The DOI matches its Crossref record; 73 of the 73 references it cites were found in a registry or an index; none of the 69 sources its claims cite is checked for support yet.
Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease
Open accessAbstract
Glia have been implicated in Alzheimer’s disease (AD) pathogenesis. Variants of the microglia receptor triggering receptor expressed on myeloid cells 2 (TREM2) increase AD risk, and activation of disease-associated microglia (DAM) is dependent on TREM2 in mouse models of AD. We surveyed gene-expression changes associated with AD pathology and TREM2 in 5XFAD mice and in human AD by single-nucleus RNA sequencing. We confirmed the presence of Trem2-dependent DAM and identified a previously undiscovered Serpina3n+C4b+ reactive oligodendrocyte population in mice. Interestingly, remarkably different glial phenotypes were evident in human AD. Microglia signature was reminiscent of IRF8-driven reactive microglia in peripheral-nerve injury. Oligodendrocyte signatures suggested impaired axonal myelination and metabolic adaptation to neuronal degeneration. Astrocyte profiles indicated weakened metabolic coordination with neurons. Notably, the reactive phenotype of microglia was less evident in TREM2-R47H and TREM2-R62H carriers than in non-carriers, demonstrating a TREM2 requirement in both mouse and human AD, despite the marked species-specific differences. Single-nucleus RNA sequencing in a mouse model of Aβ accumulation and postmortem brain tissue from people with Alzheimer’s disease reveals substantial species-specific differences in transcriptional signatures, but both point to the contribution of glia and the importance of TREM2.
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128 Own result · 38 Not checked yet · 29 Own interpretation · 21 Own method · 2 No basis given
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“Notably, the microglia cluster was much larger in the 5XFAD cortex than in the Trem2−/− 5XFAD and non-5XFAD cortices”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > snRNA-seq reveals a Trem2-dependent microgliosis at early stages of Aβ accumulation
plaincorrelationaln = 3- Asserted: passes — The authors put it forward as true.
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In the paper
“We confirmed the presence of Trem2-dependent DAM”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“the reactive phenotype of microglia was less palpable in TREM2 R47H and R62H carriers than in non-carriers”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“the Trem2−/− 5XFAD cortex contained a neuronal cluster with significantly fewer UMIs but relatively high expression of peptidylglycine alpha-amidating monooxygenase (Pam)”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > snRNA-seq reveals a Trem2-dependent microgliosis at early stages of Aβ accumulation
plaincorrelationaln = 3- 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.
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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
“the difference between microglial clusters in 5XFAD and Trem2−/− 5XFAD cortices was minimal at this stage”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > snRNA-seq reveals a Trem2-dependent microgliosis at early stages of Aβ accumulation
plainn = 3- Asserted: passes — The authors put it forward as true.
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In the paper
“identified a novel Serpina3n+C4b+ reactive oligodendrocyte population in mice.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Abstract
plain- Asserted: passes — The authors put it forward as true.
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“Co-staining for either Serpina3n or C4b along with nuclear Olig2 showed perinuclear expression of Serpina3n and C4b in oligodendrocyte lineage cells of 5XFAD and Trem2−/− 5XFAD brains”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > snRNA-seq reveals an Aβ-dependent oligodendrocyte reactive signature
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Volcano plot of 5XFAD vs WT oligodendrocytes in 7-month-old mice revealed a significant upregulation of three genes in particular – the complement component C4b, the serine protease inhibitor Serpina3n, and MHC-I (H2-D1) – in 5XFAD brains”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > snRNA-seq reveals an Aβ-dependent oligodendrocyte reactive signature
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“5XFAD brains contained more Olig2+ nuclei indicative of oligodendrocyte lineage cells than did non-5XFAD brains”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > snRNA-seq reveals an Aβ-dependent oligodendrocyte reactive signature
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Oligodendrocytes harbored the most strikingly upregulated genes.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > snRNA-seq reveals an Aβ-dependent oligodendrocyte reactive signature
plain- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 53
- Probably not a substantial claim. 55
- The quote only partly states this claim. 1
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 human AD-associated signature was present in aged controls, and highly upregulated during disease.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > Human brain AD gene signatures are distinct from those of the 5XFAD model
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
“the proportion of astrocytes was increased in AD compared to control samples, indicating reactive astrocytosis”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > Human brain AD gene signatures are distinct from those of the 5XFAD model
hedgedcorrelational- 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.
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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
“Other DAM gene homologues were either similarly expressed in AD and control samples (TYROBP), not detected (CST7, GPNMB, LPL), or even downregulated (SPP1) in human AD microglia”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > Human brain AD gene signatures are distinct from those of the 5XFAD model
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
“sub-cluster 1 was highly represented in 5XFAD mice, less so in Trem2−/− 5XFAD mice and barely detectable in WT and Trem2−/− mice”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > DAM signature is Trem2-dependent at early and late stages of Aβ accumulation
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
“We found that addition of C4b to Aβ42 peptides strongly accelerated aggregation of Aβ; Serpina3n alone modestly promoted aggregation at high Aβ42 concentrations and did not synergize with C4b”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > snRNA-seq reveals an Aβ-dependent oligodendrocyte reactive signature
boosteddirect- 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
“We also detected little colocalization of Serpina3n with astrocytes (Extended Data Fig. 4j) and Aβ plaques”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > snRNA-seq reveals an Aβ-dependent oligodendrocyte reactive signature
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
“In the microglia cluster, genes normally considered as ‘homeostatic” in mouse (TMEM119, P2RY12, CX3CR1) were, in fact, notably upregulated in AD compared to controls (Fig. 4c), along with higher expression of the transcription factor IRF8.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > Human brain AD gene signatures are distinct from those of the 5XFAD model
plaincorrelational- 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
“OPCs strongly upregulated C4b, with a fold change and p-value similar to oligodendrocyte activation genes”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > Transcriptional changes in neuronal and other non-neuronal populations in response to Aβ are minimal
boostedcorrelational- 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.
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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
“Increased expression of C4b and Serpina3n was partially dependent on Trem2 in 7-month-old (Extended Data Fig. 4a) but not in 15-month-old mice”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > snRNA-seq reveals an Aβ-dependent oligodendrocyte reactive signature
plainconditional- 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
“DAM genes, including Cst7, Csf1, Apoe, Trem2, Lpl, Lilrb4a, MHC-I (H2-d1), MHC-II (Cd74), and various cathepsin genes were notably upregulated in 5XFAD compared to WT mice. Homeostatic genes, such as P2ry12, Selplg, Tmem119, and Cx3cr1 were downregulated.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > DAM signature is Trem2-dependent at early and late stages of Aβ accumulation
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
“Astrocytes upregulated Gfap and C4b, but to a lesser extent than did oligodendrocytes”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > Transcriptional changes in neuronal and other non-neuronal populations in response to Aβ are minimal
plaincorrelational- 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.
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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 analyzed a total of 66,311 individual nuclei with a median of 1,312 genes per nucleus”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > Human brain AD gene signatures are distinct from those of the 5XFAD model
plainn = 66,311- 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
“overexpression of Irf8 in mouse microglia-like cell cultures upregulated the expression of P2RY12, which was conversely reduced in Irf8−/− cells”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > Human brain AD gene signatures are distinct from those of the 5XFAD model
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
“we demarcated 6 sub-clusters (Astro0-5) of astrocytes and confirmed the contraction of Astro3 in AD samples”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > The astrocyte signature indicates increase in glial scaring and loss of metabolic coordination between neurons and astrocytes
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
“Expression of AD-reactive oligodendrocyte genes was lower in AD R62H carriers than in AD CV carriers, yet was significantly higher in AD R62H carriers than in controls”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > Brain signatures of AD carrying TREM2 variants demonstrate reduced microglial response
plaincorrelationaln = 10- 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
“Upregulated genes, such as CA2, marked sub-cluster Oligo3, while downregulated genes such as MIR219A2, delineated clusters Oligo1 and Oligo2.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > AD-reactive oligodendrocytes reflect functional and metabolic adaptation to axonal degeneration
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
“R47H brains also had elevated expression of genes involved in oxidative stress and lipid metabolism, along with decreased expression of genes involved in autophagy, growth factor signaling, and neural connectivity”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > Brain signatures of AD carrying TREM2 variants demonstrate reduced microglial response
plaincorrelationaln = 5- 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
“NanoString data confirmed increased expression of microglia IRF8, and oligodendrocyte CA2 in AD compared to controls”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > Whole brain nCounter mRNA analysis corroborates AD glial signatures and verifies neuronal loss
plaincorrelational- 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.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“as well as increased astrocyte expression of EGFR, which has been proposed as a potential receptor for Aβ37, and a regulator of astrocytes in multiple sclerosis38.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > Whole brain nCounter mRNA analysis corroborates AD glial signatures and verifies neuronal loss
What the sources say
- Not checked yetcites [37] Wang, L. et al. Epidermal growth factor receptor is a preferred target for treating amyloid-β-induced memory loss. Proc. Natl Acad. Sci. USA 109, 16743–16748 (2012). source
- Not checked yetcites [38] Rothhammer, V. et al. Microglial control of astrocytes in response to microbial metabolites. Nature 557, 724–728 (2018). source
hedgedcorrelational- 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
“AD astrocytes also had elevated expression of genes encoding the proteoglycan NCAN and collagen COL5A3, which were enriched in Astro0 and Astro1”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > The astrocyte signature indicates increase in glial scaring and loss of metabolic coordination between neurons and astrocytes
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
“oligodendrocytes upregulated the expression of genes controlling pH and electrolytes (CA2), osmotic imbalance (SLC38A2), lipid accumulation (MID1IP1) and oxidative stress (SEPP1)”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > AD-reactive oligodendrocytes reflect functional and metabolic adaptation to axonal degeneration
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- 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
“tSNE plots of snRNA-seq of 7-month-old mouse brain showing cell type specific markers identifying each cluster.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Extended Data
plaincorrelationaln = 73,419- 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
“Cluster 12 had very low frequency and did not have a clear marker profile and was thus omitted from analysis.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Extended Data
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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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
“Notably, NanoString analysis revealed that the precise glial and neuronal gene signatures varied slightly between the three distinct cohorts analyzed”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Rests on an assumption: Post-mortem human brain tissue processed for snRNA-seq reflects the transcriptional state of the brain before death.
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
“A clear reduction in the expression of genes controlling memory networks was not evident in the 5XFAD mouse model, in which neuronal pathology is limited to neurite dystrophy.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Discussion
plain- 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.
- Rests on an assumption: The 5XFAD mouse model recapitulates key aspects of human AD relevant to glial and neuronal transcriptional responses.
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
“Some of these transcriptional changes correspond to protein changes previously detected in the CSF as AD biomarkers (see Supplementary Table 3).”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Discussion
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.
- Rests on an assumption: Post-mortem human brain tissue processed for snRNA-seq reflects the transcriptional state of the brain before death.
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
“t-SNE plot showing 13 distinguished clusters, 0–12, with cell type identities determined by expression of specific markers.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Extended Data
plainn = 3- 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
“although both transcripts were detected in human astrocytes.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Discussion
plain- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: Post-mortem human brain tissue processed for snRNA-seq reflects the transcriptional state of the brain before death.
- Rests on an assumption: The cell clusters identified by snRNA-seq correspond to bona fide astrocytes, oligodendrocytes, microglia, and neurons.
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In the paper
“t-SNE plot showing expression of NEFL in neuronal clusters, especially in cluster Ex1.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Extended Data
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In the paper
“t-SNE plot showing expression of Pam, a representative gene enriched in cluster 4.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Extended Data
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In the paper
“Representative immunofluorescence images of Serpina3n staining in 7-month-old mice of all genotypes showing colocalization of Serpina3n with oligodendrocyte marker CA2.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Extended Data
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In the paper
“Representative confocal images showing colocalization of Serpina3n with GFAP+ astrocytes in 15-month-old 5XFAD mice.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Extended Data
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In the paper
“clusters 0 and 6 (neuronal) were exclusive to cortex”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Extended Data
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In the paper
“Cluster 4 has a lower average number of UMIs compared to other neurons.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Extended Data
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In the paper
“Representative confocal images showing colocalization of Serpina3n with X04+ plaques in 15-month-old 5XFAD mice.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Extended Data
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In the paper
“t-SNE plots of human snRNA-seq showing cell type specific markers identifying each cluster.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Extended Data
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In the paper
“t-SNE plots showing expression of IL10RA and HPGDS in human microglia.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Extended Data
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In the paper
“this suggests that, although delayed by Trem2-deficiency, microgliosis can reach a plateau at late stages of disease when aging becomes the major factor.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > snRNA-seq reveals a Trem2-dependent microgliosis at early stages of Aβ accumulation
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In the paper
“Such activated microglia, which have been referred to as disease-associated microglia (DAM), has a transcriptional signature quite distinct from that of homeostatic microglia that markedly declines in mouse models of AD10,11,12.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Abstract
What the sources say
- Not checked yetcites [10] Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290.e17 (2017). source
- Not checked yetcites [11] 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
- Not checked yetcites [12] Mathys, H. et al. temporal tracking of microglia activation in neurodegeneration at single-cell resolution. Cell Rep. 21, 366–380 (2017). source
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In the paper
“Single nuclei analysis of human AD brain specimens has revealed a microglial transcriptional response that partially recapitulates the mouse DAM signature along with perturbation of oligodendrocytes and myelination that is gender-dependent20.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Abstract
What the sources say
- Not checked yetcites [20] Mathys, H. et al. Single-cell transcriptomic analysis of Alzheimer’s disease. Nature 570, 332–337 (2019). source
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In the paper
“Reactive astrocytosis and microgliosis are secondary cellular responses to pathology that occur in diseased brain regions2 and may have both negative and positive effects3,4.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Abstract
What the sources say
- Not checked yetcites [2] De Strooper, B. & Karran, E. The cellular phase of Alzheimer’s disease. Cell 164, 603–615 (2016). source
- Not checked yetcites [3] Heneka, M. T., Golenbock, D. T. & Latz, E. Innate immunity in Alzheimer’s disease. Nat. Immunol. 16, 229–236 (2015). source
- Not checked yetcites [4] Griciuc, A. et al. Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 78, 631–643 (2013). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“These findings suggest that changes in the AD brain are a combination of direct Aβ-mediated pathology and secondary responses by TREM2-dependent activated microglia.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Abstract
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“intraneuronal tau hyperphosphorylation and aggregation ensue, causing neuronal and synaptic dysfunction and cell death1.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Abstract
What the sources say
- Not checked yetcites [1] Long, J. M. & Holtzman, D. M. Alzheimer disease: an update on pathobiology and treatment strategies. Cell 179, 312–339 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“loss of TREM2 function in AD mouse models restricts the ability of microglia to surround Aβ plaques15,16, proliferate, and convert to DAM10,15,17, which in turn leads to more profound neuritic dystrophy18,19.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Abstract
What the sources say
- Not checked yetcites [15] Wang, Y. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell 160, 1061–1071 (2015). source
- Not checked yetcites [16] Jay, T. R. et al. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models. J. Exp. Med. 212, 287–295 (2015). source
- Not checked yetcites [10] Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290.e17 (2017). source
- Not checked yetcites [17] Song, W. M. et al. Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism. J. Exp. Med. 215, 745 (2018). source
- Not checked yetcites [18] 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
- Not checked yetcites [19] Wang, Y. et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J. Exp. Med. 213, 667–675 (2016). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Oligodendrocyte signatures suggested impaired axonal myelination and metabolic adaptation to neuronal degeneration.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Abstract
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“amyloid beta (Aβ) peptides produced by neurons form extracellular aggregates that initiate disease”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Abstract
What the sources say
- Not checked yetcites [1] Long, J. M. & Holtzman, D. M. Alzheimer disease: an update on pathobiology and treatment strategies. Cell 179, 312–339 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Studies of genetic risk for sporadic AD have suggested that microglia not only respond to disease but modulate disease course13.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Abstract
What the sources say
- Not checked yetcites [13] Bohlen, C. J., Friedman, B. A., Dejanovic, B. & Sheng, M. Microglia in brain development, homeostasis, and neurodegeneration. Annu. Rev. Genet. https://doi.org/10.1146/annurev-genet-112618-043515 (2019). source
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In the paper
“These studies have largely concluded that microglia undergo the most prominent changes in diseased brains, due to a combination of increased microglia numbers along with a robust transcriptional activation signature on a per-microglia basis.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Abstract
What the sources say
- Not checked yetcites [5] Gjoneska, E. et al. Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer’s disease. Nature 518, 365–369 (2015). source
- Not checked yetcites [6] Seyfried, N. T. et al. A multi-network approach identifies protein-specific co-expression in asymptomatic and symptomatic Alzheimer’s disease. Cell Syst. 4, 60–72.e4 (2017). source
- Not checked yetcites [7] Gosselin, D. et al. An environment-dependent transcriptional network specifies human microglia identity. Science 356, eaal3222 (2017). source
- Not checked yetcites [8] Olah, M. et al. A transcriptomic atlas of aged human microglia. Nat. Commun. 9, 539 (2018). source
- Not checked yetcites [9] Masuda, T. et al. Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution. Nature 566, 388–392 (2019). source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“indicating that both Aβ and Trem2 are required for DAM.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > DAM signature is Trem2-dependent at early and late stages of Aβ accumulation
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“altered iron homeostasis has been associated with senescence29.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > Human brain AD gene signatures are distinct from those of the 5XFAD model
What the sources say
- Not checked yetcites [29] Angelova, D. M. & Brown, D. R. Microglia and the aging brain: are senescent microglia the key to neurodegeneration? J. Neurochem. https://doi.org/10.1111/jnc.14860 (2019). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“SORL1 polymorphisms have been linked to susceptibility to AD28 and CHI3L1 is a prognostic fluid biomarker for preclinical AD26”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > Human brain AD gene signatures are distinct from those of the 5XFAD model
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
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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
“Reactive oligodendrocytes secrete C4b and Serpina3n, which may facilitate Aβ aggregation.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > snRNA-seq reveals an Aβ-dependent oligodendrocyte reactive signature
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Altogether, these data suggest that the signature of human microglia in AD is quite distinct from that of DAM in the 5XFAD model10,11: it is reminiscent of the reactive phenotype observed in PNI and may be in part instructed by IRF8.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > Human brain AD gene signatures are distinct from those of the 5XFAD model
What the sources say
- Not checked yetcites [10] Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290.e17 (2017). source
- Not checked yetcites [11] 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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“These results were highly concordant between the 7-month- and 15-month-old datasets (Fig. 2d) and with previously published single cell RNA-seq data of sorted microglia10,11,12.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > DAM signature is Trem2-dependent at early and late stages of Aβ accumulation
What the sources say
- Not checked yetcites [10] Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290.e17 (2017). source
- Not checked yetcites [11] 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
- Not checked yetcites [12] Mathys, H. et al. temporal tracking of microglia activation in neurodegeneration at single-cell resolution. Cell Rep. 21, 366–380 (2017). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Most samples had a median of over 2,000 UMIs per nucleus”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > Human brain AD gene signatures are distinct from those of the 5XFAD model
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.
In the paper
“likely reflecting neuronal loss associated with AD and consistent with NEFL being identified as an AD biomarker in the cerebrospinal fluid (CSF)26”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > Human brain AD gene signatures are distinct from those of the 5XFAD model
What the sources say
- Not checked yetcites [26] Molinuevo, J. L. et al. Current state of Alzheimer’s fluid biomarkers. Acta Neuropathol. (Berl.) 136, 821–853 (2018). source
hedgedconditionaln = 11- Asserted: passes — The authors put it forward as true.
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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
“gene signatures indicative of glial responses and neuronal depletion detected by NanoString in the Rush and the BRI cohorts differed somewhat between the two sets of specimens, likely reflecting differences in the transcriptional and functional profiles of glia and neurons in prefrontal and occipital cortices, respectively.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > Whole brain nCounter mRNA analysis corroborates AD glial signatures and verifies neuronal loss
hedgedconditional- 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 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
“We validated IRF8 expression in human AD microglia by NanoString and IF and showed that IRF8 drives the expression of microglial markers linked to AD, suggesting that IRF8 is likely a major driver of this signature.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“suggesting fewer microglia in the R47H than in the CV TREM2 brain specimens and/or reduced expression of these microglial genes on a per cell basis.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > Brain signatures of AD carrying TREM2 variants demonstrate reduced microglial response
hedgedcorrelationaln = 5- Asserted: passes — The authors put it forward as true.
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In the paper
“These extracellular matrix molecules may contribute to glial scarring, probably preventing axonal regeneration31.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > The astrocyte signature indicates increase in glial scaring and loss of metabolic coordination between neurons and astrocytes
What the sources say
- Not checked yetcites [31] McKeon, R. J., Jurynec, M. J. & Buck, C. R. The chondroitin sulfate proteoglycans neurocan and phosphacan are expressed by reactive astrocytes in the chronic CNS glial scar. J. Neurosci. 19, 10778–10788 (1999). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Overall, the AD astrocyte profile was quite different from that of A1 astrocytes induced by inflammatory mediators released by microglia33, reiterating a lack of bona fide inflammation in the AD brain.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > The astrocyte signature indicates increase in glial scaring and loss of metabolic coordination between neurons and astrocytes
What the sources say
- Not checked yetcites [33] Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017). source
plain- Asserted: passes — The authors put it forward as true.
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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
“likely reflecting loss of metabolic coordination between neurons and astrocytes.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Discussion
hedgedconditional- 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.
- Rests on an assumption: Post-mortem human brain tissue processed for snRNA-seq reflects the transcriptional state of the brain before death.
- Rests on an assumption: The cell clusters identified by snRNA-seq correspond to bona fide astrocytes, oligodendrocytes, microglia, and neurons.
In the paper
“reduced ADCYAP1 in human CSF and brain specimens has been associated with cognitive decline in mild cognitive impairment due to AD40”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > Whole brain nCounter mRNA analysis corroborates AD glial signatures and verifies neuronal loss
What the sources say
- Not checked yetcites [40] Han, P. et al. Association of pituitary adenylate cyclase-activating polypeptide with cognitive decline in mild cognitive impairment due to Alzheimer disease. JAMA Neurol. 72, 333–339 (2015). source
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 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
“Neuronal loss in AD may dampen the need for astrocytic scavenger functions devoted to disposal of neuronal toxic waste.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Rests on an assumption: Post-mortem human brain tissue processed for snRNA-seq reflects the transcriptional state of the brain before death.
In the paper
“NCAN polymorphisms have been associated with bipolar disorder, schizophrenia and major depression32.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > The astrocyte signature indicates increase in glial scaring and loss of metabolic coordination between neurons and astrocytes
What the sources say
- Not checked yetcites [32] Schultz, C. C. et al. Common variation in NCAN, a risk factor for bipolar disorder and schizophrenia, influences local cortical folding in schizophrenia. Psychol. Med. 44, 811–820 (2014). source
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 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
“Overall, the R47H variant seems to have a greater impact than the R62H variant on microglial response to AD pathology, consistent with the relatively higher penetrance of the R47H variant for AD.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Results > Brain signatures of AD carrying TREM2 variants demonstrate reduced microglial response
hedgedcorrelationaln = 5- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“NanoString nCounter analysis was based on multivariate linear regression with Bejamani-Yekutieli adjustment.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Online Methods > Statistics and reproducibility
plain- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“but all samples and data were processed in a high-throughput or automated fashion.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Online Methods > Mice
plain- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“A regular expression for phosphorylation was used to perform using linear discriminant analysis (LDA) and set a false discovery rate (FDR) of < 2.5%”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Online Methods > Proteomics and phospho-proteomics
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.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“PSMs with TMT reporter ion summed signal-to-noise ratios less than 55 were excluded from quantitation.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Online Methods > Proteomics and phospho-proteomics
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.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“After filtering, 38,230 nuclei were remained.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Online Methods > Single-nucleus RNA-Seq
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. The quote only partly states this claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Experiments were repeated two or more times.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Online Methods > Statistics and reproducibility
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.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“No animals were excluded from analysis.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Online Methods > Mice
plain- Asserted: passes — The authors put it forward as true.
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- 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.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“P values were adjusted based on Bonferroni correction.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Online Methods > Statistics and reproducibility
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.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“After filtering, a total of 73,419 individual nuclei across all genotypes were remained, with a median of 3,941 UMIs and 2,378 genes per nucleus for downstream analysis.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Online Methods > Single-nucleus RNA-Seq
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.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“11 age-matched controls”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Online Methods > Human samples
plainn = 11- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Sex was balanced between AD (CV) and control individuals, with 7 females and 4 males in each group; the AD (R62H) group has 5 females and 5 males.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Online Methods > Human samples
plainn = 11- Asserted: passes — The authors put it forward as true.
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- 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
“reflecting disparate demographics and/or differing regions of the brain from which the samples were obtained.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Discussion
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- 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.
- Rests on an assumption: Post-mortem human brain tissue processed for snRNA-seq reflects the transcriptional state of the brain before death.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All statistical analyses for validation assays were performed using GraphPad Prism (v.8) with unpaired Student’s t test or one- or two-way ANOVA with Tukey’s multiple comparisons test.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Online Methods > Statistics and reproducibility
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.
In the paper
“Peptide-spectrum matches (PSMs) were adjusted to a 1% false discovery rate (FDR)52”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Online Methods > Proteomics and phospho-proteomics
What the sources say
- Not checked yetcites [52] Elias, J. E. & Gygi, S. P. Target-decoy search strategy for mass spectrometry-based proteomics. Methods Mol. Biol. Clifton NJ 604, 55–71 (2010). source
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.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“After filtering, 66,311 nuclei were remained across 11 AD (CV), 10 AD (R62H) and 11 control samples, with a median of 1,951 UMIs and 1,312 genes per nucleus for downstream analysis.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Online Methods > Single-nucleus RNA-Seq
plainn = 11- 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.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Cutoffs for UMI and gene number were determined based on histograms showing cell density as a function of UMI/gene counts.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Online Methods > Single-nucleus RNA-Seq
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“nuclei with mitochondrial content greater than 5 percent were removed.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Online Methods > Single-nucleus RNA-Seq
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.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“For confocal images in Fig. 3 and Extended Data Fig. 4, at least three images per mouse brain were acquired and averaged for quantification.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Online Methods > Statistics and reproducibility
plainn = 3- 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.
None of the sources cited for this claim have been checked yet.
In the paper
“Defects in some of these molecules have been implicated in impaired memory39 and associated with mild cognitive impairment in AD40.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Discussion
What the sources say
- Not checked yetcites [39] Dickey, C. A. et al. Selectively reduced expression of synaptic plasticity-related genes in amyloid precursor protein + presenilin-1 transgenic mice. J. Neurosci. 23, 5219–5226 (2003). source
- Not checked yetcites [40] Han, P. et al. Association of pituitary adenylate cyclase-activating polypeptide with cognitive decline in mild cognitive impairment due to Alzheimer disease. JAMA Neurol. 72, 333–339 (2015). source
hedgedcorrelational- 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.
In the paper
“confidently localized sites with a AScore > 13 were selected for analysis (p-value < 0.05)54.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Online Methods > Proteomics and phospho-proteomics
What the sources say
- Not checked yetcites [54] Beausoleil, S. A., Villén, J., Gerber, S. A., Rush, J. & Gygi, S. P. A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nat. Biotechnol. 24, 1285–1292 (2006). 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.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Investigators were not blinded to experimental groups”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Online Methods > Mice
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.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Adjusted p-value was calculated based on Bonferroni correction.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Online Methods > Analysis of gene differential expression
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.
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
“a potential role for IRF8 in microglia reactivity”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Discussion
hedgedconditional- 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.
- Rests on an assumption: Post-mortem human brain tissue processed for snRNA-seq reflects the transcriptional state of the brain before death.
- Rests on an assumption: The cell clusters identified by snRNA-seq correspond to bona fide astrocytes, oligodendrocytes, microglia, and neurons.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Filtered PSMs were collapsed to a final protein-level FDR of < 2%.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Online Methods > Proteomics and phospho-proteomics
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.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Nuclei that are duplets or multiplets were filtered out by two steps.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Online Methods > Single-nucleus RNA-Seq
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.
Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“Together these data expand previous studies in mouse models of Aβ aggregation suggesting a pathogenic role for C4b and Serpina3n23,24,44,45, as well as genetic studies linking the human homologue SERPINA3 to AD risk46”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Discussion
What the sources say
- Not checked yetcites [23] Mucke, L. et al. Astroglial expression of human α1-antichymotrypsin enhances alzheimer-like pathology in amyloid protein precursor transgenic mice. Am. J. Pathol. 157, 2003–2010 (2000). source
- Not checked yetcites [24] Nilsson, L. N. et al. α-1-antichymotrypsin promotes β-sheet amyloid plaque deposition in a transgenic mouse model of Alzheimer’s disease. J. Neurosci. 21, 1444–1451 (2001). source
- Not checked yetcites [44] Hong, S. et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712–716 (2016). source
- Not checked yetcites [45] Ma, J., Yee, A., Brewer, H. B., Das, S. & Potter, H. Amyloid-associated proteins α1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer β-protein into filaments. Nature 372, 92–94 (1994). source
- Not checked yetcites [46] Kamboh, M. I., Sanghera, D. K., Ferrell, R. E. & DeKosky, S. T. APOE*4-associated Alzheimer’s disease risk is modified by α1-antichymotrypsin polymorphism. Nat. Genet. 10, 486–488 (1995). source
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.
- Rests on an assumption: In vitro Aβ aggregation induced by C4b is relevant to AD pathogenesis in vivo.
In the paper
“PSMs with poor quality, MS3 spectra with TMT reporter ion summed signal-to-noise ratios less than 110 were excluded from quantitation53.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Online Methods > Proteomics and phospho-proteomics
What the sources say
- Not checked yetcites [53] McAlister, G. C. et al. Increasing the multiplexing capacity of TMTs using reporter ion isotopologues with isobaric masses. Anal. Chem. 84, 7469–7478 (2012). 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
“Alignment of reads from Trem2-deficient mice to Trem2 exon1 reflects early transcriptional termination due to deletion of exons 3 and 4 in the design of Trem2 knockout constructs.”
§ Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and - independent cellular responses in Alzheimer’s disease > Extended Data
plaindirect- 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.
The paper relies on this without support.
Little is known about how TREM2-dependent microglial functions affect the Alzheimer's disease brain as a whole.
“Nonetheless, little is known about how TREM2-dependent microglial functions impact the AD brain as a whole.”
The paper relies on this without support.
Post-mortem human brain tissue processed for snRNA-seq reflects the transcriptional state of the brain before death.
“Post-mortem prefrontal cortical tissues from 11 AD patients with TREM2 common variant (CV), 10 AD patients carrying TREM2 R62H variant, and 11 age-matched controls from the Rush cohort were analyzed by snRNA-seq.”
The paper relies on this without support.
The 5XFAD mouse model recapitulates key aspects of human AD relevant to glial and neuronal transcriptional responses.
“In the 5XFAD model, astrocytes assumed a very modest Aβ-dependent signature marked by expression of Gfap.”
The paper relies on this without support.
The cell clusters identified by snRNA-seq correspond to bona fide astrocytes, oligodendrocytes, microglia, and neurons.
“Nuclei from broad cell types (astrocytes, microglia and oligodendrocytes clusters) were taken and re-clustered to further analyze the sub-clusters in each cell type.”
The paper relies on this without support.
In vitro Aβ aggregation induced by C4b is relevant to AD pathogenesis in vivo.
“Moreover, C4b was particularly effective in inducing Aβ aggregation in vitro.”
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 cited source doesn’t support the claim as written.
In the citing paper
“resulting in over 100,000 astrocyte nuclei in each brain region with ≈6,000 average total number of reads and ≈2,500 average total number of genes detected, which is orders of magnitude higher than previous studies9–15”
From Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease (2024) · cites this paper as [11]
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe cited source doesn’t support the claim as written.
In the citing paper
“In parallel, astrocytes uniquely upregulated DDIT4, PFKP and ADCY8, along with genes that suppress fatty acid metabolism (ANGPTL4) and promote lipid droplet storage of fatty acids (HILPDA), while microglia upregulated multiple glycogen-related genes (GBE1, UGP2 and PYGL)48 (Fig. 4m).”
From Single-cell multiregion dissection of Alzheimer’s disease (2024) · cites this paper as [48]
Checked by a reasoning model — may be wrong.
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
“This signaling pathway seems to be conserved in human microglia (Zhou et al., 2020)”
From Alzheimer's-associated PU.1 expression levels regulate microglial inflammatory response (2021) · cites this paper as Zhou et al., 2020
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
“Stage 2 DAMs (sometimes referred to as TREM2-dependent) are activated microglia that are closely associated with amyloid plaques.42,43”
From TET2-mutant myeloid cells mitigate Alzheimer’s disease progression via CNS infiltration and enhanced phagocytosis in mice (2025) · cites this paper as [42]
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
“For instance, TREM2 is one of the strongest risk factors for AD, and evidence suggests that TREM2 acts to recognize Aβ pathology and direct microglial responses toward the pathology (Guerreiro et al., 2013; Zhou et al., 2020).”
From β-amyloid accumulation enhances microtubule associated protein tau pathology in an APPNL-G-F/MAPTP301S mouse model of Alzheimer’s disease (2024) · cites this paper as Zhou et al., 2020
Experimental — accuracy not yet measured
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
“Importantly, only a subset, often a mix of A1 and A2 or pan-reactive transcripts, are upregulated in astrocytes from brains of study participants with HD74 or AD75,76, or from several mouse models of acute injuries and chronic diseases of the CNS42,69,76,77.”
From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [76]
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
“may have confounded previous studies that compared only control and severe AD donors or grouped late- and end-stage donors (Braak stage V/VI) together9–15”
From Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease (2024) · cites this paper as [11]
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
“APOE is greatly upregulated in human AD microglia (HAM) from human AD brains”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Zhou et al 2020
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
“The top hub gene in the plum3 module—Interferon Regulatory Factor 8 (Irf8)—corresponds to interferon signaling that has recently been identified to be upregulated in microglia from human AD [40].”
From Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways (2022) · cites this paper as [40]
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
“AD DEGs were consistent with published results both for region-specific DEGs and for DEGs computed jointly over all regions for multiple AD variables, and were further corroborated by comparisons with various independent studies11,12,15,19,47–53”
From Single-cell multiregion dissection of Alzheimer’s disease (2024) · cites this paper as [48]
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 the current work, we focus on cholesterol 25-hydroxylase (Ch25h), which is upregulated in DAM only when both Apoe and Trem2 are present (Krasemann et al., 2017; Zhou et al., 2020).”
From Cholesterol 25-hydroxylase mediates neuroinflammation and neurodegeneration in a mouse model of tauopathy (2024) · cites this paper as Zhou et al., 2020
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
“Single-cell transcriptomic analysis carried out in AD human and AD mouse model brain tissue have identified unique signatures of gene expression in microglia in physical proximity to amyloid plaques and tau aggregates, termed DAM (Keren-Shaul et al., 2017; Krasemann et al., 2017; Zhou et al., 2020).”
From Cholesterol 25-hydroxylase mediates neuroinflammation and neurodegeneration in a mouse model of tauopathy (2024) · cites this paper as Zhou et al., 2020
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Single-nucleus RNA sequencing (snRNA-seq) data on postmortem samples from AD patients and on samples from AD mice model also revealed that the expression of TREM2 was increased in AD pathology.164,213,214”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [213]
The cited source says what the claim attributes to it.
In the citing paper
“RNA-seq studies using human AD autopsy samples have identified myelin-related transcripts among the top altered gene clusters in patients with AD35,46.”
From Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease (2023) · cites this paper as [35]
The cited source says what the claim attributes to it.
In the citing paper
“Human single nucleus RNA sequencing data from Zhou and colleagues [10] were obtained via the AD Knowledge Portal (https://adknowledgeportal.org) study snRNAseqAD_TREM2.”
From Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease (2024) · cites this paper as [10]
The cited source says what the claim attributes to it.
In the citing paper
“We constructed metacells and performed co-expression network analysis for each major cell type in the human PFC dataset11 using the standard hdWGCNA workflow, yielding distinct network structures and sets of gene modules (Data S2 and S3).”
From hdWGCNA identifies co-expression networks in high-dimensional transcriptomics data (2023) · cites this paper as [11]
The cited source says what the claim attributes to it.
In the citing paper
“We performed consensus co-expression network analysis of microglia from three Alzheimer’s disease (AD) snRNA-seq studies,10,11,12 yielding multiple gene modules corresponding to disease-associated microglia and polygenic risk of AD.”
From hdWGCNA identifies co-expression networks in high-dimensional transcriptomics data (2023) · cites this paper as [11]
The cited source says what the claim attributes to it.
In the citing paper
“Next, we performed consensus co-expression network analysis using microglia integrated from three human AD snRNA-seq datasets,10,11,12 identifying four consensus modules (Figure 6C; Data S1).”
From hdWGCNA identifies co-expression networks in high-dimensional transcriptomics data (2023) · cites this paper as [11]
The cited source says what the claim attributes to it.
In the citing paper
“Recent advancements in scRNA-seq technology enabled in-detail trancriptomic analysis of different cell types and identified unique cellular signatures, specifically in microglia, in AD (36, 37).”
From Deletion of Abi3 gene locus exacerbates neuropathological features of Alzheimer’s disease in a mouse model of Aβ amyloidosis (2021) · cites this paper as [37]
The cited source says what the claim attributes to it.
In the citing paper
“Studying microglia using human cell models such as iPSC-derived cells is vital given the species-specific differences in microglial responses between human and mouse cells27.”
From PLCγ2 regulates TREM2 signalling and integrin-mediated adhesion and migration of human iPSC-derived macrophages (2021) · cites this paper as [27]
The cited source says what the claim attributes to it.
In the citing paper
“we found a similar observation in an independent cohort described by Zhou et al. 35 showing increased expression of SPI1 , TGFB1 and GRN in microglia isolated from the brains of individuals with AD that are heterozygous for the APOE3 and APOE4 alleles (Fig. 7h and Extended Data Fig. 6b,c).”
From APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints (2023) · cites this paper as [35]
The cited source says what the claim attributes to it.
In the citing paper
“Analysis of public single-nucleus RNA-seq data 35 of astrocytes from the brains of individuals with AD that are homozygous for the APOE3 allele and those that are heterozygous for the APOE3 and APOE4 alleles confirmed that the percentage of GFAP hi and SERPINA3 + astrocytes is increased in donors that are homozygous for the APOE3 allele compared to in those that are heterozygous for the APOE3 and”
From APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints (2023) · cites this paper as [35]
The cited source says what the claim attributes to it.
In the citing paper
“We confirmed Hif1a regulon activity in 54.3% of the cluster (from study51) transcriptionally most similar to DAM microglia13”
From Transcriptional signature in microglia associated with Aβ plaque phagocytosis (2021) · cites this paper as [51]
The cited source says what the claim attributes to it.
In the citing paper
“Previous studies described AD-associated molecular and cellular changes5–15; however, cross-study comparisons are challenging without common cell annotations.”
From Integrated multimodal cell atlas of Alzheimer’s disease (2024) · cites this paper as [8]
The cited source says what the claim attributes to it.
In the citing paper
“To corroborate the results, we harmonized snRNA-seq data and associated donor metadata from the PFC from ten additional AD studies spanning 707 donors5–14.”
From Integrated multimodal cell atlas of Alzheimer’s disease (2024) · cites this paper as [8]
The cited source says what the claim attributes to it.
In the citing paper
“but our sample sizes are similar to those reported in previous publications5–14”
From Integrated multimodal cell atlas of Alzheimer’s disease (2024) · cites this paper as [8]
The cited source says what the claim attributes to it.
In the citing paper
“our sample sizes are similar to those reported in previous publications9–17”
From Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease (2024) · cites this paper as [11]
The cited source says what the claim attributes to it.
In the citing paper
“Also, the reanalyses of snRNAseq and scRNAseq data from wildtype mice (Ximerakis et al., 2019;Zhou et al., 2020) suggest that both Ldh transcripts are expressed markedly less in mature myelinating oligodendrocytes compared to neurons and astrocytes (Figure 2j,k).”
From Downregulated expression of lactate dehydrogenase in adult oligodendrocytes and its implication for the transfer of glycolysis products to axons (2024) · cites this paper as Zhou et al., 2020
The cited source says what the claim attributes to it.
In the citing paper
“A similar C4b and H2-D1-expressing oligodendrocyte population was recently described in mouse models of Aβ pathology (Nugent et al., 2020; Zhou et al., 2020).”
From Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia (2021) · cites this paper as Zhou et al., 2020
The cited source says what the claim attributes to it.
In the citing paper
“Dysfunction of oligodendrocytes, the myelinating cells of the CNS, may contribute to AD pathogenesis (Nugent et al., 2020; Zhou et al., 2020).”
From Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia (2021) · cites this paper as Zhou et al., 2020
The cited source says what the claim attributes to it.
In the citing paper
“C4b+/H2–D1+ oligodendrocytes have also been observed in models of amyloid pathology (Nugent et al., 2020; Zhou et al., 2020).”
From Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia (2021) · cites this paper as Zhou et al., 2020
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“We found that, apart from PSEN2 (which is not essential for gamma secretase function when PSEN1 is present [13]), oligodendrocytes had elevated expression of all of these genes (Fig 1A–1D).”
From Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease (2024) · cites this paper as [10]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“transcripts of amyloid precursor protein (APP) and amyloidogenic enzymes are equally abundant in oligodendrocytes (OLs).”
From Oligodendrocytes produce amyloid-β and contribute to plaque formation alongside neurons in Alzheimer’s disease model mice (2024) · cites this paper as [12]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“We next analyzed recent snRNA-seq datasets of AD patients from two independent studies28, 33, both showing a specific upregulation of PLXNB1 in astrocytes but not other cell types in human AD brains (Fig. 2B).”
From Regulation of cell distancing in peri-plaque glial nets by Plexin-B1 affects glial activation and amyloid compaction in Alzheimer’s disease (2024) · cites this paper as [33]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Additionally, Hif1a was predicted for both 87.8% of XO4+ microglia and a subpopulation of 30% of 5xFAD microglia51”
From Transcriptional signature in microglia associated with Aβ plaque phagocytosis (2021) · cites this paper as [51]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“In both datasets, Ldha and Ldhb in particular, but also other glycolysis related genes were expressed at a low rate in OLs in comparison to neurons and astrocytes (Figures 2j,k and S3a,b).”
From Downregulated expression of lactate dehydrogenase in adult oligodendrocytes and its implication for the transfer of glycolysis products to axons (2024) · cites this paper as Zhou et al., 2020
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“To further examine the cellular and regional heterogeneity of the human brain, we developed a scalable method, scdemon, which uses sample decorrelation to annotate both ubiquitous and rare gene expression programs in each major cell type, and used annotated modules to identify functional programs associated with specific pathological variables, including a glycolysis- and energy-metabolism-linked”
From Single-cell multiregion dissection of Alzheimer’s disease (2024) · cites this paper as [48]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Expression of Ch25h is controlled by Trem2 (Zhou et al., 2020; Poliani et al., 2015)”
From Cholesterol 25-hydroxylase mediates neuroinflammation and neurodegeneration in a mouse model of tauopathy (2024) · cites this paper as Zhou et al., 2020
Experimental — accuracy not yet measuredIn the citing paper
“In addition to the downregulation of genes involved in synaptic transmission and synapse organization, there is also prominent upregulation of genes involved in cell stress, immune response activation and cell death in PFC of AD patients 257–259.”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [259]
In the citing paper
“APP-overexpressing transgenic mice exhibit an increased thickness of myelin (Xu et al. , 2014) and contain more oligodendrocytes (Zhou et al. , 2020).”
From Spatial Transcriptomics and In Situ Sequencing to Study Alzheimer’s Disease (2020) · cites this paper as Zhou et al., 2020
In the citing paper
“Analysis of homeostatic and disease-associated microglia (DAM) gene signatures in microglia from 5xFAD mice with impaired meningeal lymphatics revealed higher expression of Apoe, Lyz2, Fth1, Timp2, H2-d1, Axl, Cst7, Spp1 and Lpl (Extended Data Fig. 6e, f and Supplementary Table 2), which are involved in the transition from homeostatic to activated microglia21,26.”
From Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy (2021) · cites this paper as [26]
In the citing paper
“These observations suggest that meningeal lymphatic ablation leads to a loss of homeostatic microglia, and acquisition of the DAM signature (and/or the neurodegenerative microglial signature)21,22,26, all of which is counteracted by passive immunotherapy.”
From Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy (2021) · cites this paper as [26]
In the citing paper
“Transcriptomic signatures of disease can be studied by snRNA-seq applied to post-mortem brain tissue from patients.”
From Single-Cell Sequencing of Brain Cell Transcriptomes and Epigenomes (2021) · cites this paper as Zhou et al., 2020
In the citing paper
“Differences in gene expression profiles of different microglial populations have been recently described using single cell RNA-seq showing some microglial populations are selectively dependent on Trem2 (58–62).”
From Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [61]
In the citing paper
“Itgax/CD11C is an integrin or cell surface antigen, and is up-regulated in a number of recent RNA-seq studies in response to amyloid plaques (58,59,61,84).”
From Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [61]
In the citing paper
“Other studies have not revealed obvious phenotypes in young Trem2 R47H expressing mice, or even Trem2 knockout mice, unless they are aged or bred to amyloid mouse models (35,61,85–87).”
From Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [61]
In the citing paper
“Recent important studies have also shown that impaired/absent Trem2 function attenuates the microglial response to amyloid pathology by regulating microglial number around plaques, regulating microglial activity, and restricting neuritic damage (37,61,84–87,95–99).”
From Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [61]
In the citing paper
“There is increasing evidence that reactive microglia in diseased brains demonstrate a mixed phenotype with expression of pro- or anti-inflammatory and homeostatic markers, particularly showing heterogeneity at the single-cell level, rather than completely reproducing the phenotype obtained from homogenous in vitro polarization studies (58,60,61,100–103).”
From Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [61]
In the citing paper
“Indeed, a series of recent studies identified transcriptional signatures in response to AD-associated pathology, neurodegeneration and apoptotic neurons, which were in part dependent on Trem2 and included Igf1, Csf1, Itgax, Clec7a and Arg1, at least in mice (58,59,61,84,86).”
From Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [61]
In the citing paper
“Interestingly, when we tested expression of genes that show substantial changes in transgenic mice associated with AD (43,44) a number of aspects of gene expression were mimicked by anti-inflammatory IL-4 stimulation, particularly the increased expression of genes associated with the neurodegenerative signature, including Igf1, Itgax, Clec7a and Arg1 (58,59,61,84,86).”
From Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [61]
In the citing paper
“For instance, we found substantial region-dependence in the magnitude and timing of C4b expression (Figure 1E), a complement component and major schizophrenia risk factor (Sekar et al., 2016) that is robustly up-regulated in aged mice (Hahn et al., 2020) and models of neurodegeneration (Zhou et al., 2020).”
From Atlas of the aging mouse brain reveals white matter as vulnerable foci (2023) · cites this paper as Zhou et al., 2020
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“Indeed, a series of recent studies identified transcriptional signatures in response to AD-associated pathology, neurodegeneration and apoptotic neurons, which were in part dependent on Trem2 and included Igf1, Csf1, Itgax, Clec7a and Arg1, at least in mice (58,59,61,84,86).”
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Iron loading is a prominent feature of activated microglia in Alzheimer’s disease patients
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The Multiple Roles of Interferon Regulatory Factor family in Health and Disease
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Microglia-containing human brain organoids for the study of brain development and pathology
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Profiling senescent cells in human brains reveals neurons with CDKN2D/p19 and tau neuropathology
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Metadata
- Authors
- Zhou, Y., Song, W. M., Andhey, P. S., Swain, A., Levy, T., Miller, K. R., Poliani, P. L., Cominelli, M., Grover, S., Gilfillan, S., Cella, M., Ulland, T. K., Zaitsev, K., Miyashita, A., Ikeuchi, T., Sainouchi, M., Kakita, A., Bennett, D. A., Schneider, J. A., Nichols, M. R., Beausoleil, S. A., Ulrich, J. D., Holtzman, D. M., Artyomov, M. N., & Colonna, M.
- Affiliations
- Washington University in St. Louis (US)
- Bluefin Biomedicine (United States) (US)
- Nanostring Technologies (United States) (US)
- University of Brescia (IT)
- University of Missouri–St. Louis (US)
- University of Wisconsin–Madison (US)
- ITMO University (RU)
- Brain Research Institute, Niigata University (JP)
- Rush University Medical Center (US)
- Corresponding author
- Artyomov, Maxim N.
- Colonna, Marco
- ORCID
- Zhou, Yingyue
- Song, Wilbur M.
- Swain, Amanda
- Levy, Tyler
- Poliani, Pietro L.
- Cominelli, Manuela
- Gilfillan, Susan
- Cella, Marina
- Ulland, Tyler K.
- Zaitsev, Konstantin
- Miyashita, Akinori
- Ikeuchi, Takeshi
- Sainouchi, Makoto
- Kakita, Akiyoshi
- Bennett, David A.
- Schneider, Julie A.
- Nichols, Michael R.
- Beausoleil, Sean A.
- Ulrich, Jason D.
- Holtzman, David M.
- Artyomov, Maxim N.
- Colonna, Marco
- Venue
- Nature Medicine
- Published
- 2020-01-01
- Volume
- 26
- Issue
- 1
- Pages
- 131-142
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC6980793
- OpenAlex
- W2998795963
- Semantic Scholar
- 99ea49ab0c1c1672b94039e5c61e1144b048cb80
- Cited by
- 1,150
- References
- 68
- Citations by year
- 2026: 161 · 2025: 194 · 2024: 193 · 2023: 189 · 2022: 161 · 2021: 162 · 2020: 87
- FWCI
- 58.45
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-05-14)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion, other-oa)
- Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute on Aging (RF1 AG051485, R21 AG059176, RF1 AG059082, RF1 AG047644)
- Cure Alzheimer’s Fund
- U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (R01 NS090934)
- U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (R15 GM119070)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- Alzheimer's disease, TREM2, disease-associated microglia, microglia, oligodendrocytes, astrocytes, glial response, Serpina3n, C4b, myelination, axonal degeneration, species differences, 5xFAD mice, amyloid-beta deposition, single-nucleus transcriptomics
- MeSH terms
- Aged, Alzheimer Disease, Animals, Astrocytes, Axons, Brain, Cell Nucleus, Female, Humans, Male, Membrane Glycoproteins, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Nerve Degeneration, Oligodendroglia, Receptors, Immunologic, Transcription, Genetic, Amyloid beta-Peptides, Microglia, 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 2026-10-04, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-04 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
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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