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Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model
Open accessAbstract
Many risk genes for the development of Alzheimer’s disease (AD) are exclusively or highly expressed in myeloid cells. Microglia are dependent on colony-stimulating factor 1 receptor (CSF1R) signaling for their survival. We designed and synthesized a highly selective brain-penetrant CSF1R inhibitor (PLX5622) allowing for extended and specific microglial elimination, preceding and during pathology development. We find that in the 5xFAD mouse model of AD, plaques fail to form in the parenchymal space following microglial depletion, except in areas containing surviving microglia. Instead, Aβ deposits in cortical blood vessels reminiscent of cerebral amyloid angiopathy. Altered gene expression in the 5xFAD hippocampus is also reversed by the absence of microglia. Transcriptional analyses of the residual plaque-forming microglia show they exhibit a disease-associated microglia profile. Collectively, we describe the structure, formulation, and efficacy of PLX5622, which allows for sustained microglial depletion and identify roles of microglia in initiating plaque pathogenesis.
Overview
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TL;DR
PLX5622, a selective brain-penetrant CSF1R inhibitor, allowed sustained microglial depletion in 5xFAD mice and prevented parenchymal plaque formation, shifting Aβ deposition to cortical blood vessels. Residual plaque-forming microglia showed a disease-associated profile, and microglial repopulation restored plaque pathology.
Key findings
- PLX5622 showed >20-fold selectivity over KIT and FLT3, ~20% brain penetrance, and 1200 ppm chow reduced microglia by 90% within 5 days; treatment achieved 97–100% microglial reduction over 24 weeks and >99% cortical elimination.
- In 5xFAD mice, microglial depletion prevented dense-core parenchymal plaques except near surviving microglia in thalamus, retrosplenial cortex, and subiculum; cortical Aβ instead deposited in blood vessels as cerebral amyloid angiopathy. Plaque volumes were ~30–40% smaller, subicular plaque number was reduced by 33%, and plaque-core ApoE was reduced ~50–70%.
- Aβ38/40/42 levels and APP processing were unchanged, but hippocampal RNA-seq showed 413 differentially expressed genes in 5xFAD vs wild-type, including 77 downregulated synaptic/neuronal genes that were not downregulated when microglia were absent. Residual plaque-forming microglia expressed DAM markers such as Ccl6, Clec7a, Cst7, Ctsd, Ctsz, and Itgax.
- After PLX5622 withdrawal and microglial repopulation, plaque numbers in 5xFAD mice equaled untreated 5xFAD mice, though average plaque volumes remained smaller; vascular pathology persisted.
Methods
- Structure-guided design and synthesis of PLX5622 from PLX3397, with crystallography, kinase profiling, PK across mouse/rat/dog/monkey, and chow formulation.
- 5xFAD and 3xTg-AD mice; 5xFAD treatment began at 1.5 months for 10–24 weeks with groups Wild-type, PLX5622, 5xFAD, and 5xFAD + PLX5622 (n = 12/group, sex-balanced), plus behavioral, flow cytometry, histology, ELISA, immunoblot, and RNA-seq analyses (n = 4/group for RNA-seq).
- Human postmortem tissue from non-demented, high-pathology non-demented, and Alzheimer’s disease subjects was examined from middle frontal gyrus cortex.
Limitations
- The paper states no formal limitations section; it notes that no statistical methods were used to predetermine sample sizes and that data distribution was assumed normal but not formally tested.
- Evident from the text: findings rely on transgenic mouse models, and surviving microglia in thalamus, retrosplenial cortex, and subiculum complicate interpretation of region-specific plaque formation.
- Evident from the text: CAA and microbleeds appeared in microglia-depleted 5xFAD mice, and the long-term consequences of vascular Aβ deposition were not fully resolved.
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Figures
![Fig. 2 Design and synthesis schematic of the CSF1R inhibitor PLX5622 for extended microglial elimination. a Chemical structure of selective CSF1R inhibitor PLX5622. PLX5622 is structurally similar to CSF1R/KIT/FLT3 inhibitor PLX3397 with modifications concentrated on the two pyridine moieties. b X-ray crystal structure of the CSF1R-PLX5622 complex. PLX5622 is anchored to the active site of CSF1R by 3 hydrogen bonds (indicated by dashed lines). 7-Azaindole of PLX5622 forms two hydrogen bonds with the hinge region of CSF1R whereas the central pyridine ring forms a hydrogen bond with the main chain amino group of Phe796. The CSF1R selectivity is largely determined by the interaction between PLX5622 and Gly795 (represented as a sphere), which is a bulkier residue (cysteine) in KIT and FLT3. The substitutions on the tail pyridine ring also contribute to the selectivity. This group displaces the juxatemembrane (JM) region (absent in the structure) from the allosteric site. In contrast, PLX3397 binds CSF1R in the presence of the JM region. c Synthesis schematic for PLX5622 and subsequent formation of PLX5622-fumaric acid salt. PLX5622 was synthesized from commercially available 2-amino-6-fluoropyridine (1), 5-fluoro-2-methoxypyridine-3-carbaldehyde (2), and 3-iodo-5-methyl-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (7) using the reaction scheme. d Immunolabeling of microglia (IBA1 in green) and cell nuclei (DAPI in blue) of two-month-old animals treated with control or 1200 ppm PLX5622-formulated chow. Scale bar = 75 μm. E, Quantification of hippocampal microglial number over 5 days of treatment with PLX5622 (p < 0.001 for 3d and 5d). Two-way ANOVA with Dunnet’s post hoc test. n = 3 for Control, n = 3 for 3d PLX5622, n = 3 for 5d PLX5622. Statistical significance is denoted by ***p < 0.001. Error bars indicate SEM](/paper-figures/fc009b5c7b43408bb8cd7d0acb408552/sustained-microglial-depletion-with-csf1r-inhibitor-impairs-parenchymal-plaque-figure-2.jpg)
![Fig. 8 Remaining plaque-forming microglia in the microdissected hippocampus exhibit a DAM expression profile. a All gene expression changes where p < 0.05 for Wild-type (WT) vs. 5xFAD in all three brain regions shown as Log(2) fold change for each gene, for the 9 relevant comparisons (5xFAD vs. WT in cortex, hippocampus, or thalamus, 5xFAD + PLX5622 vs. 5xFAD in cortex, hippocampus, or thalamus, and WT + PLX5622 vs. WT in cortex, hippocampus, or thalamus). b RPKM values shown for a subset of the homeostatic microglial genes from (a), including Csf1r, Cx3cr1, C1qa, Hexb, Siglech, and Spi1. c RPKM values shown for a subset of the disease-associated microglial genes from (a), including Ccl6, Clec7a, Cst7, Ctsd, Ctsz, and Itgax. RPKM values for all genes/brain regions can be found at [https://rnaseq.mind.uci.edu/green/ad_plx/gene_search.php]. n = 4 per group for all analyses. Error bars indicate SEM](/paper-figures/4e52b3b2bcf84bfcab3cea3037f5ad7f/sustained-microglial-depletion-with-csf1r-inhibitor-impairs-parenchymal-plaque-figure-8.jpg)
![Fig. 10 Microglia seed plaques. All analyses listed in respective order for retrosplenial (RS) cortex, somatosensory (SS) cortex, and thalamus. a Experimental design: 1.5-month-old wild-type (WT) and 5xFAD mice were administered PLX5622 (1200 ppm in chow) until 4 months of age. Diet was withdrawn for 1 month to allow microglial repopulation. This figure was created with images adapted from Servier Medical Arts and is licensed under the Creative Commons Attribution 3.0 Unported License [https://creativecommons.org/licenses/by/3.0/]. b Representative hemisphere stitches of sections stained for dense core plaques (Thio-S in green) and immunolabeled for microglia (IBA1 in red). Scale bar = 1000 μm. c–e Images of dense-core plaque staining (Thio-S in green) and microglia immunolabeling (IBA1 in red). Scale bar = 100 μm for C,D; 25 μm for E. f, IBA1+ cell number (WT v 5xFAD, p = 0.001, NS, p < 0.001; WT v PLX5622, p < 0.001, p < 0.001, p < 0.001; 5xFAD v 5xFAD + PLX5622, p < 0.001, p < 0.001, p < 0.001; PLX5622 v Repopulation, NS, p = 0.054, p = 0.008; 5xFAD + PLX5622 v 5xFAD + Repopulation, p = 0.006, p < 0.001, p < 0.001; WT v Repopulation, NS, p = 0.002, NS; 5xFAD v 5xFAD + Repopulation, p < 0.001, p < 0.001, p = 0.027; Repopulation v. 5xFAD + Repopulation, NS, NS, p < 0.001). Two-way ANOVA with Tukey’s post hoc test; n = 5 for Wild-type, n = 4 for PLX5622, n = 4 for Wild-type + Repopulation, n = 8 for 5xFAD, n = 9 for 5xFAD + PLX5622, n = 6 for 5xFAD + Repopulation. g Quantification of Thio-S+ plaque number (5xFAD v 5xFAD + PLX5622, p < 0.001, p < 0.001, p = 0.007; 5xFAD + PLX5622 v 5xFAD + Repopulation, p < 0.001, p < 0.001, p = 0.001; 5xFAD v 5xFAD + Repopulation, NS, NS, NS). One-way ANOVA with Tukey’s post hoc test; n = 7 for 5xFAD, n = 9 for 5xFAD + PLX5622, n = 6 for 5xFAD + Repopulation. h Mean cortical plaque volumes (5xFAD v 5xFAD + Repopulation, p = 0.048). Two-tailed independent t-test; n = 7 for 5xFAD, n = 6 for 5xFAD + Repopulation. I Images of dense-core plaques (Thio-S in blue) and astrocytes with GFAP (in green) and S100β (in red). Scale bar = 100 μm. j GFAP+ astrocyte number in the SS cortex (WT v 5xFAD, p = 0.010; 5xFAD v 5xFAD + PLX5622, p = 0.002; 5xFAD + PLX5622 v 5xFAD + Repopulation, p < 0.001; WT + Repopulation v 5xFAD + Repopulation, p < 0.009). Two-way ANOVA with Tukey’s post hoc test; n = 4 for Wild-type, n = 4 for PLX5622, n = 4 for Wild-type + Repopulation, n = 7 for 5xFAD, n = 10 for 5xFAD + PLX5622, n = 6 for 5xFAD + Repopulation. Statistical significance is denoted by *p < 0.05, **p < 0.01, and ***p < 0.001. NS, not significant (p > 0.10). Error bars indicate SEM](/paper-figures/cbf2ea4d61fc4961bff1db5f926a49d0/sustained-microglial-depletion-with-csf1r-inhibitor-impairs-parenchymal-plaque-figure-10.jpg)
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91 Own result · 28 Own interpretation · 27 Not checked yet · 5 No basis given · 1 Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“PLX5622 was formulated in rodent chow, and administration to mice showed highly effective, causing a 90% reduction with 1200 ppm chow within 5 days of treatment (Fig. 2d, e).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Development of a CSF1R inhibitor for microglial elimination
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“Oral PLX5622 treatment led to almost complete microglial elimination (97–100% reduction; Fig. 3c and quantified in e and f), even with 24 weeks of treatment, showing that PLX5622 allows for extended elimination of microglia.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Absence of abnormalities with microglial elimination
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“Transcriptional analyses of the residual plaque-forming microglia show they exhibit a disease-associated microglia profile.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Abstract
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“Cell free kinase inhibitor profiling revealed that PLX5622 is highly specific for the CSF1R, showing > 20-fold selectivity over KIT and FLT3, the two most homologous receptors (Supplementary Table 2, 3).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Development of a CSF1R inhibitor for microglial elimination
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In the paper
“We found significant elevations in full-length (fl) APP and Carboxy-terminal fragments of APP (C99 and C83) in 5xFAD mice relative to wild-type (Fig. 5k, l), but observed no reductions in protein levels with PLX5622 treatment in 5xFAD animals.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial elimination impairs plaque formation
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“Notably, a band of plaques were found in the RS cortex, but these were primarily associated with microglia that had survived treatment (Fig. 4d). Plaques were also formed within the thalamus but were again predominantly associated with surviving microglia (Fig. 4j).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial elimination impairs plaque formation
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“Investigations into oligomeric species of Aβ (via A11 immunoblotting) found no significant changes in protein levels with microglia elimination in 5xFAD mice (Fig. 5i, j).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial elimination impairs plaque formation
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In the paper
“Additionally, gene expression analyses of AD-related genes were performed (Fig. 5m; methods described in greater detail for Figs 8, 9) and we found minimal changes with microglia depletion, other than in microglial expressed genes (i.e., Trem2, Spi1, Inpp5d, and Ctsd).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial elimination impairs plaque formation
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“Immunolabeling for the endothelial tight junction marker, Claudin-5, revealed an increase in Thio-S positive blood vessel diameter (Supplementary Figure 7I–K), consistent with prior data26, and reduced intensity of Claudin-5 staining in Aβ-associated blood vessels (Supplementary Figure 7L), suggesting impaired vascular integrity in the presence of Aβ pathology.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial elimination impairs plaque formation
What the sources say
- Not checked yetcites [26] Tian, J., Shi, J., Smallman, R., Iwatsubo, T. & Mann, D. M. Relationships in Alzheimer’s disease between the extent of Abeta deposition in cerebral blood vessel walls, as cerebral amyloid angiopathy, and the amount of cerebrovascular smooth muscle cells and collagen. Neuropathol. Appl Neurobiol. 32, 332–340 (2006). source
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In the paper
“Staining for pyroglutamate-3 Aβ, which forms the plaque cores23, revealed a sharp reduction in immunoreactivity in PLX5622-treated 5xFAD mice in the cortex (Fig. 4p; Supplementary Figure 6G–H), along with reductions in 6E10+ diffuse plaques (Fig. 4o; Supplementary Figure 6G–H).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial elimination impairs plaque formation
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“Average plaque volumes were ~30–40% smaller, across many brain regions (Fig. 4n), suggesting that microglia contribute to plaque growth in the 5xFAD brain.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial elimination impairs plaque formation
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In the paper
“Immunolabeling for the endothelial tight junction marker, Claudin-5, revealed an increase in Thio-S positive blood vessel diameter (Supplementary Figure 7I–K), consistent with prior data26, and reduced intensity of Claudin-5 staining in Aβ-associated blood vessels (Supplementary Figure 7L), suggesting impaired vascular integrity in the presence of Aβ pathology.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial elimination impairs plaque formation
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In the paper
“Close examination of the Thioflavin-S (Thio-S) stained slices revealed deposits beginning to form within cortical blood vessels (Fig. 4d, g – yellow arrows).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial elimination impairs plaque formation
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In the paper
“Astrocytes surrounding plaques in the cortex of 7-month-old 5xFAD mice appeared activated, as assessed by GFAP immunoreactivity, which usually is absent in the cortex of non-diseased brains (Supplementary Figure 5A–B).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial elimination impairs plaque formation
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“With microglial elimination, these behaviors were further exacerbated (Fig. 3g, h).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Absence of abnormalities with microglial elimination
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In the paper
“plaques fail to form in the parenchymal space following microglial depletion, except in areas containing surviving microglia.”
- Also stated in: § Microglial elimination impairs plaque formation · plain
“In the absence of microglia, we observed a stark lack of dense-core plaques within cortical regions (quantified in Fig. 4l; retrosplenial (RS) and somatosensory (SS) cortices examined).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Abstract
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- Also stated in: § Microglial elimination impairs plaque formation · plain
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In the paper
“Notably, abundant Thio-S staining was discovered within large cortical blood vessels in the 5xFAD mice devoid of microglia (i.e., Fig. 4e, h), indicative of cerebral amyloid angiopathy (CAA).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial elimination impairs plaque formation
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In the paper
“While PLX5622 treatment reduced myeloid cell numbers in the subiculum (77% reduction; Fig. 6e), we observed a tight spatial association between surviving cells and Thio-S plaques (Fig. 6b, d), similar to that seen in the thalamus of the 10-week treated 5xFAD mice (Fig. 4j).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial plaque compaction ameliorates neuritic dystrophy
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In the paper
“Thus, even with increased treatment duration to 7 months of age, plaque formation is prevented in the absence of microglia.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial elimination impairs plaque formation
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“g–i Confocal images of dense-core plaques (Thio-S in green) and microglia (IBA1 in red) in the cortex, thalamus, and subiculum, respectively, of both 5xFAD groups showing an alteration in plaque morphology with CSF1R inhibitor treatment.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial plaque compaction ameliorates neuritic dystrophy
plaincorrelationaln = 6- Asserted: passes — The authors put it forward as true.
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In the paper
“Thus, microglia in plaque forming regions in mouse and human brains can accumulate aggregated Aβ intracellularly”
- Also stated in: § Microglia contain Aβ aggregates in AD mouse models and humans · plain
“we again found non-plaque-associated microglia containing Aβ aggregates”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglia contain Aβ aggregates in AD mouse models and humans
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- Also stated in: § Microglia contain Aβ aggregates in AD mouse models and humans · plain
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In the paper
“Compared to wild-type animals, 5xFAD mice showed reduced anxiety-related behaviors compared to controls in the elevated plus maze (EPM; Fig. 3g, h).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Absence of abnormalities with microglial elimination
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In the paper
“Upon examining caudal brain regions, we found some IBA1+ cells present within the subiculum and associated white matter tracts in the otherwise microglia-devoid 5xFAD animals (mice treated through 1.5–7 months of age; Fig. 6a, b).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial plaque compaction ameliorates neuritic dystrophy
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In the paper
“Altered gene expression in the 5xFAD hippocampus is also reversed by the absence of microglia.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Abstract
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None of the sources cited for this claim have been checked yet.
In the paper
“In the MWM probe trial, PLX5622-treated wild-type mice tended to spend more time in the platform zone compared to wild-type mice (Fig. 3k), indicating that the long-term absence of microglia is not detrimental to murine cognitive function and may be beneficial, at least in this assay, which is consistent with our prior findings17,18.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Absence of abnormalities with microglial elimination
What the sources say
- Not checked yetcites [17] Elmore, M. R. et al. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 82, 380–397 (2014). source
- Not checked yetcites [18] Rice, R. A. et al. Elimination of Microglia Improves Functional Outcomes Following Extensive Neuronal Loss in the Hippocampus. J. Neurosci. 35, 9977–9989 (2015). source
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In the paper
“In the brain, 5xFAD mice displayed increased numbers of microglia/myeloid cells at both 4 and 7 months of age compared to wild-type mice, with masses of enlarged, plaque-associated cells seen throughout the brain (Fig. 3c).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Absence of abnormalities with microglial elimination
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In the paper
“While PLX5622 treatment reduced myeloid cell numbers in the subiculum (77% reduction; Fig. 6e), we observed a tight spatial association between surviving cells and Thio-S plaques (Fig. 6b, d), similar to that seen in the thalamus of the 10-week treated 5xFAD mice (Fig. 4j).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial plaque compaction ameliorates neuritic dystrophy
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In the paper
“Quantification of Thio-S+ subicular plaques revealed a 33% decrease in plaque number (Fig. 6f) with PLX5622 treatment in 5xFAD mice.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial plaque compaction ameliorates neuritic dystrophy
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In the paper
“The absence of microglia did not significantly alter the levels of Aβ38, Aβ40, or Aβ42, in detergent-soluble or -insoluble cortical and thalamic homogenates in either the 4- or 7- month cohorts (Fig. 5a–h), in line with multiple studies showing that CSF1R inhibition does not affect Aβ production/clearance10,27,28.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial elimination impairs plaque formation
What the sources say
- Not checked yetcites [10] Spangenberg, E. E. et al. Eliminating microglia in Alzheimer’s mice prevents neuronal loss without modulating amyloid-beta pathology. Brain 139, 1265–1281 (2016). source
- Not checked yetcites [27] Dagher, N. N. et al. Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice. J. Neuroinflamm. 12, 139 (2015). source
- Not checked yetcites [28] Olmos-Alonso, A. et al. Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology. Brain 139, 891–907 (2016). source
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In the paper
“Consistent with the 10-week treated 5xFAD mice, examination of pathology in the 24 week treated mice revealed diminished Thio-S+ dense-core plaque numbers in the cortices of the 5xFAD mice devoid of microglia (Fig. 4e, h; quantified in M).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial elimination impairs plaque formation
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In the paper
“The absence of microglia for 24 weeks in wild-type mice did not induce any measurable negative effects in animal behavior, including tests of anxiety (elevated plus maze; Fig. 3g, h) and motor-function (open field; Supplementary Figure 3A–D).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Absence of abnormalities with microglial elimination
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“In vivo PLX5622 demonstrated desirable PK properties in mice, rats, dogs, and monkeys (Supplementary Table 5), with a brain penetrance of ~20% (compared to ~5% for PLX339717; Supplementary Table 6).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Development of a CSF1R inhibitor for microglial elimination
What the sources say
- Not checked yetcites [17] Elmore, M. R. et al. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 82, 380–397 (2014). source
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In the paper
“In contrast, GFAP expression was sharply reduced in 5xFAD mice devoid of microglia (Supplementary Figure 5A–C).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial elimination impairs plaque formation
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In the paper
“Staining for pyroglutamate-3 Aβ, which forms the plaque cores23, revealed a sharp reduction in immunoreactivity in PLX5622-treated 5xFAD mice in the cortex (Fig. 4p; Supplementary Figure 6G–H), along with reductions in 6E10+ diffuse plaques (Fig. 4o; Supplementary Figure 6G–H).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial elimination impairs plaque formation
What the sources say
- Not checked yetcites [23] Harigaya, Y. et al. Amyloid beta protein starting pyroglutamate at position 3 is a major component of the amyloid deposits in the Alzheimer’s disease brain. Biochem Biophys. Res Commun. 276, 422–427 (2000). source
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In the paper
“Examination for microbleeds in 4- (Supplementary Figure 7A–D) and 7- (Supplementary Figure 7E–H) month cohorts of mice revealed notable iron deposits in the thalamus of four treated 5xFAD mice (2 animals/cohort).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial elimination impairs plaque formation
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In the paper
“We found significant elevations in full-length (fl) APP and Carboxy-terminal fragments of APP (C99 and C83) in 5xFAD mice relative to wild-type (Fig. 5k, l), but observed no reductions in protein levels with PLX5622 treatment in 5xFAD animals.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial elimination impairs plaque formation
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In the paper
“Using PLX5622, we were able to eliminate > 95% of microglia from the brains of 5xFAD mice prior to and during the formation of AD pathology – a treatment duration of up to 6 months - and elucidate their roles in plaque formation.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Discussion
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In the paper
“First, the 2-fluoro substitution on the middle pyridine ring of PLX5622 is designed to access the CSF1R-unique space next to Gly-795 (a gate-keeper to the interior allosteric pocket); both KIT and FLT3 have a bulkier cysteine at the equivalent position.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Development of a CSF1R inhibitor for microglial elimination
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In the paper
“Two key structural differences between PLX5622 and PLX3397 contribute to the improved selectivity based on crystallographic analysis (Fig. 2b; Supplementary Table 4).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Development of a CSF1R inhibitor for microglial elimination
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In the paper
“We quantified ApoE immunoreactivity in Thio-S dense core plaques in the cortex and thalamus, revealing a ~50–70% reduction in core ApoE (Fig. 6n).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial plaque compaction ameliorates neuritic dystrophy
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In the paper
“Furthermore, from our extended cohort of 5xFAD mice devoid of microglia, we know that plaque formation is severely diminished in treated 5xFAD animals, even by 7 months of age (Fig. 4e, h, m).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial repopulation seeds plaques
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In the paper
“Once formed, these plaques persist thereafter, even long after plaque-associated microglia are eliminated.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Discussion
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In the paper
“These microglia are most apparent in the thalamus, retrosplenial cortex, and subiculum.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Discussion
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In the paper
“Structural examination of the plaques that had formed in PLX5622-treated 5xFAD mice (treated through 1.5–7 months of age), presumably due to the presence of surviving microglia at the time of their formation, revealed morphological differences compared to plaques formed and maintained in the presence of microglia (Fig. 6g–i).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial plaque compaction ameliorates neuritic dystrophy
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In the paper
“Analyses of downregulated pathways in 5xFAD vs. wild-type hippocampi revealed that the most highly significant pathways were related to neuronal functioning, such as glutamate receptors, synaptic vesicles, and neuronal membranes (Fig. 9f).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Gene expression analyses across three brain regions
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In the paper
“Importantly, many of these pathways were upregulated – or more accurately, never downregulated – with the absence of microglia (Fig. 9f), indicating that microglia influence neuronal gene expression pathways in response to AD pathology.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Gene expression analyses across three brain regions
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In the paper
“Notably, vascular pathology was still present in the repopulated brains (Fig. 10d), showing that the reintroduction of microglia does not reverse the vascular deposition of Aβ, at least within this one-month timeframe.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial repopulation seeds plaques
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In the paper
“Colocalization with the microglia/myeloid marker IBA1 revealed that these ApoE positive processes were indeed microglia (Fig. 6l), confirming that plaque-associated microglia are a source of ApoE30.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial plaque compaction ameliorates neuritic dystrophy
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In the paper
“Second, the terminal pyridine group of PLX5622 is optimized to stabilize the allosteric pocket of CSF1R vacated by the displaced juxtamembrane domain.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Development of a CSF1R inhibitor for microglial elimination
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In the paper
“Of note, the expression of homeostatic microglial genes was higher in the 5xFAD + PLX5622 hippocampus than other microdissected brain regions (or wild-type mice), reflecting the population of surviving microglia identified in the subiculum (Fig. 6d).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Gene expression analyses across three brain regions
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In the paper
“To evaluate the role of microglia in regulating the growth of dystrophic neurites, we stained for LAMP1 (Fig. 6o) and APP (Fig. 6q) and found that the absence of microglia enhanced the dystrophic neurite halo area (Fig. 6p, r).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial plaque compaction ameliorates neuritic dystrophy
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In the paper
“Here, we find that plaque formation is prevented in the absence of microglia, even over extended periods of time.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Discussion
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In the paper
“In the absence of microglia, this disease-associated downregulation of neuronal and synaptic genes was prevented (Fig. 9e), highlighting the detrimental role microglia may have on hippocampal plasticity in the 5xFAD brain.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Gene expression analyses across three brain regions
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In the paper
“Consistent with these genes being predominantly expressed by microglia, their expression was markedly reduced with treatment in either 5xFAD or wild-type mice. We selected a subset of homeostatic microglial genes (Csf1r, Cx3cr1, C1qa, Hexb, Siglech, and Spi1) and displayed the expression (RPKM) values for each of the brain regions (Fig. 8b). The expression of these genes was nearly undetectable”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Gene expression analyses across three brain regions
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In the paper
“We identified expression of Ccl6, Clec7a, Cst7, Ctsd, Ctsz, and Itgax as main genes that follow this expression pattern (Fig. 8c), as well as Asb10, B2m, Ccl3, Ch25h, Gpr65, Grn, Hcar2, Hexa, Ly9, Lyz2, Oasl2, Pdcd1, Plcg2, and Treml2.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Gene expression analyses across three brain regions
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In the paper
“Although we confirmed that the absence of microglia/treatment with PLX5622 did not alter the amount of Aβ produced, we wanted to explore the impact of pathology and microglia on genes associated with APP processing, Aβ clearance and metabolism, and AD in general (Fig. 5m).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Gene expression analyses across three brain regions
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In the paper
“The absence of microglia prevented many of these changes in 5xFAD mice, despite the continued presence of hippocampal plaques, due to a small population of surviving myeloid cells in the subiculum.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Discussion
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In the paper
“Here, we observe aggregated Aβ within the lysosome of ramified microglia distal to plaques in two different mouse models of AD (Fig. 1), as well as the human brain (Supplementary Figure 1).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Discussion
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In the paper
“RNA-seq analysis revealed that nearly all significantly altered genes, in 5xFAD compared to WT mice, were associated with microgliosis in the cortex and thalamus, while the hippocampus displayed reductions in gene expression associated with neuronal and synaptic function.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Discussion
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In the paper
“RNA-seq analysis revealed that nearly all significantly altered genes, in 5xFAD compared to WT mice, were associated with microgliosis in the cortex and thalamus, while the hippocampus displayed reductions in gene expression associated with neuronal and synaptic function.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Discussion
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In the paper
“In accordance, we find that plaque growth ceases in the absence of microglia, consistent with recent data demonstrating microglial cellular death as a contributor to plaque growth59, suggesting a mechanism by which microglia deliver Aβ to the plaque seed/core.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Discussion
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In the paper
“Notably, we find hippocampal gene expression is greatly influenced by the presence of AD pathology relative to the cortex and thalamus, despite abundant plaque load in all these regions.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Discussion
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“In conclusion, we have designed and created a specific CSF1R inhibitor, PLX5622, that allows for the sustained and specific elimination of microglia.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Discussion
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In the paper
“The absence of microglia prevented many of these changes in 5xFAD mice, despite the continued presence of hippocampal plaques, due to a small population of surviving myeloid cells in the subiculum.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Discussion
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In the paper
“Notably, the absence of microglia is associated with no alterations in immune- and synapse-related genes, suggesting that microglia mediate most AD pathology-induced changes in gene expression.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Discussion
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In the paper
“Many risk genes for the development of Alzheimer’s disease (AD) are exclusively or highly expressed in myeloid cells.”
- Also stated in: § Introduction · plain
“Several of the top identified risk-conveying genes are highly enriched in myeloid cells (CR1, CD33, ABCA7, TREM2, MS4A, EPHA1, SPI14–6), highlighting the link between myeloid biology and the risk for developing AD.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Abstract
What the sources say
- Not checked yetcites [4] Naj, A. C. et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat. Genet. 43, 436–441 (2011). source
- Not checked yetcites [5] Guerreiro, R. et al. TREM2 variants in Alzheimer’s disease. N. Engl. J. Med. 368, 117–127 (2013). source
- Not checked yetcites [6] Huang, K. L. et al. A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer’s disease. Nat. Neurosci. 20, 1052–1061 (2017). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Introduction · plain
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In the paper
“Despite this response, however, Aβ clearance and plaque modulation/dynamics is unaffected10–12”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Introduction
What the sources say
- Not checked yetcites [10] Spangenberg, E. E. et al. Eliminating microglia in Alzheimer’s mice prevents neuronal loss without modulating amyloid-beta pathology. Brain 139, 1265–1281 (2016). source
- Not checked yetcites [11] Grathwohl, S. A. et al. Formation and maintenance of Alzheimer’s disease beta-amyloid plaques in the absence of microglia. Nat. Neurosci. 12, 1361–1363 (2009). source
- Not checked yetcites [12] Jankowsky, J. L. et al. Persistent amyloidosis following suppression of Abeta production in a transgenic model of Alzheimer disease. PLoS Med 2, e355 (2005). source
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In the paper
“As we previously demonstrated, microglia are critically dependent on CSF1R signaling for their survival17”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Development of a CSF1R inhibitor for microglial elimination
What the sources say
- Not checked yetcites [17] Elmore, M. R. et al. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 82, 380–397 (2014). source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“suggesting that microglia contribute to plaque growth in the 5xFAD brain.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial elimination impairs plaque formation
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In the paper
“suggesting impaired vascular integrity in the presence of Aβ pathology.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial elimination impairs plaque formation
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In contrast to the extracellular space, microglial lysosomes provide a suitable environment to facilitate Aβ aggregation, potentially contributing to the onset of plaque pathology15.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglia contain Aβ aggregates in AD mouse models and humans
What the sources say
- Not checked yetcites [15] Hu, X. et al. Amyloid seeds formed by cellular uptake, concentration, and aggregation of the amyloid-beta peptide. Proc. Natl. Acad. Sci. USA 106, 20324–20329 (2009). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“These data suggest that microglia regulate astrocyte reactivity in disease, fully consistent with previous reports19,20.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial elimination impairs plaque formation
What the sources say
- Not checked yetcites [19] Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017). source
- Not checked yetcites [20] Pascual, O., Ben Achour, S., Rostaing, P., Triller, A. & Bessis, A. Microglia activation triggers astrocyte-mediated modulation of excitatory neurotransmission. Proc. Natl. Acad. Sci. USA 109, E197–E205 (2012). source
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In the paper
“Notably, vascular pathology was still present in the repopulated brains (Fig. 10d), showing that the reintroduction of microglia does not reverse the vascular deposition of Aβ, at least within this one-month timeframe.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial repopulation seeds plaques
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In the paper
“Thus, microglia surrounding plaques are a major source of plaque-associated ApoE, supporting recent findings30,31.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial plaque compaction ameliorates neuritic dystrophy
What the sources say
- Not checked yetcites [30] Parhizkar, S. et al. Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat Neurosci (2019). source
- Not checked yetcites [31] Krasemann, S. et al. The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases. Immunity 47, 566–581 e9 (2017). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In addition, we show that microglia are necessary for the development of plaques - these findings are supported by recent data showing that plaque seeding is accelerated in Trem2 knockout mice30, suggesting that microglial functions involved in the initial formation of plaques are related to TREM2 signaling.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Discussion
What the sources say
- Not checked yetcites [30] Parhizkar, S. et al. Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat Neurosci (2019). source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Importantly, many of these pathways were upregulated – or more accurately, never downregulated – with the absence of microglia (Fig. 9f), indicating that microglia influence neuronal gene expression pathways in response to AD pathology.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Gene expression analyses across three brain regions
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In the paper
“In addition, we show that microglia are necessary for the development of plaques - these findings are supported by recent data showing that plaque seeding is accelerated in Trem2 knockout mice30, suggesting that microglial functions involved in the initial formation of plaques are related to TREM2 signaling.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Discussion
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In the paper
“Thus, peripheral CSF1R inhibition or simply the presence of CSF1R inhibitor within the CNS do not attribute to the reductions in plaque pathology and more complete microglial elimination is necessary to perturb plaque formation processes.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Alternative CSF1R inhibitor confirms diminished plaque load
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In the paper
“We established that PLX3397 formulated at 600 ppm in chow could achieve robust brain-wide microglial elimination ( > 99%)38, and thus, treated 1.5-month-old 5xFAD mice with this formulation until 5 months of age (Fig. 7a).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Alternative CSF1R inhibitor confirms diminished plaque load
What the sources say
- Not checked yetcites [38] Najafi, A. R. et al. A limited capacity for microglial repopulation in the adult brain. Glia (2018). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The improved blood-brain barrier (BBB) penetrance of PLX5622 over PLX3397 is consistent with the physicochemical properties of the two compounds (Supplementary Table 7).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Development of a CSF1R inhibitor for microglial elimination
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In the absence of microglia, this disease-associated downregulation of neuronal and synaptic genes was prevented (Fig. 9e), highlighting the detrimental role microglia may have on hippocampal plasticity in the 5xFAD brain.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Gene expression analyses across three brain regions
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In the paper
“Thus, the reintroduction of microglia in the 5xFAD brain via CSF1R inhibitor withdrawal coincides with a full restoration of plaque pathology and implicate the reappearance of microglia in the brain with the seeding and formation of plaques.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial repopulation seeds plaques
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“These features were common to all areas explored, including in the subiculum, where some IBA1+ cells were still present, suggesting that some threshold density of microglial cells may be required for full plaque compaction/restructuring.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial plaque compaction ameliorates neuritic dystrophy
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In the paper
“Thus, our results demonstrate that plaque onset relies on the presence and activity of microglia.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Discussion
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In the paper
“Thus, the reintroduction of microglia in the 5xFAD brain via CSF1R inhibitor withdrawal coincides with a full restoration of plaque pathology and implicate the reappearance of microglia in the brain with the seeding and formation of plaques.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial repopulation seeds plaques
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Thus, both AD pathology and the absence of microglia have minimal effects on AD-related genes, and importantly, we observe no alterations in gene expression or protein production in the absence of microglia that could account for reduced plaque formation.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Gene expression analyses across three brain regions
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Colocalization with the microglia/myeloid marker IBA1 revealed that these ApoE positive processes were indeed microglia (Fig. 6l), confirming that plaque-associated microglia are a source of ApoE30.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial plaque compaction ameliorates neuritic dystrophy
What the sources say
- Not checked yetcites [30] Parhizkar, S. et al. Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat Neurosci (2019). source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In accordance, we find that plaque growth ceases in the absence of microglia, consistent with recent data demonstrating microglial cellular death as a contributor to plaque growth59, suggesting a mechanism by which microglia deliver Aβ to the plaque seed/core.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Discussion
What the sources say
- Not checked yetcites [59] Baik, S. H., Kang, S., Son, S. M. & Mook-Jung, I. Microglia contributes to plaque growth by cell death due to uptake of amyloid beta in the brain of Alzheimer’s disease mouse model. Glia 64, 2274–2290 (2016). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Although plaque-associated microglia may protect against local neurite damage, the presence of microglia is also required for the reduction in expression of synaptic and neuronal genes in the hippocampus associated with AD.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This novel method of microglial depletion provided us with the means to eliminate microglia for the duration of AD pathogenesis.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Notably, the absence of microglia is associated with no alterations in immune- and synapse-related genes, suggesting that microglia mediate most AD pathology-induced changes in gene expression.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The absence of microglia prevented many of these changes in 5xFAD mice, despite the continued presence of hippocampal plaques, due to a small population of surviving myeloid cells in the subiculum.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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- Probably not a substantial claim. 10
- It may state two separate claims as one. 54
Every source the paper cites for this claim was checked and supports it.
In the paper
“These results are consistent with prior studies showing that microglia form a physical barrier around plaques and compact Aβ into dense deposits, protecting against local neurite damage35–37.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial plaque compaction ameliorates neuritic dystrophy
What the sources say
- Supportedcites [35] Condello, C., Yuan, P., Schain, A. & Grutzendler, J. Microglia constitute a barrier that prevents neurotoxic protofibrillar Abeta42 hotspots around plaques. Nat. Commun. 6, 6176 (2015). source
The Discussion describes microglial envelopment as a physical barrier that promotes plaque compaction and associates greater coverage with fewer dystrophic neurites. The Results also report that increased microglial coverage reduced local neurotoxicity, chiefly around smaller plaques. (LLM, conf=0.92)
- Supportedcites [36] Wang, Y. et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J. Exp. Med 213, 667–675 (2016). source
The Concluding remarks report that microglia form a physical barrier around Aβ plaques, creating compact regions, and that uncovered, less compact regions are associated with more severe axonal dystrophy. The paper’s own findings also link less dense plaques in TREM2-deficient mice with increased neuritic dystrophy. (LLM, conf=0.93)
- Supportedcites [37] Yuan, P. et al. 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). source
The Introduction describes microglial processes wrapping around plaques to form a physical barrier, promoting compact plaque regions; adjacent axons show less dystrophy where microglia cover the plaque. The Discussion reports that microglial envelopment may induce fibril compaction and reduce exposure of surrounding neural structures to potentially neurotoxic fibrils. No page numbers are available in our copy. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The appearance of CAA occurred only in microglia-depleted 5xFAD mice, as CAA was not observed in untreated 5xFAD mice or in treated wild-type mice.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial elimination impairs plaque formation
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It may state two separate claims as one.
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In the paper
“Treatment of 5xFAD mice with PLX5622 again reduced > 99% of microglia in the cortex (Fig. 4d, g), but as noted in wild-type mice, a fraction of cells remained in the thalamus (Fig. 4j).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial elimination impairs plaque formation
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Absolute numbers of astrocytes were not highly affected by pathology or microglial depletion, as measured by S100β+ cells (quantified in Supplementary Figure 5D), except for a small increase in the RS cortex in 5xFAD mice.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial elimination impairs plaque formation
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“With an additional 14 weeks of treatment (i.e., 24 weeks treated animals), microglia were eliminated brain wide (Fig. 4e, k), but Thio-S plaques persisted in these areas (i.e., the thalamus and RS cortex).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial elimination impairs plaque formation
plain- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“In addition to Thio-S, CAA and plaques stained postiviely for Aβ fibrils, via the conformation specific antibody OC21 (Fig. 4r; Supplementary Figure 6C–D) and Aβ42 (Fig. 4s; Supplementary Figure 6E–F), but were negative for Aβ oligomers via A11 antibody22 (Fig. 4q; Supplementary Figure 6A–B).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial elimination impairs plaque formation
What the sources say
- Not checked yetcites [21] Kayed, R. et al. Fibril specific, conformation dependent antibodies recognize a generic epitope common to amyloid fibrils and fibrillar oligomers that is absent in prefibrillar oligomers. Mol. Neurodegener. 2, 18 (2007). source
- Not checked yetcites [22] Kayed, R. et al. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300, 486–489 (2003). source
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Of note, pyroglutamate-3 immunoreactivity was found in areas of treated 5xFAD mice that exhibited plaque pathology (i.e., thalamus; Supplementary Figure 6I–J).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial elimination impairs plaque formation
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“To assess hippocampal-dependent memory, mice underwent testing using Y-Maze, Morris water maze (MWM), and Contextual fear conditioning (CFC) and 5xFAD animals did not show impairments in any of these tasks (Supplementary Figure 3E–G; Fig. 3i–k).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Absence of abnormalities with microglial elimination
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In wild-type mice, CSF1R inhibitor treatment for 10 weeks eliminated > 99% of microglia in the cortex (Fig. 4a–f), but a fraction of cells remained in the thalamus (Fig. 4i; enlarged in Supplementary Figure 4).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial elimination impairs plaque formation
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In fact, plaques were predominantly observed in the immediate vicinity of surviving IBA1+ cells – within the subiculum and associated white matter tract – while the cortex contained only vascular Thio-S+ deposits, in stark contrast to untreated 5xFAD mice (Fig. 6a vs. b).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial plaque compaction ameliorates neuritic dystrophy
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“PLX5622 has lower molecular weight, higher lipophilicity and better cell permeability, all factors known to influence the ability of a compound to cross the BBB.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Development of a CSF1R inhibitor for microglial elimination
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“While some plaques form in specific brain areas with treatment, we find that these few remaining plaques are associated with a small subset of microglia initially resistant to CSF1R-inhibition.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These features were common to all areas explored, including in the subiculum, where some IBA1+ cells were still present, suggesting that some threshold density of microglial cells may be required for full plaque compaction/restructuring.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial plaque compaction ameliorates neuritic dystrophy
hedged- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These plaques displayed an irregular shape with structured filaments radiating out from a central fissure/point and lacked the homogenous staining intensity of plaques in microglia-intact 5xFAD mice.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial plaque compaction ameliorates neuritic dystrophy
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Again, examination of the brains of these treated mice showed minimal plaque pathology and the appearance of CAA (Fig. 7c, d – zoomed image of CAA in D).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Alternative CSF1R inhibitor confirms diminished plaque load
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As demonstrated previously, untreated 5xFAD mice exhibit cortical plaques at 4 months of age, but 5xFAD mice devoid of microglia show reduced plaque formation (Fig. 4d, g, l).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial repopulation seeds plaques
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Transgene expression in 5xFAD mice (consisting of App, Psen1, and Thy1) was increased by ~2-fold over endogenous expression across brain regions (Fig. 9b) and was not impacted by treatment, consistent with the protein expression data (Fig. 5k, l).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Gene expression analyses across three brain regions
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As such, both plaque circularity (Fig. 6j) and mean Thio-S intensities (Fig. 6k) were reduced in the 5xFAD mice devoid of microglia.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial plaque compaction ameliorates neuritic dystrophy
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Enrichment analyses of the hippocampus revealed an upregulation in immune function-associated pathways in 5xFAD vs. wild-type, and accordingly, these pathways were all highly significantly downregulated with PLX5622 treatment (Fig. 9f).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Gene expression analyses across three brain regions
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Microglia repopulated all areas of the brain in both wild-type and 5xFAD mice (Fig. 10b), although overall densities were lower than the untreated mice in cortical regions (Fig. 10c, d; quantified in F).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial repopulation seeds plaques
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Consistent with this, ApoE immunoreactivity was apparent within dense core plaques, but also in cellular processes surrounding the cores (Fig. 6l).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial plaque compaction ameliorates neuritic dystrophy
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We compared the number of differentially expressed genes (adjusted p-values < 0.05) induced by AD pathology in each of the three microdissected brain regions (i.e., wild-type vs. 5xFAD) and found that the hippocampus was most impacted (413 genes), while both cortex and thalamus exhibited fewer changes in gene expression (141 and 107 genes respectively; Fig. 9a).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Gene expression analyses across three brain regions
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This lower dose achieved brain levels of ~1 μM, compared to ~10 μM with the higher dose (Fig. 7b), and accordingly, microglia numbers were unchanged relative to untreated animals (Fig. 7e–i).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Alternative CSF1R inhibitor confirms diminished plaque load
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, examination of microglia-repopulated 5xFAD brains revealed the appearance of robust plaque pathology (Fig. 10d) with plaque numbers being equal to the untreated 5xFAD mice (Fig. 10g), although average plaque volumes were smaller (Fig. 10h).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial repopulation seeds plaques
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“All common genes were upregulated and the vast majority are microglia-associated, reflecting the microgliosis occurring in 5xFAD mice.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Gene expression analyses across three brain regions
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The only significant changes in gene expression in 5xFAD mice compared to wild-type were the upregulation of the transgenes (App and Psen1; as expected due to overexpression), and Apoe, all of which were not altered by the absence of microglia, and the downregulation of myeloid-expressed Trem2, Ctsb, Ctsc, and Ctsd in the absence of microglia, as expected.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Gene expression analyses across three brain regions
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Repopulating microglia associate with the new plaques but do not appear to react to the vascular deposits (Fig. 10e).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial repopulation seeds plaques
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Accordingly, overlapping microglia genes were increased and neuronal genes decreased in 5xFAD mice compared to wild-type mice, which did not occur with PLX5622 treatment (Supplementary Figure 9).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Gene expression analyses across three brain regions
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Consistent with our expectations, we detected expression of many of these genes (i.e., Ccl6, Clec7a, and Cst7) in PLX5622-treated 5xFAD hippocampi (but not cortex or thalamus), reflecting the population of surviving microglia in this region (see images of subicula in Fig. 6c–d, which are included in microdissected hippocampi) and providing a gene expression signature of plaque-forming/associated”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Gene expression analyses across three brain regions
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Moreover, GFAP+ astrocytes associated with plaques in both control and repopulated 5xFAD brains (Fig. 10i, j), but were absent in 5xFAD brains devoid of microglia.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial repopulation seeds plaques
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“To that end, we designed and created PLX5622, which shows high selectivity for the CSF1R (Supplementary Table 2), desirable PK characteristics across species (mouse, rat, dog, monkey; Supplementary Table 5) including oral bioavailability, a > 20% brain penetrance (Supplementary Table 6), and rapid/sustained elimination of microglia (Figs 2, 3).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Discussion
What the sources say
- Not checked yetcites Supplementary Table 2
- Not checked yetcites Supplementary Table 5
- Not checked yetcites Supplementary Table 6
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The hippocampus displayed a unique gene expression profile relative to the cortex and thalamus and included a unique subset of downregulated genes.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Gene expression analyses across three brain regions
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Comparisons of changes in expression between brain regions showed regional differences in Ache, Apoe, Ptk2b, Sorl1, and Sort1.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Gene expression analyses across three brain regions
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Examination of ApoE immunoreactivity in microglia-devoid 5xFAD mice showed that the ApoE+ microglial processes surrounding dense core plaques were absent, as expected, but also the plaque cores themselves lacked ApoE staining (Fig. 6m).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial plaque compaction ameliorates neuritic dystrophy
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“With 75 ppm PLX3397, no reductions in plaque load or appearance of CAA were detected in treated 5xFAD animals compared to controls (Fig. 7f, h, j–k).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Alternative CSF1R inhibitor confirms diminished plaque load
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Of note, only 1 downregulated gene was identified in the cortex and none were detected in the thalamus.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Gene expression analyses across three brain regions
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Of the 413 identified genes, 77 were downregulated in the 5xFAD hippocampus (Fig. 9c, and individual genes plotted in D). Notably, these transcripts were primarily synaptic and neuronal in nature, including genes such as Dlk2, Dync1l1, Gls, Kcnq3, Nrg3, and Scn1b.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Gene expression analyses across three brain regions
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Ultimately, these data demonstrate that microglial elimination is associated with the prevention of plaque formation and the downregulation of hippocampal neuronal genes that occur in a preclinical model of AD progression.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Discussion
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“indicating that the long-term absence of microglia is not detrimental to murine cognitive function and may be beneficial, at least in this assay, which is consistent with our prior findings17,18.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Absence of abnormalities with microglial elimination
What the sources say
- Not checked yetcites [17] Elmore, M. R. et al. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 82, 380–397 (2014). source
- Not checked yetcites [18] Rice, R. A. et al. Elimination of Microglia Improves Functional Outcomes Following Extensive Neuronal Loss in the Hippocampus. J. Neurosci. 35, 9977–9989 (2015). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Importantly, these results highlight a clear relationship between microglia/myeloid cells and the appearance of plaques, suggesting a role of microglia/myeloid cells in facilitating plaque formation, and emphasizes that few cells are required for this process to occur.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial plaque compaction ameliorates neuritic dystrophy
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, the absence of microglia modulates the location of Aβ accumulation (i.e., parenchyma vs. vasculature) but does not alter the net amounts present.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial elimination impairs plaque formation
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results suggest that microglia may be critical regulators of plaque formation and that few surviving microglial cells are sufficient to facilitate some degree of plaque formation (i.e., as seen in the thalamus).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial elimination impairs plaque formation
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results implicate microglia as critical and causative in the development and progression of multiple facets of AD pathology.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Introduction
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“yet the removal of the microglia at advanced stages of pathology protects against synaptic and neuronal loss10.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Introduction
What the sources say
- Not checked yetcites [10] Spangenberg, E. E. et al. Eliminating microglia in Alzheimer’s mice prevents neuronal loss without modulating amyloid-beta pathology. Brain 139, 1265–1281 (2016). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“The aggregation of Aβ is an initial step in the formation of plaques, requiring an acidic pH13 and micromolar concentrations of Aβ monomers14.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglia contain Aβ aggregates in AD mouse models and humans
What the sources say
- Not checked yetcites [13] Su, Y. & Chang, P. T. Acidic pH promotes the formation of toxic fibrils from beta-amyloid peptide. Brain Res 893, 287–291 (2001). source
- Not checked yetcites [14] Tseng, B. P. et al. Deposition of monomeric, not oligomeric, Abeta mediates growth of Alzheimer’s disease amyloid plaques in human brain preparations. Biochemistry 38, 10424–10431 (1999). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The extracellular space does not meet these requisite conditions, suggesting that Aβ aggregation originates elsewhere.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglia contain Aβ aggregates in AD mouse models and humans
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The expression of these genes was nearly undetectable from PLX5622-treated mice, highlighting their specific expression by microglia and the specificity of PLX5622 on microglial survival.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Gene expression analyses across three brain regions
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Data presented here show that long-term PLX5622-mediated microglial depletion is highly robust, sustainable, and specific to the microglial compartment.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Discussion
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Dystrophic neurites are found in a halo around fibrillar plaques and are characterized by the accumulation of LAMP1 and APP32–34.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial plaque compaction ameliorates neuritic dystrophy
What the sources say
- Not checked yetcites [32] Andrew, R. J. et al. Lack of BACE1 S-palmitoylation reduces amyloid burden and mitigates memory deficits in transgenic mouse models of Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 114, E9665–e9674 (2017). source
- Not checked yetcites [33] Cummings, B. J. et al. Aggregation of the amyloid precursor protein within degenerating neurons and dystrophic neurites in Alzheimer’s disease. Neuroscience 48, 763–777 (1992). source
- Not checked yetcites [34] Gowrishankar, S. et al. Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques. Proc. Natl. Acad. Sci. USA 112, E3699–E3708 (2015). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“While microglia can be indefinitely depleted via the continued administration of CSF1R inhibitors, the microglial compartment can also be repopulated upon CSF1R inhibitor withdrawal17,40,41.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial repopulation seeds plaques
What the sources say
- Not checked yetcites [17] Elmore, M. R. et al. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 82, 380–397 (2014). source
- Not checked yetcites [40] Elmore, M. R. P. et al. Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice. Aging Cell 17, e12832 (2018). source
- Not checked yetcites [41] Rice, R. A. et al. Microglial repopulation resolves inflammation and promotes brain recovery after injury. Glia 65, 931–944 (2017). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Notably, several of these genes are known markers of disease-associated microglia39 (DAM).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Gene expression analyses across three brain regions
What the sources say
- Not checked yetcites [39] Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290 e17 (2017). source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“We further examined the role of peripheral CSF1R inhibition on AD pathology by treating 1.5-month-old 5xFAD mice until 5 months of age with PLX3397 (75 ppm) chow (Fig. 7a) – a formulation that provides robust peripheral CSF1R inhibition without microglial elimination17.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Alternative CSF1R inhibitor confirms diminished plaque load
What the sources say
- Not checked yetcites [17] Elmore, M. R. et al. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 82, 380–397 (2014). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, both AD pathology and the absence of microglia have minimal effects on AD-related genes, and importantly, we observe no alterations in gene expression or protein production in the absence of microglia that could account for reduced plaque formation.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Gene expression analyses across three brain regions
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Most importantly, CSF1R inhibition is the only currently available method capable of achieving sustained long-term microglial elimination.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, peripheral CSF1R inhibition or simply the presence of CSF1R inhibitor within the CNS do not attribute to the reductions in plaque pathology and more complete microglial elimination is necessary to perturb plaque formation processes.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Alternative CSF1R inhibitor confirms diminished plaque load
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Focusing on plaque structure, we next evaluated the presence of ApoE within plaque cores – previous reports describe the coaggregation of ApoE with Aβ fibrils in both plaques and vascular pathology29,30.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial plaque compaction ameliorates neuritic dystrophy
What the sources say
- Not checked yetcites [29] Liao, F. et al. Murine versus human apolipoprotein E4: differential facilitation of and co-localization in cerebral amyloid angiopathy and amyloid plaques in APP transgenic mouse models. Acta Neuropathol. Commun. 3, 70 (2015). source
- Not checked yetcites [30] Parhizkar, S. et al. Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat Neurosci (2019). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Therefore, microglia appear to have complex and contrasting roles within AD61, namely their facilitation of plaque formation, plaque growth, plaque compaction, and neuronal damage.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Discussion
What the sources say
- Not checked yetcites [61] Moore, Z., Taylor, J. M. & Crack, P. J. The involvement of microglia in Alzheimer’s disease: a new dog in the fight. Br. J. Pharmacol. (2018). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results indicate that microglia appear to contribute to multiple facets of AD etiology – microglia appear crucial to the initial appearance and structure of plaques, and following plaque formation, promote a chronic inflammatory state modulating neuronal gene expression changes in response to Aβ/AD pathology.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“No statistical methods were used to predetermine sample sizes; however, our sample sizes are similar to those reported in recently published similar studies10,28.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Methods > Statistics
What the sources say
- Not checked yetcites [10] Spangenberg, E. E. et al. Eliminating microglia in Alzheimer’s mice prevents neuronal loss without modulating amyloid-beta pathology. Brain 139, 1265–1281 (2016). source
- Not checked yetcites [28] Olmos-Alonso, A. et al. Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology. Brain 139, 891–907 (2016). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, microglia appear to have detrimental and beneficial roles in a preclinical model of AD.”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Plaque-associated microglia may protect against local neurite damage.
The paper relies on this without support.
5xFAD mice exhibit plaque pathology from 3 months of age.
“To that end, 5xFAD animals, which exhibit plaque pathology from 3 months of age, underwent treatment at 1.5 months of age with PLX5622-formulated chow (1200 ppm) or control diet continuously for either 10–24 weeks.”
The paper relies on this without support.
The 5xFAD mouse model is a valid model of Alzheimer's disease pathology relevant to human AD.
“We find that in the 5xFAD mouse model of AD, plaques fail to form in the parenchymal space following microglial depletion, except in areas containing surviving microglia.”
The paper relies on this without support.
Plaque-associated microglia may protect against local neurite damage.
“Although plaque-associated microglia may protect against local neurite damage, the presence of microglia is also required for the reduction in expression of synaptic and neuronal genes in the hippocampus associated with AD.”
The authors state this as an assumption.
Data distribution is normal.
“Data distribution was assumed to be normal, but this was not formally tested.”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Our results are in line with studies showing that reduced microglial colocalization with β-amyloid is associated with a reduced β-amyloid burden (D’Errico et al., 2022; Spangenberg et al., 2019).”
From A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation (2023) · cites this paper as Spangenberg et al., 2019
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In support of this interpretation, previous studies have shown that microglial depletion can have beneficial effects in transgenic mice that model AD hallmarks, including reduction in brain accumulation of both amyloid-β and tau (Sosna et al., 2018; Spangenberg et al., 2019).”
From A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation (2023) · cites this paper as Spangenberg et al., 2019
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“It enables sustained microglial depletion without breaching the BBB, without toxicity and without initiating an inflammatory response, as seen with other microglial depletion methods [295, 299, 331].”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [295]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“microglia depletion before or after the formation of Aβ pathology in mouse models of AD resulted in improved contextual memory”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [295]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“TREM2, a receptor expressed by DAM/MGnD, which exerts its protective function in AD via ligation of ApoE (apolipoprotein E), which binds to loose Aβ aggregates, or direct ligation of Aβ oligomers [286, 295, 338, 357, 366]”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [295]
Experimental — accuracy not yet measured
The cited source says what the claim attributes to it.
In the citing paper
“Aβ aggregates were found within the lysosomes of microglia in brain regions where plaques were not yet formed in non-PLX5622-treated 5xFAD mice [295]”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [295]
The cited source says what the claim attributes to it.
In the citing paper
“a fraction of microglia in the thalamus were resistant to 10 weeks of PLX5622 treatment and were associated with the few plaques that had formed [295]”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [295]
The cited source says what the claim attributes to it.
In the citing paper
“Microglial ablation using PLX3397 in two-month-old 5xFAD mice [294] or PLX5622 in 1.5-month-old 5xFAD [295] mice prevented intraneuronal amyloid and neuritic plaque formation [294] and significantly reduced plaque formation [295], respectively”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [295]
The cited source says what the claim attributes to it.
In the citing paper
“Thus, even a small number of microglial cells are sufficient to initiate plaque pathology.”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [295]
The cited source says what the claim attributes to it.
In the citing paper
“gene expression analysis showed that pathways related to neuronal function (i.e., glutamate receptors, synaptic vesicles, and neuronal membranes), were downregulated in the hippocampus of 5xFAD mice [295]”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [295]
The cited source says what the claim attributes to it.
In the citing paper
“further implicating microglia in neuronal and/or synaptic loss [294–296]”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [295]
The cited source says what the claim attributes to it.
In the citing paper
“This pattern was reversed in the absence of microglia”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [295]
The cited source says what the claim attributes to it.
In the citing paper
“suggesting that these cells restrict gene expression pathways crucial to neuronal function in AD [295]”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [295]
The cited source says what the claim attributes to it.
In the citing paper
“In this context, microglia appear crucial to the initial appearance and structure of plaques and, following plaque formation, promote a chronic inflammatory state modulating neuronal gene expression changes in response to Aβ during AD pathology [84].”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [84]
The cited source says what the claim attributes to it.
In the citing paper
“Similarly, Spangenberg et al. observed a reduction in dense-core plaques in the cortex of the same mouse model following chronic administration of an inhibitor of microglial proliferation [84].”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [84]
In the citing paper
“the microglial response to amyloid plaques and/or tau pathology is increasingly thought to cause or contribute heavily to disease-related neurodegeneration [10], [11], [12], [13].”
From Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain (2020) · cites this paper as [12]
In the citing paper
“Microglia from these mice have been extensively characterized, revealing the canonical upregulation of disease-associated microglial markers (e.g. Cst7, Axl, Trem2, Apoe, Ctss) and loss of homoestatic markers (P2ry12, Tmem119) that reflect disease-related changes in form and function [12, 50, 51].”
From Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain (2020) · cites this paper as [12]
In the citing paper
“Microglial depletion also enhances performance in certain memory tasks [12, 14, 16] and prevents the forgetting of remote memories, and in association, the dissociation of memory engram cells in healthy adult mice [18].”
From Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain (2020) · cites this paper as [12]
In the citing paper
“We previously reported that neuronal and synaptic genes (e.g. Dlk2, Kcnq3, Nrg3, Scn1b) and related functional pathways (e.g. synaptic vesicles, glutamate receptors, neuronal membranes) were extensively and uniquely downregulated in the 7mo 5xFAD hippocampus compared to WT hippocampus and other 5xFAD brain regions [12], respectively, in addition to a loss of subiculum neurons and dendritic spines”
From Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain (2020) · cites this paper as [12]
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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial plaque compaction ameliorates neuritic dystrophy
“while the cortex contained only vascular Thio-S+ deposits, in stark contrast to untreated 5xFAD mice (Fig. 6a vs. b).”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial elimination impairs plaque formation
“With an additional 14 weeks of treatment (i.e., 24 weeks treated animals), microglia were eliminated brain wide (Fig. 4e, k), but Thio-S plaques persisted in these areas (i.e., the thalamus and RS cortex).”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial elimination impairs plaque formation
“With an additional 14 weeks of treatment (i.e., 24 weeks treated animals), microglia were eliminated brain wide (Fig. 4e, k)”
§ Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model > Results > Microglial plaque compaction ameliorates neuritic dystrophy
“Upon examining caudal brain regions, we found some IBA1+ cells present within the subiculum and associated white matter tracts in the otherwise microglia-devoid 5xFAD animals (mice treated through 1.5–7 months of age; Fig. 6a, b).”
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Alzheimer Disease: An Update on Pathobiology and Treatment Strategies
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Systematic phenotyping and characterization of the 5xFAD mouse model of Alzheimer’s disease.
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Self-citation
Metadata
- Authors
- Spangenberg, E., Severson, P. L., Hohsfield, L. A., Crapser, J., Zhang, J., Burton, E. A., Zhang, Y., Spevak, W., Lin, J., Phan, N. Y., Habets, G., Rymar, A., Tsang, G., Walters, J., Nespi, M., Singh, P., Broome, S., Ibrahim, P., Zhang, C., Bollag, G., West, B. L., & Green, K. N.
- Affiliations
- University of California, Irvine (US)
- Plexxikon (United States) (US)
- Corresponding author
- Green, Kim N.
- ORCID
- Venue
- Nature Communications
- Published
- 2019-08-21
- Volume
- 10
- Issue
- 1
- Pages
- 3758-3758
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6704256
- OpenAlex
- W2969940182
- Semantic Scholar
- 3e694fe2e99a78fdb9cd33e218acd99a93cc12a0
- Cited by
- 939
- References
- 71
- Citations by year
- 2026: 114 · 2025: 122 · 2024: 201 · 2023: 139 · 2022: 137 · 2021: 132 · 2020: 82 · 2019: 10
- FWCI
- 39.95
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion, cc-by)
- Funders
- U.S. Department of Energy (-AC02-05CH11231, 05CH11231, DE AC02 05CH11231, DE-AC02-)
- Alzheimer's Association (AARF-16-442762)
- National Institutes of Health (DE-AC02–05CH11231)
- Office of Science (DEAC02–05CH11231, AC02-05CH11231, DE-AC02)
- National Institute on Aging (R01 AG056768, T32 AG00096, P50AG016573, F31AG059367, RF1AG056768, T32AG000096)
- National Institute of Neurological Disorders and Stroke (R01NS083801, R01AG056768)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- Alzheimer's disease, microglia, CSF1R inhibition, PLX5622, microglial depletion, amyloid plaques, 5xFAD mice, cerebral amyloid angiopathy, amyloid-beta deposition, disease-associated microglia, hippocampus
- MeSH terms
- Alzheimer Disease, Animals, Behavior, Animal, Brain, Disease Models, Animal, Gene Expression Regulation, Hippocampus, Humans, Memory, Mice, Transgenic, Organic Chemicals, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Microglia, Mice, Plaque, Amyloid, Transcriptome
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.
A language model drew the claims from the paper on 2026-10-06, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-06 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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