Microglial APOE3 Christchurch protects neurons from Tau pathology in a human iPSC-based model of Alzheimer’s disease
Open accessAbstract
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder characterized by extracellular amyloid plaques and neuronal Tau tangles. A recent study found that the APOE3 Christchurch (APOECh) variant could delay AD progression. However, the underlying mechanisms remain unclear. In this study, we established neuron-microglia co-cultures and neuroimmune organoids using isogenic APOE3 and APOECh microglia derived from human induced pluripotent stem cells (hiPSCs) with PSEN1 mutant neurons or brain organoids. We show that APOECh microglia are resistant to Aβ-induced lipid peroxidation and ferroptosis and therefore preserve the phagocytic activity and promote pTau clearance, providing mechanistic insights into the neuroprotective role of APOE3Ch microglia. Moreover, we show that an APOE mimetic peptide can mimic the protective effects of APOECh microglia. These findings demonstrate that the APOECh microglia plays a causal role in microglial neuroprotection, which can be exploited for therapeutic development for AD.
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Written from the paper’s full text.
TL;DR
Using isogenic APOE3 and APOE3 Christchurch (APOECh) hiPSC-derived microglia co-cultured with PSEN1 mutant neurons or brain organoids, APOECh microglia resist Aβ-induced lipid peroxidation and ferroptosis, preserve phagocytosis, and reduce pTau. An APOE mimetic peptide mimics the protective effects of APOECh microglia.
Key findings
- APOECh microglia co-cultured with PSEN1 mutant neurons showed a higher phagocytosis index and lower IL-1β induction than APOE3 microglia; no significant difference was seen with WT neurons.
- RNA-seq of microglia isolated from co-cultures showed APOECh-upregulated DEGs enriched in phagocytosis, lipid particles, folic acid, and Aβ binding, while downregulated DEGs related to inflammatory response, apoptosis, ferroptosis, ion homeostasis, and AD pathways. qRT-PCR validated elevated ACSL1, TFRC, and SAT1 in APOE3 versus APOECh microglia with PSEN1 mutant neurons, and elevated ANXA3, CD93, and SLC11A1 in APOECh microglia.
- Aβ42 or PSEN1 mutant neuronal conditioned medium induced lipid droplets, lipid peroxidation, TFRC expression, and reduced phagocytosis in APOE3 but not APOECh microglia; liproxstatin-1 rescued APOE3 phagocytosis, and inducible TFRC overexpression reduced phagocytosis in both APOE3 and APOECh microglia.
- APOECh microglia reduced residual oTau and pTau+Tuj1+ neurons, preserved MEA neural network activity after AD human synaptosome challenge, and reduced pTau in PSEN1 mutant brain organoids; an APOE mimetic peptide reduced lipid droplets, lipid peroxidation, and pTau in APOE3 microglia/neuron co-cultures.
Methods
- Isogenic APOECh iPSC lines were generated from APOE3 controls by CRISPR-Cas9, with additional patient-derived and Jackson Laboratory lines; microglia and neurons were differentiated, and a PSEN1 E280A mutant iPSC line was made by CRISPR-Cas9 editing.
- 2D neuron-microglia co-cultures used an N:MG ratio of 5:2 and were maintained for 10 days; 3D brain organoids received microglia at day 50 at 4×10^5 cells per organoid and were analyzed 20 days later.
- Exposures included postmortem AD brain-derived oTau at 40 ng/mL for 5 days, AD human synaptosomes at 100 μg/mL for 24 h, 500 nM Aβ42, and 10 μM DAPT; readouts included RNA-seq of immunomagnetically purified microglia, qRT-PCR, immunostaining, western blotting, phagocytosis assays, and multi-electrode array recording. Statistics used GraphPad Prism with one-way or two-way ANOVA plus Tukey post hoc tests, or unpaired two-tailed Student’s t tests, with significance at p < 0.05.
Limitations
- The paper states that the protective mechanism remains to be validated in human brain tissues from APOECh carriers.
- The paper states that how the APOE mimetic peptide exerts its protective effect and whether it acts on neurons, microglia, or the neuron-microglia interface remain to be explored.
- Evident from the text: the study relies on hiPSC-derived 2D and 3D models and postmortem-derived materials, used one clone for each isogenic iPSC line, and included mouse astrocytes as feeder cells in MEA experiments.
Model-written summary. Check it against the paper before relying on it.
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Cites
Statistics
Claims the paper makes
7 of 11 cited sources checked · 4 supported · 0 flagged · accuracy not yet measured
- Premisecitation
The protective effect of APOECh is partly due to its reduced affinity for heparan sulfate proteoglycans or other cellular receptors for APOE.
“It has been shown that the protective effect of APOECh is partly due to its reduced affinity for heparan sulfate proteoglycans (HSPG) or other cellular receptors for APOE.21”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [21] Arboleda-Velasquez, 2019, Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report, Nat. Med. source
The paper’s Abstract reports that ApoE3ch had the lowest heparin binding of the tested isoforms and postulates that its beneficial effect is related in part to altered affinity for HSPG or other ApoE receptors. It does not establish that reduced receptor affinity causes the protective effect, as the citing sentence’s “has been shown” implies. No page number is provided in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Premisecitation
Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain.
“Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain.71”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [71] Marschallinger, 2020, Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain, Nat. Neurosci. source
- Interpretationown data
The APOECh variant is causal to neuroprotection.
“In this study, we have demonstrated that the APOECh variant is causal to neuroprotection, extending the observation made in the 2019 single-patient study21 and providing strong rationale for developing potential AD therapies by targeting the protective APOECh variant and using the APOECh variant-carrying cells.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [21] Arboleda-Velasquez, 2019, Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report, Nat. Med. source
- Rests on an assumption: Phenotypes observed in hiPSC-derived N-MG co-cultures and neuroimmune organoids are predictive of human AD pathogenesis and of APOECh-mediated neuroprotection in humans.
- Premisecitation
Lipid accumulation impairs microglial surveillance of neuronal network activity.
“Additionally, lipid accumulation impairs microglial surveillance of neuronal network activity.72”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [72] Victor, 2022, Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity, Cell Stem Cell source
- Findingown data
There is no significant difference in phagocytosis index between APOECh and APOE3 microglia when co-cultured with WT neurons.
“We found a substantial decrease of the phagocytosis index in APOE3 microglia compared to APOECh microglia when co-cultured with PSEN1 mutant neurons but no significant difference in the phagocytosis index between APOECh and APOE3 microglia when co-cultured with WT neurons (Figures 1G and 1H).”
Quote in the paperNot a substantial claim
- Findingown data
SAT1 expression is increased in APOE3 microglia compared to APOECh microglia co-cultured with PSEN1 mutant neurons.
“Notably, TFRC and SAT1 exhibited increased expression levels in APOE3 microglia compared to APOECh microglia that were co-cultured with PSEN1 mutant neurons (Figure 2F).”
Quote in the paperSubstantial claim - Findingown data
TFRC expression is increased in APOE3 microglia compared to APOECh microglia co-cultured with PSEN1 mutant neurons.
“Notably, TFRC and SAT1 exhibited increased expression levels in APOE3 microglia compared to APOECh microglia that were co-cultured with PSEN1 mutant neurons (Figure 2F).”
Quote in the paperNot a substantial claim - Findingown data
APOE3 microglia co-cultured with PSEN1 mutant neurons exhibit higher IL-1β induction than APOECh microglia co-cultured with PSEN1 mutant neurons.
“Moreover, APOE3 microglia co-cultured with PSEN1 mutant neurons exhibited elevated neuroinflammatory response as revealed by a higher induction of IL-1β than that in APOECh microglia co-cultured with PSEN1 mutant neurons (Figure S2C).”
Quote in the paperNot a substantial claim - Findingown data
Phagocytosis-related genes ANXA3, CD93, and SLC11A1 display elevated expression levels in APOECh microglia compared to APOE3 microglia when co-cultured with PSEN1 mutant neurons.
“Conversely, phagocytosis-related genes, such as ANXA3,50 CD93,51,52 and SLC11A1,53 displayed elevated expression levels in APOECh microglia compared to APOE3 microglia when co-cultured with PSEN1 mutant neurons (Figure 2G).”
Quote in the paperSubstantial claim - Findingown data
Aβ42 treatment induces ACSL1 expression in APOE3 but not APOECh microglia.
“Indeed, treatment with Aβ42 induced ACSL1 expression in APOE3 but not APOECh microglia (Figure S3A).”
Quote in the paperSubstantial claim - Findingown data
RNA-seq of APOE3 versus APOECh microglia from co-cultures shows upregulated DEGs primarily associated with phagocytosis, lipid particles, folic acid, and Aβ binding pathways.
“The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of differentially expressed genes (DEGs) revealed that the upregulated DEGs are primarily associated with phagocytosis, lipid particles, folic acid, and Aβ binding pathways (Figure 2B), while the downregulated DEGs are mainly related to inflammatory response, apoptosis, ferroptosis, ion homeostasis, and AD”
Quote in the paperSubstantial claim - Findingown data
ACSL1 expression is substantially elevated in APOE3 microglia compared to APOECh microglia when co-cultured with PSEN1 mutant neurons.
“We detected substantially elevated expression of ACSL1, a gene encoding a key enzyme for lipid droplet biogenesis,45,46 in APOE3 microglia compared to APOECh microglia when co-cultured with PSEN1 mutant neurons (Figure 2E).”
Quote in the paperSubstantial claim - Findingown data
In N-MG co-cultures with PSEN1 mutant neurons, APOECh microglia show a substantially higher phagocytosis index than APOE3 microglia.
“We found a substantial decrease of the phagocytosis index in APOE3 microglia compared to APOECh microglia when co-cultured with PSEN1 mutant neurons but no significant difference in the phagocytosis index between APOECh and APOE3 microglia when co-cultured with WT neurons (Figures 1G and 1H).”
Quote in the paperSubstantial claim - Findingown data
An APOE mimetic peptide can mimic the protective effects of APOECh microglia.
“Moreover, we show that an APOE mimetic peptide can mimic the protective effects of APOECh microglia.”
Quote in the paperSubstantial claim - Findingown data
APOECh microglia are resistant to Aβ-induced lipid peroxidation and ferroptosis.
“We show that APOECh microglia are resistant to Aβ-induced lipid peroxidation and ferroptosis and therefore preserve the phagocytic activity and promote pTau clearance, providing mechanistic insights into the neuroprotective role of APOE3Ch microglia.”
Quote in the paperSubstantial claim - Findingown data
NCM from PSEN1 mutant neurons induces increased lipid droplet formation in APOE3 microglia compared to NCM from WT neurons.
“Similarly, treatment with neuronal conditioned medium (NCM) from PSEN1 mutant neurons induced increased lipid droplet formation in APOE3 microglia compared to treatment with NCM from WT neurons.”
Quote in the paperSubstantial claim - Findingown data
There is no significant difference in expression of ITGAX and TREM2 in APOE3 and APOECh microglia treated with Aβ42.
“We did not see a significant difference in the expression of genes associated with disease-associated microglia, such as ITGAX and TREM2, in APOE3 and APOECh microglia treated with Aβ42 (Figure S3B).”
Quote in the paperNot a substantial claim - Findingown data
Downregulated DEGs in APOE3 versus APOECh microglia are mainly related to inflammatory response, apoptosis, ferroptosis, ion homeostasis, and AD pathways.
“The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of differentially expressed genes (DEGs) revealed that the upregulated DEGs are primarily associated with phagocytosis, lipid particles, folic acid, and Aβ binding pathways (Figure 2B), while the downregulated DEGs are mainly related to inflammatory response, apoptosis, ferroptosis, ion homeostasis, and AD”
Quote in the paperSubstantial claim - Findingown data
Aβ42 treatment increases lipid droplet number in APOE3 but not APOECh microglia.
“Consistent with the ACSL1 gene expression pattern, we detected substantially increased lipid droplet number in APOE3 but not APOECh microglia (Figures 3A–3C).”
Quote in the paperSubstantial claim - Findingown data
NCM from PSEN1 mutant neurons fails to induce increased lipid droplet formation in APOECh microglia.
“In contrast, NCM from PSEN1 mutant neurons failed to induce increased lipid droplet formation in APOECh microglia.”
Quote in the paperSubstantial claim - Findingown data
Reduced phagocytosis in Aβ42-treated APOE3 microglia is correlated with reduced cell viability.
“The reduced phagocytosis in Aβ42-treated APOE3 microglia was correlated with reduced cell viability, which could be rescued by the treatment with the ferroptosis inhibitor Liproxstatin-1 (Figure S4), suggesting that the reduced phagocytosis is caused by ferroptosis of microglia.”
Quote in the paperSubstantial claim - Findingown data
Treatment of APOECh microglia co-cultured with PSEN1 mutant neurons with liproxstatin-1, Alimta, or folic acid has no significant effect on their phagocytic activity.
“Treatment of APOECh microglia co-cultured with PSEN1 mutant neurons with liproxstastin-1, Alimta, or folic acid had no significant effect on their phagocytic activity (Figure 4D).”
Quote in the paperSubstantial claim - Findingown data
Introduction of the APOE mimetic peptide results in a substantial decrease in lipid droplet number in APOE3 microglia to a level comparable to that in APOECh microglia.
“Remarkably, introduction of the APOE mimetic peptide resulted in a substantial decrease in the lipid droplet number and the level of lipid peroxidation in APOE3 microglia to a level that is comparable to that in APOECh microglia (Figures 6A–6D).”
Quote in the paperSubstantial claim - Findingown data
Neither Alimta nor folic acid rescues phagocytic capacity of APOE3 microglia co-cultured with PSEN1 mutant neurons.
“Neither Alimta nor folic acid exhibited such a rescuing effect (Figure 4D).”
Quote in the paperSubstantial claim - Findingown data
Treatment of APOE3 microglia co-cultured with PSEN1 mutant neurons with liproxstatin-1 rescues phagocytic capacity substantially.
“Treatment of APOE3 microglia co-cultured with PSEN1 mutant neurons with liproxstastin-1 rescued the phagocytic capacity of APOE3 microglia substantially.”
Quote in the paperSubstantial claim - Findingown data
NCM from PSEN1 mutant neurons reduces phagocytic activity of APOE3 but not APOECh microglia.
“Treatment with NCM from PSEN1 mutant neurons also reduced phagocytic activity of APOE3 but not APOECh microglia, while NCM from DAPT-treated PSEN1 mutant neurons did not affect the phagocytosis of APOE3 or APOECh microglia (Figure 3K).”
Quote in the paperSubstantial claim - Findingown data
NCM from PSEN1 mutant neurons increases the percentage of Bodipy ox+ cells in APOE3 but not APOECh microglia compared to NCM from WT neurons.
“Similarly, treatment with NCM from PSEN1 mutant neurons increased the percentage of Bodipy ox+ cells in APOE3 but not APOECh microglia, compared to treatment with NCM from WT neurons. (Figures 3G and S3D).”
Quote in the paperSubstantial claim - Findingown data
The APOE mimetic peptide prevents Aβ-induced impairment of phagocytosis in APOE3 microglia.
“Accordingly, the APOE mimetic peptide prevented Aβ-induced impairment of phagocytosis in APOE3 microglia (Figure 6E).”
Quote in the paperSubstantial claim - Findingown data
The increase of pTau level following ADHS challenge is mitigated in neurons co-cultured with APOECh microglia.
“However, the increase of pTau level was mitigated in neurons co-cultured with APOECh microglia (Figures 5B–5D and S6C).”
Quote in the paperSubstantial claim - Findingown data
Introduction of the APOE mimetic peptide results in a substantial decrease in the level of lipid peroxidation in APOE3 microglia to a level comparable to that in APOECh microglia.
“Remarkably, introduction of the APOE mimetic peptide resulted in a substantial decrease in the lipid droplet number and the level of lipid peroxidation in APOE3 microglia to a level that is comparable to that in APOECh microglia (Figures 6A–6D).”
Quote in the paperSubstantial claim - Findingown data
ADHS treatment induces neuroinflammatory response in co-cultures with APOE3 microglia as revealed by induction of IL-1β expression.
“ADHS treatment also induced neuroinflammatory response in the co-cultures with APOE3 microglia as revealed by the induction of IL-1β expression, whereas the inflammatory response was much dampened in co-cultures with APOECh microglia (Figure S6F).”
Quote in the paperNot a substantial claim - Findingown data
NCM from DAPT-treated PSEN1 mutant neurons does not affect phagocytosis of APOE3 or APOECh microglia.
“Treatment with NCM from PSEN1 mutant neurons also reduced phagocytic activity of APOE3 but not APOECh microglia, while NCM from DAPT-treated PSEN1 mutant neurons did not affect the phagocytosis of APOE3 or APOECh microglia (Figure 3K).”
Quote in the paperSubstantial claim - Findingown data
Aβ42 treatment increases the percentage of Bodipy ox+ cells substantially in APOE3 but not APOECh microglia compared to vehicle treatment.
“We found that Aβ42 treatment increased the percentage of Bodipy ox+ cells substantially in APOE3 but not APOECh microglia, compared to vehicle treatment (Figures 3E and 3F).”
Quote in the paperSubstantial claim - Findingown data
There is a higher percentage of pTau+Tuj1+ cells in N-MG co-cultures with APOE3 microglia than in N-MG co-cultures with APOECh microglia.
“We found a higher percentage of pTau+Tuj1+ cells in N-MG co-cultures with APOE3 microglia than that in N-MG co-cultures with APOECh microglia (Figure S5F, control panel).”
Quote in the paperSubstantial claim - Findingown data
Induction of TFRC leads to substantially reduced phagocytosis in both APOE3 and APOECh microglia co-cultured with WT or PSEN1 mutant neurons.
“Induction of TFRC led to substantially reduced phagocytosis in both APOE3 and APOECh microglia co-cultured with WT or PSEN1 mutant neurons (Figure 4B).”
Quote in the paperSubstantial claim - Findingown data
The inflammatory response following ADHS treatment is much dampened in co-cultures with APOECh microglia.
“ADHS treatment also induced neuroinflammatory response in the co-cultures with APOE3 microglia as revealed by the induction of IL-1β expression, whereas the inflammatory response was much dampened in co-cultures with APOECh microglia (Figure S6F).”
Quote in the paperSubstantial claim - Findingown data
Neural network activity is largely preserved in ADHS-treated WT and PSEN1 mutant neurons co-cultured with APOECh microglia.
“In contrast, the neural network activity was largely preserved in ADHS-treated neurons (WT and PSEN1 mutant) co-cultured with APOECh microglia (Figures 5F, 5G, S5E, and S5F).”
Quote in the paperSubstantial claim - Findingown data
Reduced cell viability in Aβ42-treated APOE3 microglia can be rescued by Liproxstatin-1.
“The reduced phagocytosis in Aβ42-treated APOE3 microglia was correlated with reduced cell viability, which could be rescued by the treatment with the ferroptosis inhibitor Liproxstatin-1 (Figure S4), suggesting that the reduced phagocytosis is caused by ferroptosis of microglia.”
Quote in the paperSubstantial claim - Findingown data
APOECh microglia are resistant to oTau-induced inflammatory response.
“In contrast, APOECh microglia were resistant to oTau-induced inflammatory response (Figure S5G).”
Quote in the paperSubstantial claim - Findingown data
Aβ42 treatment elevates TFRC expression in APOE3 but not APOECh microglia.
“Furthermore, we detected elevated expression of TFRC, an important regulator of ferroptosis, in Aβ42-treated APOE3 but not APOECh microglia (Figures 3H and 3I).”
Quote in the paperSubstantial claim - Findingown data
Treatment of N-MG co-cultures with cytochalasin D leads to dramatically increased pTau level in neurons co-cultured with either APOE3 or APOECh microglia.
“Moreover, treatment of the N-MG co-cultures with the phagocytosis inhibitor cytochalasin D (cytoD) led to dramatically increased pTau level in neurons co-cultured with either APOE3 or APOECh microglia (Figures S5E and S5F), suggesting that the reduced pTau level in neurons co-cultured with APOECh microglia could be due to the enhanced phagocytosis capacity of APOECh microglia.”
Quote in the paperSubstantial claim - Findingown data
There is no significant difference in residual oTau between APOECh and APOE3 N-MG co-cultures containing WT neurons.
“There was no significant difference in the amount of residual oTau between APOECh and APOE3 N-MG co-cultures containing WT neurons.”
Quote in the paperNot a substantial claim - Findingown data
Following ADHS challenge, pTau levels increase substantially in both soluble and insoluble forms in neurons co-cultured with APOE3 microglia, including WT and PSEN1 mutant neurons.
“Following ADHS challenge, we detected a substantial increase in pTau levels (Figures 5B–5D and S6C), in both soluble form and insoluble form (Figures 5C and 5D), in neurons co-cultured with APOE3 microglia, including WT and PSEN1 mutant neurons.”
Quote in the paperSubstantial claim - Findingown data
NCM from PSEN1 mutant neurons treated with DAPT fails to induce lipid droplets in APOE3 microglia.
“Addition of NCM from PSEN1 mutant neurons treated with the γ-secretase inhibitor (2S)-N-[(3,5-Difluorophenyl)acetyl]-L-alanyl-2-phenyl]glycine 1,1-dimethylethyl ester (DAPT) failed to induce lipid droplets in APOE3 microglia (Figures 3D and S3C).”
Quote in the paperSubstantial claim - Findingown data
When oTau is added to N-MG co-cultures containing PSEN1 mutant neurons, residual oTau level is substantially lower in co-cultures with APOECh microglia than in co-cultures with APOE3 microglia.
“However, when oTau was added to the N-MG co-cultures containing PSEN1 mutant neurons, substantially lower residual oTau level was observed in co-cultures with APOECh microglia compared to that in co-cultures with APOE3 microglia (Figures S5C and S5D).”
Quote in the paperSubstantial claim - Findingown data
Treatment of APOE3 microglia-PSEN1 mutant neuron co-cultures with a ferroptosis inhibitor rescued the ability of APOE3 microglia to phagocytose synaptosome and clear oTau to a level similar to APOECh microglia.
“Treatment of APOE3 microglia-PSEN1 mutant neuron co-cultures with a ferroptosis inhibitor rescued the ability of APOE3 microglia to phagocytose synaptosome and clear oTau to a level similar to APOECh microglia, suggesting that the enhanced phagocytic capacity and Tau clearance by APOECh microglia could result from reduced ferroptosis.”
Quote in the paperSubstantial claim - Findingown data
APOECh microglia are much more effective in reducing pTau levels in PSEN1 mutant brain organoids than APOE3 microglia.
“We found that APOECh microglia were much more effective in reducing pTau levels in PSEN1 mutant brain organoids than APOE3 microglia (Figures 7D–7H), indicating a protective role of APOECh microglia in PSEN1 mutant brain organoids by ameliorating pTau pathology.”
Quote in the paperSubstantial claim - Findingown data
The APOE mimetic peptide dramatically reduces the percentage of pTau+Tuj1+ neurons in both WT and PSEN1 mutant neurons treated with ADHS.
“Furthermore, the APOE mimetic peptide dramatically reduced the percentage of pTau+Tuj1+ neurons in both WT and PSEN1 mutant neurons treated with ADHS (Figure 6F), indicating the beneficial effects of the APOE mimetic peptide in protecting neurons from pathological insults.”
Quote in the paperSubstantial claim - Findingown data
At day 70 of organoid development, PSEN1 mutant brain organoids have significantly higher levels of pTau compared to WT brain organoids.
“At day 70 of organoid development, we observed significantly higher levels of pTau in PSEN1 mutant brain organoids compared to WT brain organoids (Figures 7B and 7C).”
Quote in the paperSubstantial claim - Interpretationreasoning
APOECh microglia play a causal role in microglial neuroprotection.
“These findings demonstrate that the APOECh microglia plays a causal role in microglial neuroprotection, which can be exploited for therapeutic development for AD.”
Quote in the paperSubstantial claim- Rests on an assumption: Phenotypes observed in hiPSC-derived N-MG co-cultures and neuroimmune organoids are predictive of human AD pathogenesis and of APOECh-mediated neuroprotection in humans.
- Premisecitation
PSEN1 E280A mutant neurons produce more Aβ42 than WT neurons.
“Because PSEN1 E280A mutant neurons produce more Aβ42 than WT neurons,54 the elevated expression of ACSL1 in APOE3 microglia co-cultured with PSEN1 mutant but not WT neurons prompted us to investigate the role of Aβ42 in the induction of ACSL1 expression.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [54] Lemere, 1996, The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 deposition and severe cerebellar pathology, Nat. Med. source
- Interpretationown data
Reduced ferroptosis is a critical factor for enhanced phagocytosis in APOECh microglia.
“These results indicate that ferroptosis affects microglial phagocytosis and reduced ferroptosis is a critical factor for enhanced phagocytosis in APOECh microglia.”
Quote in the paperSubstantial claim - Interpretationown data
Ferroptosis affects microglial phagocytosis.
“These results indicate that ferroptosis affects microglial phagocytosis and reduced ferroptosis is a critical factor for enhanced phagocytosis in APOECh microglia.”
Quote in the paperSubstantial claim - Interpretationown data
The reduced pTau level in neurons co-cultured with APOECh microglia could be due to the enhanced phagocytosis capacity of APOECh microglia.
“Moreover, treatment of the N-MG co-cultures with the phagocytosis inhibitor cytochalasin D (cytoD) led to dramatically increased pTau level in neurons co-cultured with either APOE3 or APOECh microglia (Figures S5E and S5F), suggesting that the reduced pTau level in neurons co-cultured with APOECh microglia could be due to the enhanced phagocytosis capacity of APOECh microglia.”
Quote in the paperSubstantial claim - Interpretationown data
APOECh microglia are more effective at clearing oTau compared to APOE3 microglia.
“These results indicate that APOECh microglia are more effective at clearing oTau compared to APOE3 microglia.”
Quote in the paperSubstantial claim - Interpretationown data
Reduced phagocytosis in Aβ42-treated APOE3 microglia is caused by ferroptosis of microglia.
“The reduced phagocytosis in Aβ42-treated APOE3 microglia was correlated with reduced cell viability, which could be rescued by the treatment with the ferroptosis inhibitor Liproxstatin-1 (Figure S4), suggesting that the reduced phagocytosis is caused by ferroptosis of microglia.”
Quote in the paperSubstantial claim - Premisecitation
An APOE mimetic peptide spanning APOE amino acid residues 133-149 can block the interaction of APOE with its receptors.
“Because an APOE mimetic peptide spanning APOE amino acid residues 133–149 can block the interaction of APOE with its receptors,62 we asked whether the APOE mimetic peptide can mimic the APOECh protective effect.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [62] Laskowitz, 2001, Downregulation of microglial activation by apolipoprotein E and apoE-mimetic peptides, Exp. Neurol. source
- Interpretationown data
APOECh microglia have a protective role in PSEN1 mutant brain organoids by ameliorating pTau pathology.
“We found that APOECh microglia were much more effective in reducing pTau levels in PSEN1 mutant brain organoids than APOE3 microglia (Figures 7D–7H), indicating a protective role of APOECh microglia in PSEN1 mutant brain organoids by ameliorating pTau pathology.”
Quote in the paperSubstantial claim- Rests on an assumption: Phenotypes observed in hiPSC-derived N-MG co-cultures and neuroimmune organoids are predictive of human AD pathogenesis and of APOECh-mediated neuroprotection in humans.
- Interpretationown data
APOECh microglia could help neurons maintain their neural network integrity when challenged with ADHS.
“Additionally, we showed that APOECh microglia could help neurons to maintain their neural network integrity when challenged with ADHS.”
Quote in the paperSubstantial claim - Interpretationown data
The enhanced phagocytic capacity and Tau clearance by APOECh microglia could result from reduced ferroptosis.
“Treatment of APOE3 microglia-PSEN1 mutant neuron co-cultures with a ferroptosis inhibitor rescued the ability of APOE3 microglia to phagocytose synaptosome and clear oTau to a level similar to APOECh microglia, suggesting that the enhanced phagocytic capacity and Tau clearance by APOECh microglia could result from reduced ferroptosis.”
Quote in the paperSubstantial claim - Interpretationown data
The APOE mimetic peptide has beneficial effects in protecting neurons from pathological insults.
“Furthermore, the APOE mimetic peptide dramatically reduced the percentage of pTau+Tuj1+ neurons in both WT and PSEN1 mutant neurons treated with ADHS (Figure 6F), indicating the beneficial effects of the APOE mimetic peptide in protecting neurons from pathological insults.”
Quote in the paperSubstantial claim- Rests on an assumption: The APOE mimetic peptide's protective effects in the iPSC-derived N-MG co-culture model mimic the protective effects of APOECh microglia in humans.
- Interpretationown data
The Aβ42 peptide may be used to study amyloid-induced phenotypes in iPSC-derived cellular models.
“In this study, we showed that ACSL1 can be induced in APOE3 microglia co-cultured with PSEN1 neurons or treated with the Aβ42 peptide but were not induced in APOECh microglia under the same treatment condition, suggesting that the Aβ42 peptide may be used to study amyloid-induced phenotypes in iPSC-derived cellular models.”
Quote in the paperSubstantial claim - Interpretationown data
Inhibition of ferroptosis is critical for preserving phagocytosis capacity of microglia.
“By using a ferroptosis inhibitor, we showed that inhibition of ferroptosis is critical for preserving phagocytosis capacity of microglia.”
Quote in the paperSubstantial claim - Interpretationown data
RNA-seq analysis suggests a possible link between lipid metabolism, ferroptosis, and phagocytosis in microglia.
“Our RNA-seq analysis suggests a possible link between lipid metabolism, ferroptosis, and phagocytosis in microglia.”
Quote in the paperSubstantial claim - Premisecitation
Aβ42 can induce lipid droplet formation and lipid peroxidation in microglia.
“Recent studies have shown that Aβ42 can induce lipid droplet formation and lipid peroxidation in microglia.70”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [70] Prakash, 2023, Amyloid β Induces Lipid Droplet-Mediated Microglial Dysfunction in Alzheimer’s Disease, bioRxiv
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Study design and conductown data
DEGs enriched in the lipid metabolism and ferroptosis pathway were validated using qRT-PCR.
“We validated DEGs enriched in the lipid metabolism and the ferroptosis pathway using qRT-PCR.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 6
- May combine two claims. 17
- The quote only partly states this claim. 1
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAPOE4 has been linked to detrimental effects on lipid droplets in AD microglia through ACSL1.
“APOE4 has been linked to detrimental effects on lipid droplets in AD microglia through ACSL1.73”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [73] Haney, 2024, APOE4/4 is linked to damaging lipid droplets in Alzheimer's disease microglia, Nature source
May combine two claims.
PremisecitationoTau are neurotoxic and can induce neurodegeneration.
“It has been shown that oTau are neurotoxic and can induce neurodegeneration.58,67,68”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [58] Lasagna-Reeves, 2012, Identification of oligomers at early stages of tau aggregation in Alzheimer's disease, Faseb. J. source
- cites [67] Gómez-Ramos, 2006, Extracellular tau is toxic to neuronal cells, FEBS Lett. source
Section 3.1 reports that the recombinant tau preparation contained some oligomers, and Section 3.2 reports that tau preparations increased death in cultured neuroblastoma cells. The paper does not separately show that oligomeric tau (oTau) induced that cell death; its proposed spread of neurodegeneration to neighboring cells is a working hypothesis in the Discussion, not a demonstrated outcome. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [68] Kopeikina, 2012, Soluble forms of tau are toxic in Alzheimer's disease, Transl. Neurosci. source
The “Pathological forms of tau” section reports that injected tau oligomers caused synaptic deficits, mitochondrial dysfunction and memory impairments in mice, supporting their neurotoxicity. It also reports cell death from altered or overexpressed tau in vitro, but does not specifically show that tau oligomers induce neuronal death or broader neurodegeneration. (LLM, conf=0.82)
Experimental — accuracy not yet measured
May combine two claims.
FindingreasoningAPOECh microglia preserve phagocytic activity and promote pTau clearance.
“We show that APOECh microglia are resistant to Aβ-induced lipid peroxidation and ferroptosis and therefore preserve the phagocytic activity and promote pTau clearance, providing mechanistic insights into the neuroprotective role of APOE3Ch microglia.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAβ42 treatment reduces phagocytosis in APOE3 microglia while APOECh microglia preserve phagocytotic capacity.
“When treated with Aβ42, APOE3 microglia exhibited reduced phagocytosis, while APOECh microglia preserved their phagocytotic capacity (Figure 3J).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataoTau treatment enhances inflammatory response in APOE3 microglia co-cultured with both WT and PSEN1 mutant neurons, with a more dramatic increase in APOE3 microglia co-cultured with PSEN1 mutant neurons.
“Moreover, treatment with oTau enhanced the inflammatory response in APOE3 microglia co-cultured with both WT and PSEN1 mutant neurons, with more dramatic increase in APOE3 microglia co-cultured with PSEN1 mutant neurons.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataADHS treatment decreases neural network activity substantially in both WT and PSEN1 mutant neurons co-cultured with APOE3 microglia, with a more dramatic decrease in PSEN1 neurons.
“ADHS treatment decreased neural network activity substantially in both WT and PSEN1 mutant neurons co-cultured with APOE3 microglia, with more dramatic decrease in PSEN1 neurons.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataADHS treatment elevates total Tau level in neurons, with higher elevation in neurons co-cultured with APOE3 microglia than in neurons co-cultured with APOECh microglia.
“An elevation of total Tau level was also detected in neurons when the co-cultures were treated with ADHS, with higher elevation in neurons co-cultured with APOE3 microglia than that in neurons co-cultured with APOECh microglia (Figure S6D).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataAPOECh microglia are resistant to Aβ-induced ferroptosis, unlike APOE3 microglia, which succumbed to Aβ-induced ferroptosis.
“We found that APOECh microglia are resistant to Aβ-induced ferroptosis, unlike APOE3 microglia, which succumbed to Aβ-induced ferroptosis.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataACSL1 can be induced in APOE3 microglia co-cultured with PSEN1 neurons or treated with the Aβ42 peptide but is not induced in APOECh microglia under the same treatment condition.
“In this study, we showed that ACSL1 can be induced in APOE3 microglia co-cultured with PSEN1 neurons or treated with the Aβ42 peptide but were not induced in APOECh microglia under the same treatment condition, suggesting that the Aβ42 peptide may be used to study amyloid-induced phenotypes in iPSC-derived cellular models.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataAPOECh microglia could exert a protective effect by suppressing lipid droplet formation and ferroptosis but preserving phagocytosis function.
“These findings suggest that APOECh microglia could exert a protective effect by suppressing lipid droplet formation and ferroptosis but preserving the phagocytosis function.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataAPOECh microglia could protect neurons from pTau accumulation, presumably by preventing the propagation of ADHS-originated pTau across neurons through active phagocytosis.
“These results indicate that APOECh microglia could protect neurons from pTau accumulation, presumably by preventing the propagation of ADHS-originated pTau across neurons through active phagocytosis.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataAPOECh microglia can protect not only PSEN1 mutant neurons but also WT neurons that are subjected to AD insults.
“These results indicate that APOECh microglia can protect not only PSEN1 mutant neurons but also WT neurons that are subjected to AD insults.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningImpaired phagocytic activity could lead to an elevated level of pTau and collapse of the neural network.
“Impaired phagocytic activity could lead to an elevated level of pTau and collapse of the neural network.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataIn MEA experiments, neuronal activity was measured as a baseline control before microglia addition.
“We first seeded neurons onto MEA plates and measured their neuronal activity as the baseline control.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningAPOECh microglia are more effective in clearing toxic oTau, presumably due to their resilience to PSEN1 neuron-induced decline in phagocytic capacity.
“Our results indicate that APOECh microglia are more effective in clearing toxic oTau, presumably due to their resilience to PSEN1 neuron-induced decline in phagocytic capacity.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataAPOECh microglia are resistant to Aβ-induced lipid droplet accumulation, lipid peroxidation, and subsequent ferroptosis, thus preserving microglial phagocytic activity, which could in turn prevent pathological Tau propagation and reduce pTau levels in neurons.
“We have shown that APOECh microglia are resistant to Aβ-induced lipid droplet accumulation, lipid peroxidation, and subsequent ferroptosis, thus preserving microglial phagocytic activity, which could in turn prevent pathological Tau propagation and reduce pTau levels in neurons.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThe study included vehicle, the folic acid pathway inhibitor Alimta, and folic acid as controls for liproxstatin-1 treatment.
“We included vehicle, the folic acid pathway inhibitor Alimta, and folic acid as controls.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataLipid droplet dynamics and lipid peroxidation are important in microglial phagocytic activity and involve the ACSL1 gene.
“We have demonstrated the importance of lipid droplet dynamics and lipid peroxidation in microglial phagocytic activity and the involvement of the ACSL1 gene.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenG-banded karyotyping analysis was performed by the Cytogenetics Core at City of Hope.
“The G-banded karyotyping analysis was performed by the Cytogenetics Core at City of Hope.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataAPOECh microglia reduce pTau level in PSEN1 mutant brain organoids, presumably by clearing pTau spread or preventing pTau generation.
“Consistent with our findings in 2D co-cultures, we observed that APOECh microglia were able to reduce pTau level in PSEN1 mutant brain organoids, presumably by clearing pTau spread or preventing pTau generation.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenRNA quality control was performed by the Integrative Genomics Core at City of Hope.
“RNA quality control was performed by the Integrative Genomics Core at City of Hope.”
Quote in the paperNot a substantial claimMay combine two claims. The quote only partly states this claim.
Study design and conductown dataAPOE3 and APOECh microglia were derived from isogenic iPSC lines generated by CRISPR-Cas9 editing, controlling genetic background.
“To elucidate the role of APOECh variant in the pathogenesis of AD, we generated two isogenic APOECh iPSC lines from two control APOE3 (E3) iPSC lines by CRISPR-Cas9 editing and obtained a pair of isogenic APOECh and APOE3 iPSC lines from the Jackson laboratory (Figures 1A, 1B, and S1; Tables S1 and S2).”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductown dataThe tau oligomers (oTau) used in the experiments were validated by western blot analysis.
“tau oligomers were obtained by immunoprecipitation with anti-oligomer Tau antibody T22 (Sigma Aldrich, Cat. ABN454) from the PBS-soluble fractions and validated by western blot analysis.”
Quote in the paperSubstantial claim
The paper relies on this without support.
Phenotypes observed in hiPSC-derived N-MG co-cultures and neuroimmune organoids are predictive of human AD pathogenesis and of APOECh-mediated neuroprotection in humans.
“This mechanism of protection remains to be validated in human brain tissues from APOECh carriers.”
“In this study, we have demonstrated that the APOECh variant is causal to neuroprotection, extending the observation made in the 2019 single-patient study21 and providing strong rationale for developing potential AD therapies by targeting the protective APOECh variant and using the APOECh variant-carrying cells.”
The paper relies on this without support.
The APOE mimetic peptide's protective effects in the iPSC-derived N-MG co-culture model mimic the protective effects of APOECh microglia in humans.
“Our study provides a strategy that can protect individuals at risk, mimicking the protection provided by APOECh.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
E3S/S microglia show increased tau uptake and clearance.
“These findings suggest that E3S/S microglia show increased tau uptake and clearance, consistent with prior studies15,42.”
From The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway (2025) · cites this paper as [42]
The Results report greater oligomeric tau clearance by APOE3 Christchurch microglia in co-cultures with PSEN1-mutant neurons, but no significant clearance difference with wild-type neurons. They suggest enhanced phagocytosis as the mechanism; increased tau uptake by the microglia was not directly demonstrated. The claim omits that condition and presents uptake as an observed increase. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAPOE3Ch was reported to modulate immune-related pathways in tauopathy mice and in iPSC-derived microglia like cells.
“APOE3Ch was also reported to modulate immune-related pathways in tauopathy mice (Naguib et al., 2025) and in iPSC-derive microglia like cells (Sun et al., 2024).”
From APOE3-Christchurch variant enhances neurovascular support functions of iPSC-derived mesenchymal stromal cells (2026) · cites this paper as Sun et al., 2024
APOE3Ch microglia derived from human iPSC led to resistance to Aβ-induced lipid peroxidation and resulting ferroptosis.
“A recent study demonstrated that APOE3Ch microglia derived from human iPSC led to resistance to Aβ-induced lipid peroxidation and resulting ferroptosis [41].”
From Astrocytic APOE3-Christchurch expression ameliorates brain amyloid-β pathology in 5xFAD mice (2026) · cites this paper as [41]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Conflicting AD synaptosome incubation times before MEA recording
MajorThe MEA methods say AD synaptosomes were incubated with co-cultures for 2 days before recording, while the synaptosome-treatment methods specify 24 hours before MEA analysis.
“For AD synaptosome treatment, synaptosomes isolated from postmortem brain tissues of patients with AD were introduced into the N-MG cocultures and incubated for 2 days. After that neuronal activity was recorded and compared to the baseline recording.”
“For synaptosome treatment, we applied synaptosomes from patients with AD to the microglia alone or coculture of neurons and microglia at final concentration of 100 μg/mL for 24 h, followed by MEA analysis, phagocytosis assays, immunostaining, qRT-PCR and western blotting analysis.”
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ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer’s disease
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Amyloid β Induces Lipid Droplet‐Mediated Microglial Dysfunction in Alzheimer’s Disease
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Amyloid β Induces Lipid Droplet-Mediated Microglial Dysfunction in Alzheimer’s Disease
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Soluble CD93 is an apoptotic cell opsonin recognized by α x β 2
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Self-citationLipid composition dictates the rate of lipid peroxidation in artificial lipid droplets
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Regulation of NRAMP1 gene expression by 1alpha,25-dihydroxy-vitamin D(3) in HL-60 phagocytes.
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Self-citationContext matters: hPSC-derived microglia thrive in a humanized brain environment in vivo
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Self-citation
Flagged first, then by citations
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Protective ApoE variants support neuronal function by effluxing oxidized phospholipids
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Organoid–microglia system for modeling the immune microenvironment of the brain and retina
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Exercise mitigates Alzheimer’s disease by targeting ferroptosis driven by cellular senescence
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The Alzheimer disease continuum : findings from monogenic Alzheimer disease
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New mechanisms highlight the complex relationship of Apolipoprotein E and tau pathogenesis
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The Christchurch point mutation in mouse APOE reduces Aβ-induced tau and α-synuclein pathologiesPreprint
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- Authors
- Sun, G. G., Wang, C., Mazzarino, R. C., Perez-Corredor, P. A., Davtyan, H., Blurton-Jones, M., Lopera, F., Arboleda-Velasquez, J. F., & Shi, Y.
- Affiliations
- City Of Hope National Medical Center (US)
- Massachusetts Eye and Ear Infirmary (US)
- University of California, Irvine (US)
- Universidad de Antioquia (CO)
- Corresponding author
- Shi, Yanhong
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2024-12
- Volume
- 43
- Issue
- 12
- Pages
- 114982
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC11753789
- OpenAlex
- W4404772363
- Semantic Scholar
- db2eda1eccb98f0eda00a72d0ccf129aa33e6e43
- Cited by
- 36
- References
- 82
- Citations by year
- 2026: 24 · 2025: 11 · 2024: 1
- FWCI
- 10.25
- Type
- journal article
- Language
- en
- Update notices
- erratum (2026-08-25)
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute on Aging (P30 AG066530)
- National Institutes of Health (AG016573, RF1 AG079307, RF1 AG061794, R01 AG072291)
- Remondi Family Foundation
- Good Ventures Foundation
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- Alzheimer's disease, microglia, tau pathology, neuroprotection, ferroptosis, lipid peroxidation, amyloid-beta, phagocytosis, human induced pluripotent stem cells
- MeSH terms
- Ferroptosis, Alzheimer Disease, Humans, Neurons, Organoids, Phagocytosis, Lipid Peroxidation, Amyloid beta-Peptides, tau Proteins, Microglia, Coculture Techniques, Presenilin-1, Induced Pluripotent Stem Cells
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 2026-10-31.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-31.
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