is still under intense debate ( 71 , 72 ) since other factors, such as hyperphosphorylated tau protein ( 71 , 72 ), brain inflammation ( 73 ), and other yet- to- be-identified mechanisms, can contribute to the initiation and disease development.”
Phosphorylated Tau in Alzheimer’s Disease and Other Tauopathies
Rawat, P., Sehar, U., Bisht, J., Selman, A., Culberson, J., & Reddy, P. H. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232112841 · Cited by 509 · cited 2× · see citing works
“…is involved in AD progression and cognitive decline is still under intense debate ( 71 , 72 ) since other factors, such as hyperphosphorylated tau protein ( 71 , 72 ), brain inflammation ( 73 ), and other yet- to- be-identified mechanisms, can contribute to the initiation and disease development.”
Caseation of human tuberculosis granulomas correlates with elevated host lipid metabolism
Kim, M., Wainwright, H. C., Locketz, M., Bekker, L., Walther, G. B., Dittrich, C., Visser, A., Wang, W., Hsu, F., Wiehart, U., et al. (2010) · EMBO Molecular Medicine · doi:10.1002/emmm.201000079 · Cited by 489 · see citing works
Krabbe, G., Halle, A., Matyash, V., Rinnenthal, J. L., Eom, G. D., Bernhardt, U., Miller, K. R., Prokop, S., Kettenmann, H., & Heppner, F. L. (2013) · PLoS ONE · doi:10.1371/journal.pone.0060921 · Cited by 478 · see citing works
Hawkes, C. A., & McLaurin, J. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0805453106 · Cited by 397 · cited 1× · see citing works
“Moreover, the LD-mediated impairment of BAM phagocytosis may also lead to insufficient waste clearance at the brain interface and in the perivascular space, causing the excessive deposition of debris, such as A β ( 68 , 69 ).”
Elmore, M. R. P., Hohsfield, L. A., Kramár, E. A., Soreq, L., Lee, R. J., Pham, S. T., Najafi, A. R., Spangenberg, E. E., Wood, M. A., West, B. L., et al. (2018) · Aging Cell · doi:10.1111/acel.12832 · Cited by 380 · cited 1× · see citing works
“Many studies have underscored the therapeutic importance of re-storing microglial phagocytosis ( 54 – 56 ).”
Transcriptional signature in microglia associated with Aβ plaque phagocytosis
Grubman, A., Choo, X. Y., Chew, G., Ouyang, J. F., Sun, G., Croft, N. P., Rossello, F. J., Simmons, R., Buckberry, S., Landin, D. V., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-23111-1 · Cited by 357 · cited 1× · see citing works
“Similarly, microglia participating in A β phagocytosis expressed higher levels of MHCII-related genes ( 61 ).”
Faraco, G., Sugiyama, Y., Lane, D., Garcia-Bonilla, L., Chang, H., Santisteban, M. M., Racchumi, G., Murphy, M., Van Rooijen, N., Anrather, J., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci86950 · Cited by 350 · cited 1× · see citing works
“LD accumulation in macrophages can elevate their ROS production ( 9 , 11 ), promoting neurovascular dysfunction ( 67 ).”
Njie, E. G., Boelen, E., Stassen, F. R., Steinbusch, H. W. M., Borchelt, D. R., & Streit, W. J. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.05.008 · Cited by 335 · cited 1× · see citing works
“However, perturbations in microglial activity, often associated with aging, can affect the effective clearance of these neuron-derived A β fibrils, leading to increased plaque formation and the progression of cognitive and behavioral impairments ( 17 – 20 ).”
Parenchymal border macrophages regulate the flow dynamics of the cerebrospinal fluid
Drieu, A., Du, S., Storck, S. E., Rustenhoven, J., Papadopoulos, Z., Dykstra, T., Zhong, F., Kim, K., Blackburn, S., Mamuladze, T., et al. (2022) · Nature · doi:10.1038/s41586-022-05397-3 · Cited by 325 · see citing works
Metabolic Reprograming of Microglia in the Regulation of the Innate Inflammatory Response
Lauro, C., & Limatola, C. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00493 · Cited by 315 · see citing works
scds: computational annotation of doublets in single-cell RNA sequencing data
Bais, A. S., & Kostka, D. (2020) · Bioinformatics · doi:10.1093/bioinformatics/btz698 · Cited by 308 · see citing works
De Schepper, S., Ge, J. Z., Sierksma, A., Crowley, G., Ferreira, L. S. S., Garceau, D., Toomey, C. E., Sokolova, D., Rueda-Carrasco, J., Shin, S.-H., et al. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01257-z · Cited by 295 · cited 1× · see citing works
“However, as aging progresses and amyloidosis and/or tauopathy worsen, BAMs may adopt harmful activation profiles that exacerbate microglial overacti-vation, contributing to excessive synaptic pruning and neuronal dysfunction ( 65 ).”
Microglia in Alzheimer’s disease: pathogenesis, mechanisms, and therapeutic potentials
Miao, J., Ma, H., Yang, Y., Liao, Y., Lin, C., Zheng, J., Yu, M., & Lan, J. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1201982 · Cited by 293 · cited 2× · see citing works
“Phagocytosis is the major mechanism contributing to A β aggregate clearance in the brain, with microglia serving as the main effector cells for engulfing and degrading A β ( 30 ).”
Gui, Y., Zheng, H., & Cao, R. Y. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.845942 · Cited by 258 · see citing works
Lipid and Lipoprotein Metabolism in Microglia
Loving, B. A., & Bruce, K. D. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00393 · Cited by 255 · cited 1× · see citing works
“In our study, a series of proteins involved in extracellular lipid uptake, such as TREM2 and LPL ( 35 ), were highly expressed in mRNA in microglia obtained from the AD brain.”
Evolutionarily conserved gene family important for fat storage
Kadereit, B., Kumar, P., Wang, W.-J., Miranda, D., Snapp, E. L., Severina, N., Torregroza, I., Evans, T., & Silver, D. L. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0708579105 · Cited by 252 · cited 2× · see citing works
“For instance, in vitro FIT2 overexpression promoted LD accumulation in human embryonic kidney 293 cells, while FIT2 knockdown reduced TG levels and LD accumulation in mouse adipocytes ( 58 ).”
Immune hyperreactivity of Aβ plaque-associated microglia in Alzheimer's disease
Yin, Z., Raj, D., Saiepour, N., Van Dam, D., Brouwer, N., Holtman, I. R., Eggen, B. J. L., Möller, T., Tamm, J. A., Abdourahman, A., et al. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.03.021 · Cited by 238 · cited 1× · see citing works
“Microglia play a crucial role in clearing A β plaques in the brain during AD progression ( 25 , 26 ).”
Li, R.-Y., Qin, Q., Yang, H.-C., Wang, Y.-Y., Mi, Y.-X., Yin, Y.-S., Wang, M., Yu, C.-J., & Tang, Y. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00542-y · Cited by 204 · cited 1× · see citing works
“TREM2 binds to various lipid ligands, such as APOE particles (main cholesterol carriers in the brain) and myelin debris, to mediate lipid sensing and uptake ( 36 ).”
Self-citationClaes, C., Danhash, E. P., Hasselmann, J., Chadarevian, J. P., Shabestari, S. K., England, W. E., Lim, T. E., Hidalgo, J. L. S., Spitale, R. C., Davtyan, H., et al. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00473-0 · Cited by 197 · cited 1× · see citing works
“Mutations affecting the TREM2 function impair microglial activation ( 37 ) and reduce their ability to accumulate LDs in the AD brain ( 38 ).”
Role of adipose specific lipid droplet proteins in maintaining whole body energy homeostasis
Konige, M., Wang, H., & Sztalryd, C. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.05.007 · Cited by 140 · see citing works
Regulation of myelination by microglia
Santos, E. N., & Fields, R. D. (2021) · Science Advances · doi:10.1126/sciadv.abk1131 · Cited by 137 · cited 1× · see citing works
“Brain microglia can increase their intracellular lipid content ( 33 ) by assimi-lating lipids (e.g., myelin debris) from their environment ( 34 ).”
Fairley, L. H., Lai, K. O., Wong, J. H., Chong, W. J., Vincent, A. S., D’Agostino, G. A., Wu, X., Naik, R. R., Jayaraman, A., Langley, S. R., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2209177120 · Cited by 127 · cited 2× · see citing works
“A β oligomerization was conducted as previously described ( 51 ).”
Self-citationLipid accumulation in macrophages confers protumorigenic polarization and immunity in gastric cancer
Luo, Q., Zheng, N., Jiang, L., Wang, T., Zhang, P., Liu, Y., Zheng, P., Wang, W., Xie, G., Chen, L., et al. (2020) · Cancer Science · doi:10.1111/cas.14616 · Cited by 126 · cited 1× · see citing works
“In line with this proposed strategy, reversing the lipid-laden phenotype of tumoral macrophages has already been successfully used to suppress the development of gastric cancer ( 62 ).”
TREM2 regulates microglial lipid droplet formation and represses post-ischemic brain injury
Wei, W., Zhang, L., Xin, W., Pan, Y., Tatenhorst, L., Hao, Z., Gerner, S. T., Huber, S., Juenemann, M., Butz, M., et al. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115962 · Cited by 122 · cited 2× · see citing works
“In ischemic brain injury, for instance, LDs mitigate the microglial pro-inflammatory response, decrease infarct volume, and improve their neurobehavioral performance ( 63 , 64 ).”
Mitochondrial Regulation of Microglial Immunometabolism in Alzheimer’s Disease
Fairley, L. H., Wong, J. H., & Barron, A. M. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.624538 · Cited by 120 · cited 1× · see citing works
“Thus, in the AD brain, chronic and A β - induced inflammation could promote a sustained metabolic shift from mitochondrial oxidative phosphorylation to glycolysis ( 44 ), resulting in the excessive formation and accumulation of LDs within microglia.”
CD4 T Cells Induce A Subset of MHCII-Expressing Microglia that Attenuates Alzheimer Pathology
Mittal, K., Eremenko, E., Berner, O., Elyahu, Y., Strominger, I., Apelblat, D., Nemirovsky, A., Spiegel, I., & Monsonego, A. (2019) · iScience · doi:10.1016/j.isci.2019.05.039 · Cited by 114 · cited 1× · see citing works
“MHCII + microglia exhibited higher rates of phagocytosis than their MHCII − counterparts in 5xFAD mice ( 60 ).”
Shim, D., Kim, H., & Shin, S. J. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00910 · Cited by 113 · see citing works
Microglial efferocytosis: Diving into the Alzheimer’s disease gene pool
Romero-Molina, C., Garretti, F., Andrews, S. J., Marcora, E., & Goate, A. M. (2022) · Neuron · doi:10.1016/j.neuron.2022.10.015 · Cited by 111 · cited 2× · see citing works
“Microglia also contribute to the maintenance of brain homeostasis by clearing apoptotic cells in the brain via efferocytosis ( 27 – 29 ).”
A cell therapy approach to restore microglial Trem2 function in a mouse model of Alzheimer’s disease
Yoo, Y., Neumayer, G., Shibuya, Y., Mader, M. M.-D., & Wernig, M. (2023) · Cell Stem Cell · doi:10.1016/j.stem.2023.07.006 · Cited by 109 · cited 1× · see citing works
“Many studies have underscored the therapeutic importance of re-storing microglial phagocytosis ( 54 – 56 ).”
McDonald, C. L., Hennessy, E., Rubio-Araiz, A., Keogh, B., McCormack, W., McGuirk, P., Reilly, M., & Lynch, M. A. (2016) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2016.07.143 · Cited by 108 · cited 1× · see citing works
“More-over, we found that genes encoding Toll-like receptors (TLRs) such as Tlr2 , which participates in A β recognition in the brains of AD model mice ( 40 , 41 ), were up-regulated in the CD11c + microglia.”
Hughes, C., Choi, M. L., Yi, J.-H., Kim, S.-C., Drews, A., George-Hyslop, P. S., Bryant, C., Gandhi, S., Cho, K., & Klenerman, D. (2020) · Communications Biology · doi:10.1038/s42003-020-0792-9 · Cited by 107 · cited 1× · see citing works
“More-over, we found that genes encoding Toll-like receptors (TLRs) such as Tlr2 , which participates in A β recognition in the brains of AD model mice ( 40 , 41 ), were up-regulated in the CD11c + microglia.”
Aged lipid‐laden microglia display impaired responses to stroke
Arbaizar‐Rovirosa, M., Pedragosa, J., Lozano, J. J., Casal, C., Pol, A., Gallizioli, M., & Planas, A. M. (2023) · EMBO Molecular Medicine · doi:10.15252/emmm.202217175 · Cited by 94 · cited 4× · see citing works
“Moreover, the initial neuroprotective effect of LDs after injury may gradually become detrimental over time ( 13 ).”
InfluentialLatif-Hernandez, A., Shah, D., Craessaerts, K., Saido, T., Saito, T., De Strooper, B., Van der Linden, A., & D’Hooge, R. (2019) · Behavioural Brain Research · doi:10.1016/j.bbr.2017.11.017 · Cited by 92 · see citing works
Hellwig, S., Masuch, A., Nestel, S., Katzmarski, N., Meyer-Luehmann, M., & Biber, K. (2015) · Scientific Reports · doi:10.1038/srep14624 · Cited by 91 · see citing works
Sphingolipids in neuroinflammation: a potential target for diagnosis and therapy
Lee, J. Y., Jin, H. K., & Bae, J.-S. (2020) · BMB Reports · doi:10.5483/bmbrep.2020.53.1.278 · Cited by 80 · cited 1× · see citing works
“These abnormal changes in sphingolipid levels have been closely linked to neuroinflammatory disorders, as they play a crucial role in cell signaling and are, therefore, frequently discussed as potential therapeutic targets ( 45 , 46 ).”
Uekawa, K., Hattori, Y., Ahn, S. J., Seo, J., Casey, N., Anfray, A., Zhou, P., Luo, W., Anrather, J., Park, L., et al. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00660-1 · Cited by 80 · cited 1× · see citing works
“Moreover, the LD-mediated impairment of BAM phagocytosis may also lead to insufficient waste clearance at the brain interface and in the perivascular space, causing the excessive deposition of debris, such as A β ( 68 , 69 ).”
Lipid bodies: structural markers of inflammatory macrophages in innate immunity
Melo, R. C. N., Fabrino, D. L., Dias, F. F., & Parreira, G. G. (2006) · Inflammation Research · doi:10.1007/s00011-006-5205-0 · Cited by 73 · see citing works
Fat Storage-inducing Transmembrane Protein 2 Is Required for Normal Fat Storage in Adipose Tissue
Miranda, D. A., Kim, J.-H., Nguyen, L. N., Cheng, W., Tan, B. C., Goh, V. J., Tan, J. S. Y., Yaligar, J., KN, B. P., Velan, S. S., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.547687 · Cited by 71 · cited 3× · see citing works
“S4B), we next crossed the Cx3cr1 CreERT2 mouse strain with the Fit2 fl/fl mouse strain ( 24 ) to generate an inducible Fit2 i Δ M φ mouse strain.”
Lipid-loaded macrophages as new therapeutic target in cancer
Marelli, G., Morina, N., Portale, F., Pandini, M., Iovino, M., Di Conza, G., Ho, P.-C., & Di Mitri, D. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-004584 · Cited by 69 · cited 3× · see citing works
“LD accumulation in macrophages has also been documented in lipid-rich microenvironments in the peripheral, such as atherosclerosis plaques ( 5 ), white adipose tissue ( 10 ), and tumors ( 9 ).”
CNS Border-Associated Macrophages: Ontogeny and Potential Implication in Disease
Dermitzakis, I., Theotokis, P., Evangelidis, P., Delilampou, E., Evangelidis, N., Chatzisavvidou, A., Avramidou, E., & Μanthou, M. E. (2023) · Current Issues in Molecular Biology · doi:10.3390/cimb45050272 · Cited by 68 · cited 2× · see citing works
“…present study aimed to investigate the formation of LD-loaded brain macrophages during AD progression, focusing specifically on microglia and including distinct border-associated macrophages (BAMs), recently recognized for their potential contribution to central nervous system diseases ( 21 – 23 ).”
Wang, M., Tang, G., Zhou, C., Guo, H., Hu, Z., Hu, Q., & Li, G. (2023) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2023.110387 · Cited by 62 · cited 1× · see citing works
“…is involved in AD progression and cognitive decline is still under intense debate ( 71 , 72 ) since other factors, such as hyperphosphorylated tau protein ( 71 , 72 ), brain inflammation ( 73 ), and other yet- to- be-identified mechanisms, can contribute to the initiation and disease development.”
Chen, Q., Lai, S. M., Xu, S., Tan, Y., Leong, K., Liu, D., Tan, J. C., Naik, R. R., Barron, A. M., Adav, S. S., et al. (2021) · The EMBO Reports · doi:10.15252/embr.202152835 · Cited by 56 · cited 3× · see citing works
“LD accumulation in macrophages has also been documented in lipid-rich microenvironments in the peripheral, such as atherosclerosis plaques ( 5 ), white adipose tissue ( 10 ), and tumors ( 9 ).”
Self-citationWu, X., Saito, T., Saido, T. C., Barron, A. M., & Ruedl, C. (2021) · eLife · doi:10.7554/elife.71879 · Cited by 52 · cited 1× · see citing works
“Microglia were isolated as previously described ( 75 ).”
Self-citationZheng, X., Ho, Q. W. C., Chua, M., Stelmashenko, O., Yeo, X. Y., Muralidharan, S., Torta, F., Chew, E. G. Y., Lian, M. M., Foo, J. N., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2113074119 · Cited by 48 · cited 1× · see citing works
“The in vivo loss of FIT2 in adipocytes and pancreatic β cells also resulted in failed LD formation ( 24 , 59 ).”
Fernandes, T., Domingues, M. R., Moreira, P. I., & Pereira, C. (2023) · Biology · doi:10.3390/biology12030414 · Cited by 44 · see citing works
Li, H., Liu, P., Deng, S., Zhu, L., Cao, X., Bao, X., Xia, S., Xu, Y., & Zhang, B. (2023) · Inflammation · doi:10.1007/s10753-023-01844-z · Cited by 43 · cited 1× · see citing works
“In ischemic brain injury, for instance, LDs mitigate the microglial pro-inflammatory response, decrease infarct volume, and improve their neurobehavioral performance ( 63 , 64 ).”
Mesquita, S. D., & Rua, R. (2024) · Trends in Immunology · doi:10.1016/j.it.2024.03.007 · Cited by 43 · cited 1× · see citing works
“The contribution of BAMs to the development of neurodegenerative and neuroinflammatory diseases such as AD is still widely debated but becoming increasingly recognized ( 21 , 22 ).”
Metabolism in tumour-associated macrophages: a<i>quid pro quo</i>with the tumour microenvironment
Zheng, X., Mansouri, S., Krager, A., Grimminger, F., Seeger, W., Pullamsetti, S. S., Wheelock, C. E., & Savai, R. (2020) · European Respiratory Review · doi:10.1183/16000617.0134-2020 · Cited by 41 · see citing works
Amyloid β Induces Lipid Droplet‐Mediated Microglial Dysfunction in Alzheimer’s Disease
Prakash, P., Manchanda, P., Paouri, E., Bisht, K., Sharma, K. P., Rajpoot, J., Wendt, V., Hossain, A., Wijewardhane, P. R., Randolph, C. E., et al. (2023) · Alzheimer s & Dementia · doi:10.1002/alz.075938 · Cited by 38 · see citing works
Amyloid β Induces Lipid Droplet-Mediated Microglial Dysfunction in Alzheimer’s Disease
Prakash, P., Manchanda, P., Paouri, E., Bisht, K., Sharma, K., Rajpoot, J., Wendt, V., Hossain, A., Wijewardhane, P. R., Randolph, C. E., et al. (2023) · doi:10.1101/2023.06.04.543525 · Cited by 38 · cited 3× · see citing works
“A recent study demonstrated that primary microglia undergo profound lipidome perturbations to promote LD formation upon exposure to A β aggregates ( 39 ).”
Wang, X., Li, H., Sheng, Y., He, B., Liu, Z., Li, W., Yu, S., Wang, J., Zhang, Y., Chen, J., et al. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.116071 · Cited by 29 · cited 1× · see citing works
“These abnormal changes in sphingolipid levels have been closely linked to neuroinflammatory disorders, as they play a crucial role in cell signaling and are, therefore, frequently discussed as potential therapeutic targets ( 45 , 46 ).”
The role of efferocytosis in neuro-degenerative diseases
Taheri, F., Taghizadeh, E., Navashenaq, J. G., Rezaee, M., & Gheibihayat, S. M. (2022) · Neurological Sciences · doi:10.1007/s10072-021-05835-6 · Cited by 25 · cited 1× · see citing works
“The decreased phagocytic activity also results in the insufficient clearance of apoptotic cells (efferocytosis) in the brain; the release of intracellular content from dead and dying cells, in turn, induces secondary necrosis and inflammation, which exacerbates disease pathology ( 47 ).”
Cabrera-Reyes, F., Parra-Ruiz, C., Yuseff, M. I., & Zanlungo, S. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.790568 · Cited by 24 · cited 1× · see citing works
“LD overload could also induce lysosomal defects ( 49 ), ultimately leading to phagocytosis impairment.”
Játiva, S., Calle, P., Torrico, S., et al. (2022) · Biomedicines · doi:10.3390/biomedicines10020329 · Cited by 18 · cited 1× · see citing works
“Moreover, increased lipid accumulation promotes fatty acid oxidation and ROS production, leading to mitochondrial damage ( 50 ) and phagocytosis inhibition ( 51 ); these defects can be mitigated by mitochondrial transplantation ( 52 ).”
Zhang, L., Xie, Z., Yu, H., Du, H., Wang, X., Cai, J., Qiu, Y., Chen, R., Jiang, X., Liu, Z., et al. (2021) · Annals of Translational Medicine · doi:10.21037/atm-21-4012 · Cited by 12 · cited 1× · see citing works
“In accordance, TLR2 inhibition has been shown to markedly mitigate lipopolysaccharide-induced lipid accumulation in hepatic cells ( 42 ).”
Xia, Z., Zhou, Y., Li, J., & He, J. (2022) · Cancers · doi:10.3390/cancers14225506 · Cited by 12 · see citing works
Reestablishing microglia function: good news for Alzheimer's therapy?
Biber, K. (2017) · The EMBO Journal · doi:10.15252/embj.201796627 · Cited by 3 · see citing works
Tobin, M. P., Ivanovska, I. L., & Discher, D. E. (2023) · Biophysical Journal · doi:10.1016/j.bpj.2022.11.2223 · Cited by 1 · cited 1× · see citing works
“Furthermore, in microglia, small LDs can interfere with structural filaments, leading to cytoskeletal dysfunction and reduced phagocytic activity ( 53 ).”
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Decoding microglial immunometabolism: a new frontier in Alzheimer's disease research
Jung, E. S., Choi, H., & Mook-Jung, I. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00825-0 · Cited by 124 · see citing works
PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia
Kozlova, A., Zhang, S., Sudwarts, A., Zhang, H., Smirnou, S., Byeon, S. K., Thapa, C., Sun, X., Stephenson, K., Zhao, X., et al. (2025) · Nature · doi:10.1038/s41586-025-09486-x · Cited by 53 · see citing works
“We next conducted a phagocytosis assay for LOAD-risk-allele iMGs in the presence or absence of the LD blocker (TrC) 10,18,19,39,40 to confirm whether LD accumulation impairs phagocytosis as seen in mouse microglia 10,43 .”
Macrophage Signaling Pathways in Health and Disease: From Bench to Bedside Applications
Chi, Y., Jiang, H., Yin, Y., Zhou, X., Shao, Y., Li, Y., & Rao, J. (2025) · MedComm · doi:10.1002/mco2.70256 · Cited by 49 · see citing works
Microglial phagocytosis in Alzheimer disease
Brown, G. C., St George-Hyslop, P., Paolicelli, R. C., & Lemke, G. (2026) · Nature Reviews Neurology · doi:10.1038/s41582-025-01162-y · Cited by 36 · see citing works
“In an amyloid mouse model, plaque-associated microglia were found to accumulate lipid droplets and had reduced phagocytosis compared with microglia not associated with plaques, and the decrease in phagocytosis was reversed by reducing lipid droplet accumulation, resulting in reduced pathology 33 .”
Lipid droplet accumulation in microglia and their potential roles
Li, Y., Zhao, Q., Wang, Y., Du, W., Yang, R., Wu, J., & Li, Y. (2025) · Lipids in Health and Disease · doi:10.1186/s12944-025-02633-3 · Cited by 35 · see citing works
“Therefore, the induced amyloid precursor protein-KI/Fit2i Delta M phi transgenic mouse model, specifically designed to reduce microglial LDs, demonstrates consistent enhancement of phagocytic capacity and significant Aβ deposition reduction [196].”
Self-citationLipid and lipoprotein metabolism in microglia: Alzheimer’s disease mechanisms and interventions
Sprenger, K. G., Lietzke, E. E., Melchior, J., & Bruce, K. D. (2025) · Journal of Lipid Research · doi:10.1016/j.jlr.2025.100872 · Cited by 40 · see citing works
Chen, J., Zhao, S., Zhou, Y., Wang, L., Chen, Q., & Zheng, K. (2025) · BioScience Trends · doi:10.5582/bst.2025.01148 · Cited by 27 · see citing works
Lü, N., Jin, Z., Liu, N., Zhu, C., Wei, H., & Xu, Q. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03546-9 · Cited by 22 · see citing works
“Recent studies align with our observations, showing glycolytic microglia exhibit impaired lysosomal degradation capacity and chronic lipid accumulation in aging and AD models [11, 39, 44].”
Microglia in Brain Aging and Age-Related Diseases: Friends or Foes?
Ishikawa, K., Fujikawa, R., Okita, K., Kimura, F., Watanabe, T., Katsurabayashi, S., & Iwasaki, K. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262311494 · Cited by 17 · see citing works
APOE-Targeted Therapeutics for Alzheimer's Disease
Yassine, H. N., Hugo, C., O’Donovan, B., Stephens, I. O., Johnson, L. A., Cole, G. M., Julia, T. C. W., Johansson, J. O., Kisler, K., & Chiba‐Falek, O. (2025) · Journal of Neuroscience · doi:10.1523/jneurosci.1388-25.2025 · Cited by 16 · see citing works
Njoku, G. C., & Kanmogne, G. D. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26189069 · Cited by 15 · see citing works
“Supporting evidence suggests that as A β levels rise, microglia become overstimulated and enter a chronic inflammatory state that paradoxically impairs their phagocytic function [89–93].”
Luo, L., Que, M., Zeng, L., Wang, X., Sun, T., Zhou, Z., Zhao, Y., Li, S., & Luo, A. (2025) · Pharmacological Research · doi:10.1016/j.phrs.2025.107947 · Cited by 11 · see citing works
Lipid-associated macrophages and metabolic inflammatory diseases
Zheng, Y., Tu, D., Dong, C., Zhao, H., & Wang, H. (2026) · Cell Insight · doi:10.1016/j.cellin.2026.100312 · Cited by 10 · see citing works
Li, T., Zhang, J., Song, H., Zhang, R., Fan, F., Huang, Z., Zeng, M., Peng, B., & Zhang, J. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03631-z · Cited by 10 · see citing works
Loss of Plxdc2 exacerbates microglia-mediated neuroinflammation and ischemic brain injury
Yang, L., Geng, Y., Qian, Y., Zong, N., Xia, S., Yang, H., Bao, X., Chen, J., & Xu, Y. (2025) · Experimental Neurology · doi:10.1016/j.expneurol.2025.115302 · Cited by 6 · see citing works
Xie, G., Jiang, G., Huang, L., Sun, S., Wan, Y., Li, F., Wu, B., Zhang, Y., Li, X., Xiong, B., et al. (2025) · Pharmaceuticals · doi:10.3390/ph18060790 · Cited by 10 · see citing works
“Wu et al. [156] recently reported that lipid droplets (LDs) accumulated in microglia and border-associated macrophages (BAMs) impaired phagocytosis function and aggravated A β plaque formation.”
Zhang, H., Xing, N., Xing, N., et al. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102846 · Cited by 6 · see citing works
Reduced triacylglycerols and lipid droplets are associated with resilience to Alzheimer's disease
van der Vliet, D., de Vries, L. E., Di, X., Wever, D. D., de Jong, B., van der Meij, M. T. C., van der Peet, M., Harms, A. C., Hankemeier, T., Swaab, D. F., et al. (2026) · Alzheimer s & Dementia · doi:10.1002/alz.71083 · Cited by 6 · see citing works
“52 AlthoughothershaveshownthatLDsarestronglyasso-ciated with APOE ε 4 16,47,53 in our data TAGs and LDs did not correlate with APOE ε 4.”
Haskell, A. K., Kulas, J. A., Carter, W., Javens‐Wolfe, J., Hinkel, R. D., Moussaif, M., Smiley, J. S., Lazaro, O., Robertson, S., Palkowitz, A. D., et al. (2026) · Alzheimer s & Dementia · doi:10.1002/alz.71117 · Cited by 6 · see citing works
Multi-omics technologies: Novel tools and methods for assessing nerve injury and regeneration
Zhou, Q., Zhao, Z., Tan, D., Fang, C., Shen, Z., Li, S., & Chen, X. (2025) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-25-00610 · Cited by 7 · see citing works
Tong, P., Li, X., Li, S., Li, S., Chen, B., Chen, D., & Xia, C. (2025) · Phytomedicine · doi:10.1016/j.phymed.2025.157591 · Cited by 6 · see citing works
Lipid metabolism, microglia, and stroke
Chen, L., Zhang, M., Wei, W., Li, Q., Wang, L., Zhao, M., He, L., Xu, H., Yang, P., & Zhang, P. (2025) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-24-01523 · Cited by 7 · see citing works
Zhong, F., Wu, J., Deng, Z., Yu, W., Song, J., Chen, Y., Yu, W., & Lü, Y. (2025) · Genes & Diseases · doi:10.1016/j.gendis.2025.101888 · Cited by 4 · see citing works
“30,31 These microglia are referred to as plaque-associated microglia.”
Cellular mechanisms of brain lipid metabolism in health and disease
Petrelli, F., Gilardi, C., Igelbüscher, C. M., Panfilova, D., Rey, A., Paolicelli, R. C., & Knobloch, M. (2026) · Nature Cell Biology · doi:10.1038/s41556-026-01880-5 · Cited by 7 · see citing works
Lipid Droplet-Accumulating Microglia as a Therapeutic Node in Neurodegenerative Disease
Guo, S., Zhang, Q. Y., Guo, R., Fu, L., Zhu, H., & Zhang, Q. (2026) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.6c00284 · Cited by 4 · see citing works
An updated overview of lipid-regulated immunobiology in macrophages
Huang, Z.-Y., Xu, H., Lin, H., & Zhou, Q. (2025) · Acta Biochimica et Biophysica Sinica · doi:10.3724/abbs.2025239 · Cited by 4 · see citing works
Uemura, K., Hiro, S., Attachaipanich, S., Du, R., Yusof, N. I. S. M., Kinoshita, M., Hikosaka, M., & Ohtsuki, G. (2026) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2025.1669272 · Cited by 5 · see citing works
Huang, R., Lin, B.-B., Lu, Z., Hao, Y., Li, C. F., Lin, Z., Zhang, Y., Wei, N., & Chen, J. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1770509 · Cited by 3 · see citing works
“Consistent with this observation, LDAM abundance was increased in APOE4/4 AD brains and has recently been shown to actively promote AD pathology (20, 23).”
Glymphatic system impairment in neurological disorders: potential mechanisms and therapeutic targets
Wang, N., Liu, Z. H., Wang, Y., Cao, F., & Xu, D. (2026) · Molecular Biomedicine · doi:10.1186/s43556-026-00489-2 · Cited by 5 · see citing works
“Enlarged perivascular spaces and a reduced ALPS index have been observed in individuals with attention-deficit/hyperactivity disorder [167], pediatric tourette syndrome [168], and autism spectrum disorder [169].”
Self-citationFu, Y., Zhang, X.-Y., Li, L.-L., Jiang, H., Ren, Q., Yi, T., Zhang, Y., & Lu, Y. (2025) · Antioxidants · doi:10.3390/antiox14111321 · Cited by 2 · see citing works
“As a key pathological biomarker of AD [55], A β staining in mouse brain tissue revealed accumulation in the hippocampus and cortex of AD models.”
Some Basics on Innate Neuroimmunology for Nonspecialists
Konsman, J. P. (2025) · NeuroImmunoModulation · doi:10.1159/000550200 · Cited by 2 · see citing works
How does type 2 diabetes modify the risk of Alzheimer's disease?
Sutherland, G. T., Chen, A., Nguyen‐Hao, H., Mundell, H. D., Aladyeva, E., Hofer, M. J., Harari, O., & Twigg, S. M. (2026) · Alzheimer s & Dementia · doi:10.1002/alz.71471 · Cited by 2 · see citing works
“59,73 Inhibiting triglyceride biosynthesis restored homeostasis in APOE4-derived microglia, suggesting a future potential therapeutic direction, which is discussed further below.”
Targeting inflammaging in Alzheimer’s disease: molecular pathways and emerging pharmacotherapies
Alotaibi, M. O., Al‐kuraishy, H. M., Fahad, E. H., Abdelaziz, A. M., & Batiha, G. E. (2026) · Inflammopharmacology · doi:10.1007/s10787-026-02281-8 · Cited by 3 · see citing works
Hu, P., Guo, S., Ren, Y., Zhao, R., Su, L., Cheng, J., & Tian, X. (2026) · ACS Sensors · doi:10.1021/acssensors.6c01055 · Cited by 2 · see citing works
ApoE expression across the CNS: Who, What, Where, When, and How (much)?
Nolt, G. L., Lucido, C. C., Smith, L. M., & Johnson, L. A. (2026) · Molecular Neurodegeneration Advances · doi:10.1186/s44477-026-00028-x · Cited by 2 · see citing works
Wang, W., Wen, R., Li, Q., Cai, Z., Ou, Z., & Zheng, L. (2025) · Aggregate · doi:10.1002/agt2.70182 · Cited by 1 · see citing works
Wang, Y., Lei, B., Jiang, K., Chen, X., Qu, Y., Song, X., Dui, X., Zhao, Q., Zhao, X., Zou, Y., et al. (2026) · Alzheimer s & Dementia · doi:10.1002/alz.71437 · Cited by 1 · see citing works
Self-citationEmerging diagnostic biomarkers and therapeutic targets in Alzheimer's disease
Dineshbhai, T. K., Rafaliya, D., Singh, A., Maheshwari, S., Lalan, M. S., & Chakraborthy, G. S. (2026) · Inflammopharmacology · doi:10.1007/s10787-026-02341-z · Cited by 1 · see citing works
“Additionally, certain compounds enhance Aβ clearance by promoting proteolytic degradation and facilitating microglial phagocytosis. hereby reducing plaque formation and neurotoxicity (Wu et al. 2025).”
Progranulin deficiency induces lipid droplet accumulation in microglia via a STAT3-GPAT3 axisPreprint
Li, J., Shi, Y., Guan, H., Lü, Y., Yi, T., Li, W., Wang, Y., Guo, Y., Li, B., & Zhu, C. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.01.17.700052 · Cited by 1 · see citing works
Self-citationCatto, F., Dadgar‐Kiani, E., Kirschenbaum, D., Economides, A. E., Reuss, A. M., Trevisan, C., Caredio, D., Delic, M., Frick, L. D., Weber‐Stadlbauer, U., et al. (2025) · PLoS ONE · doi:10.1371/journal.pone.0309489
PCSK9 and High-Fat Diet Synergistically Induce Neurovascular Dysfunction and NeuroinflammationPreprint
Zhang, M., Letian, A., Mohl, G. A., Kroke, B., Arkelius, K., Clelland, C. D., Goldberg, E. L., & Singhal, N. S. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.29.685380
STING–IFN–CH25H lipid axis links innate immune activation to tau pathologyPreprint
Chen, H., Fan, L., Wong, M. Y., Ambaw, Y. A., Zhu, J., Norman, K., Ye, P., Foxe, N., Zhu, D., Wan, Y., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.16.694702
ApoE-directed CpG nano-immunoadjuvant ameliorates Alzheimer's-like pathology in mice
Huang, X., Sun, Y.-Y., Qin, Y.-R., Chen, H., Pan, T.-T., Zhao, S., Cai, Q., Zhang, X., Nie, X.-D., Feng, L., et al. (2026) · Journal of Controlled Release · doi:10.1016/j.jconrel.2026.114687
Chen, Y.-C., Chiu, T.-J., Wu, Y.-Y., Wang, Y.-T., Wu, K.-H., Yeh, T., Hsieh, Y., Chen, W.-S., & Chiu, C. (2026) · Life Sciences · doi:10.1016/j.lfs.2026.124274
Self-citationMera-Reina, C., Codocedo, J. F., Fallen, P. B., Scott, J., Lasagna‐Reeves, C. A., & Landreth, G. E. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.03.01.708896
Fukui, M., Kaise, T., Masaki, T., Sakamoto, T., & Kageyama, R. (2026) · Cell Reports · doi:10.1016/j.celrep.2026.117250
Delbaz, A., & John, J. A. S. (2026) · Cells · doi:10.3390/cells15080690 · Cited by 2 · see citing works
Hu, X., Yao, M., Xu, F., Wang, H., Lu, M., & Chen, Q. (2026) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-25-01276
Peck, M. R., Chapman, J. E., Hill, T., Quinn, K., Ikiz, E. D., Lopez, A., Hascup, E. R., Bae, C., & Hascup, K. N. (2026) · Journal of Alzheimer s Disease · doi:10.1177/13872877261444307
Engulfment by brain macrophages in a short-lived vertebratePreprint
Nagvekar, R., Pogson, A. N., Kalakuntla, P. R., Barr, H. J., Jaimes, A. M. M., Perry, S., Costa, E. K., Chen, J., Boos, F., Negredo, P. N., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.04.28.721434
Hall‐Roberts, H., Maguire, E., Shaw, B., O’Donoghue, R., Winston, J., Keat, S., Capitani, L., Mahoney, R., Geary, B., Faber, K., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.04.29.721607
“Excessive neutral lipid accumulation is observed in AD plaque-associated microglia (Wu et al., 2025), so we assessed total cellular neutral lipid levels using HCS LipidTox Green Neutral Lipid Stain, using cyclosporin A as a positive control for lipid accumulation (Fig 4B).”
Bang-feng, L., Chen, X., Xie, R., Mo, Y.-F., Wu, Y.-Z., Meng, Y., Han, X.-L., Chen, M., & Peng, Y. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1818802 · Cited by 2 · see citing works
Fatty Acid Metabolism in Health and Cancer: From Fundamental Mechanisms to Therapeutic Application
Hang, N., Zhao, R., Zhang, F., Guo, D., Li, Q., Shen, Z., Gao, R., Gao, C., Xie, Z., Fu, S., et al. (2026) · MedComm · doi:10.1002/mco2.70749 · Cited by 1 · see citing works
“Research has found that MG located near A β plaques have a higher LD load, and the intracellular LD content is negatively correlated with phagocytic activity [ 360 ].”
APOE interacts with COX-2 on lipid droplets to modulate inflammatory lipid signalingPreprint
Powers, A. E., Kamble, K., Nair, M., Windham, I. A., Miner, G. E., Prim, C. E., Mills, C. A., Lyons, S. P., Herring, L. E., Chirasani, V. R., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.06.09.730852
Mook‐Jung, I. (2026) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2026.103234
Wang, H., Gu, S., Jiang, Y., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.06.16.732486
“It is well-documented that autophagy-regulated uptake and lysosomal degradation of Aβs are essential for reducing neurotoxicity 49,50 .”
Li, Z., Ming, Q., Fu, L., Yang, J., Lv, Y., Chen, B., & Lu, Z. (2026) · Frontiers in Nutrition · doi:10.3389/fnut.2026.1886340 · Cited by 1 · see citing works
“Reducing microglial lipid load in an Alzheimer mouse model enhances phagocytosis and improves amyloid handling (55).”
Zhang, Y., Li, S.-Y., Hu, Y.-Z., Ding, Y., Zhang, Y.-T., Zhang, H., Zhang, Y., Xu, L., Zhang, Z., & Li, L. (2026) · Journal of Neuroinflammation · doi:10.1186/s12974-026-03949-2
Xiao, L., Green, J. M., Mochizuki, M., & Nakahara, T. (2026) · Cells · doi:10.3390/cells15151368
“Within the aging and neurodegenerative hippocampal niche, lipid-droplet-accumulating microglia exhibit profound phagocytic dysfunction, resulting in impaired A β clearance and the accumulation of neurotoxic debris [138,139].”
Engulfment by brain macrophages in a short-lived vertebratePreprint
Nagvekar, R., Pogson, A. N., Kalakuntla, P. R., Barr, H. J., Jaimes, A. M. M., Perry, S., Costa, E. K., Chen, J., Boos, F., Negredo, P. N., et al. (2026) · eLife · doi:10.7554/elife.112503.1
Engulfment by brain macrophages in a short-lived vertebratePreprint
Nagvekar, R., Pogson, A. N., Kalakuntla, P. R., Barr, H. J., Jaimes, A. M. M., Perry, S., Costa, E. K., Chen, J., Boos, F., Negredo, P. N., et al. (2026) · eLife · doi:10.7554/elife.112503
Yang, S., Li, Y., Guo, Y., Li, Y., Li, M., Li, H., & Zhang, Y. (2026) · Molecular Neurobiology · doi:10.1007/s12035-026-06100-7 · Cited by 1 · see citing works
Liao, J., Chen, Y., Lu, Y., Qu, F., Xie, X., Yang, Z., & Wen, W. (2026) · Behavioural Neurology · doi:10.1155/bn/6222269
Liu, A., Xing, L., Li, J., Gao, W., Yao, M., Song, J., & Li, H. (2026) · Ageing Research Reviews · doi:10.1016/j.arr.2026.103352
Lysosomes as chemical and metabolic organizers of central nervous system injury and repair
Zhao, T., Huang, H., Wang, Y., Zhong, Y., Zhong, Z., Xue, D., Zhu, W., & Xu, K. (2026) · Frontiers in Chemistry · doi:10.3389/fchem.2026.1891677
“In line with this, reducing the lipid load of microglia in the AD mouse model enhanced β -amyloid clearance, which supports the view that lysosomes under lipid stress may limit the degradation ability of microglia (Wu et al., 2025).”
InfluentialSelf-citationLi, J., Jiang, L., 晁凤蕾, Zhang, L., 胡春年, Zhou, Y., Wang, S., Pan, Q., Luo, Y., Tang, J., et al. (2026) · Molecular Psychiatry · doi:10.1038/s41380-026-03907-7
Porphyromonas gingivalis Promotes Lipid Droplet–Mediated Microglial Dysfunction
Rajoka, M. S. R., Valladares, K. N., Prairie, C. L., Li, W., King, P. H., Katz, J., Michalek, S. M., & Zhang, P. (2026) · Journal of Dental Research · doi:10.1177/00220345261478558
Yang, S., Wu, D., Li, Y., et al. (2026) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2026.154628
Multifaceted response of microglia in the cuprizone model of demyelination
Shanahan, A., Eichfeld, G., Todd, L., & Niraula, A. (2026) · PLOS One · doi:10.1371/journal.pone.0355981
- Authors
- Wu, X., Miller, J. A., Lee, B. T. K., Wang, Y., & Ruedl, C.
- Affiliations
- Nanyang Technological University (SG)
- Corresponding author
- Ruedl, Christiane
- Venue
- Science Advances
- Published
- 2025-02-07
- Volume
- 11
- Issue
- 6
- Pages
- eadq6038-eadq6038
- ISSN
- 2375-2548 (ISSN-L)
- PMC
- PMC11797491
- OpenAlex
- W4407160042
- Semantic Scholar
- 0815847baab032d14202ad8d89f033e44cf8dd40
- Cited by
- 67
- References
- 80
- Citations by year
- 2026: 40 · 2025: 27
- FWCI
- 19.72
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- Science Advances (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- DR-NTU (Nanyang Technological University) (publishedVersion, cc-by-nc)
- PubMed Central (submittedVersion, cc-by-nc)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- Alzheimer's disease, microglia, lipid droplets, border-associated macrophages, efferocytosis, lipid metabolism, CX3CR1, amyloid plaques, neuroinflammation
- MeSH terms
- CX3C Chemokine Receptor 1, Alzheimer Disease, Animals, Brain, Disease Models, Animal, Humans, Macrophages, Mice, Transgenic, Phagocytosis, Amyloid beta-Peptides, Microglia, Lipid Metabolism, Mice, Plaque, Amyloid, Lipid Droplets
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-20.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-20.
Cited sources are checked by gpt-6-sol.
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