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Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation
Open accessPublished version of a preprint
Abstract
Damage-associated microglia (DAM) profiles observed in Alzheimer's disease (AD)-related mouse models reflect an activation state that could modulate AD risk or progression. To learn whether human AD microglia (HAM) display a similar profile, we develop a method for purifying cell types from frozen cerebrocortical tissues for RNA-seq analysis, allowing better transcriptome coverage than typical single-nucleus RNA-seq approaches. The HAM profile we observe bears little resemblance to the DAM profile. Instead, HAM display an enhanced human aging profile, in addition to other disease-related changes such as APOE upregulation. Analyses of whole-tissue RNA-seq and single-cell/nucleus RNA-seq datasets corroborate our findings and suggest that the lack of DAM response in human microglia occurs specifically in AD tissues, not other neurodegenerative settings. These results, which can be browsed at http://research-pub.gene.com/BrainMyeloidLandscape, provide a genome-wide picture of microglial activation in human AD and highlight considerable differences between mouse models and human disease.
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TL;DR
Human Alzheimer’s disease microglia (HAM) purified from frozen cortex show a transcriptional profile that is largely distinct from the mouse damage-associated microglia (DAM) profile, with a prominent enhanced aging signature and APOE upregulation. The HAM signature is validated across cortical regions and whole-tissue datasets, while DAM-like induction is stronger in multiple sclerosis lesions and human microglia xenotransplanted into 5xFAD mice than in AD microglia.
Key findings
- In sorted CD11b+ microglia from superior frontal gyrus, genome-wide differential expression identified 45 genes increased and 21 decreased in AD versus control; only APOE upregulation survived genome-wide correction (fold change = 4.1, adjusted p = 0.0004).
- The HAM profile bore little resemblance to mouse DAM: the mouse neurodegeneration-related/DAM module was only slightly increased in AD microglia (p = 0.045), and among more than 100 module genes only APOE was significantly increased.
- AD microglia displayed an enhanced human aging phenotype: age-related DE scores were significantly higher in AD microglia than controls, with older-subject genes such as IL15, MS4A6A, MS4A4A, NME8, and GPR141 trending upward and CECR2 trending downward; this was not explained by age differences between groups.
- Validation in fusiform gyrus qRT-PCR replicated the direction of effect for nearly every DE gene tested (22 genes), and whole-tissue datasets (GSE95587, GSE125583, ROSMAP) showed significant elevation of the HAM-Up gene set, most apparent in later Braak stages. DAM induction was stronger in MS lesion microglia and human xenografted microglia in 5xFAD mouse brains than in AD microglia.
Methods
- The authors adapted a method for isolating cell types from frozen post-mortem human brain: brief Accutase treatment at 4°C, mechanical dissociation, ethanol fixation, immunolabeling, and FACS for NeuN+ neurons, GFAP+ astrocytes, CD31+ endothelial cells, and CD11b+ microglia/myeloid cells, followed by RNA-seq or qPCR.
- Frontal cortex (superior frontal gyrus) samples were processed from 22 AD and 21 control tissues; after QC, 113 cell-type-specific expression profiles were retained, including microglia profiles from 15 control and 10 AD subjects. Temporal cortex (fusiform gyrus) samples totaled 25 AD and 21 control tissues and were analyzed by qRT-PCR.
- Analyses included DESeq2 differential expression with Cook’s distance filtering, gene set scoring, myeloid balancing for whole-tissue datasets, and pseudobulk analysis of published single-cell/single-nucleus RNA-seq datasets from AD, MS, and xenotransplanted microglia.
Limitations
- The paper states that RNA quality after purification was poor, with Bioanalyzer RIN scores typically 1–3 due to freeze-thaw, fixation, and post-mortem tissue processing; alternative dissociation and fixation conditions were unsuccessful or counterproductive.
- The authors state that the sorted-cell approach does not afford single-cell resolution, and the SFG RNA-seq cohort was small (10 AD and 15 control microglia profiles). They also note that snRNA-seq datasets suffer from extensive gene dropout, making downregulated gene sets difficult to detect.
- The text makes evident additional limitations: APOE4 carrier status was imbalanced between AD and control groups (0 controls versus 9 AD subjects overall; 0 versus 6 among QC-passing myeloid profiles), and the new whole-tissue cohort had imperfect age matching, with AD cases on average about a half decade younger. The authors also present alternative interpretations for aging-related changes, including possible increased peripheral monocyte/macrophage infiltration versus microglial transcriptional modulation toward a monocyte-like state.
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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
“we saw that most HAM genes exhibiting age-related DE in the Galatro et al. (2017) study showed corresponding expression changes in monocytes relative to microglia (Figure 6D).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > AD Microglia Display an Enhanced Human Aging Phenotype
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In the paper
“we develop a method for purifying cell types from frozen cerebrocortical tissues for RNA-seq analysis, allowing better transcriptome coverage than typical single-nucleus RNA-seq approaches.”
- Also stated in: § Defining the HAM Gene Expression Profile Using Frozen Tissues · plain
“our bulk-sorted microglia profiles from frozen tissues displayed coverage of the transcriptome similar to that of bulk-sorted microglia from fresh post-mortem tissues (Galatro et al., 2017; Gosselin et al., 2017) and better coverage than snRNA-seq profiles”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > Abstract
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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
“We observed that the HAM-Up gene set was more robustly elevated in AD whole-tissue RNA than either of the mouse-derived gene sets (Figures 3D and S4C)”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > Validation of the HAM Profile in Multiple Cortical Regions and Datasets
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In the paper
“we observed a clear tendency for genes whose expression changed with age in Galatro et al. (2017)’s dataset to show the same direction of age-related change among our control microglia samples (Figure 5C), validating our SFG RNA-seq profiles.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > AD Microglia Display an Enhanced Human Aging Phenotype
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In the paper
“For instance, GPNMB upregulation was robust in xMG and MS cells, but in AD microglia, it was meager or absent (Figure S7B).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > HAM, DAM, and Aging Comparisons in Human AD, Xenograft AD, and Human MS Tissues
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In the paper
“The microglia and brain myeloid gene modules that define resting or homeostatic microglia and are downregulated in response to virtually any perturbation in mice (Friedman et al., 2018) showed no hint of downregulation in AD microglia (Figure 4A).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > The HAM Profile Is Unlike Known Mouse Microglial Activation States
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In the paper
“Despite the different disease contexts of FuG and SFG tissues, the direction of effect for AD versus control across RNA samples from CD11b+ cells was replicated for nearly every DE gene tested (Figures 3B and S3B).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > Validation of the HAM Profile in Multiple Cortical Regions and Datasets
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In the paper
“In our data, in addition to APOE, we found that the lipoprotein receptor LSR and the lysosomal enzyme ARSA—a gene in which homozygous mutations cause metachromatic leukodystrophy (Cesani et al., 2016)—were elevated in HAM.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > DISCUSSION
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In the paper
“Second, the HAM signal was stronger than the DAM signal in snRNA-seq profiles from both AD tissues and MS lesions.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > DISCUSSION
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In the paper
“induction of DAM genes was stronger in human xenotransplanted microglia (xMG) in 5xFAD mouse brains, and in microglia from MS lesions, than it was in AD microglia (Figure 7).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > HAM, DAM, and Aging Comparisons in Human AD, Xenograft AD, and Human MS Tissues
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In the paper
“In all three whole-tissue datasets, the HAM-Up gene set was significantly increased (Figure 3D)”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > Validation of the HAM Profile in Multiple Cortical Regions and Datasets
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In the paper
“only APOE upregulation in microglia remained significant after correction for genome-wide testing (fold change = 4.1, adjusted p = 0.0004).”
- Also stated in: § Abstract · plain
“other disease-related changes such as APOE upregulation.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > Defining the HAM Gene Expression Profile Using Frozen Tissues
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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
“This increase was more substantial than the increased expression of the DAM gene set, which was marginal, thus corroborating our analyses in whole-tissue RNA profiles (Figure 3D) and SFG-sorted microglia profiles (Figure 4A).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > HAM, DAM, and Aging Comparisons in Human AD, Xenograft AD, and Human MS Tissues
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In the paper
“We detected increased expression of the HAM-Up gene set in microglial nuclei from tissues with high AD pathology (Figure 7).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > HAM, DAM, and Aging Comparisons in Human AD, Xenograft AD, and Human MS Tissues
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In the paper
“The microglial nuclei from high AD pathology tissues also showed increased expression of the Aging-Up gene set.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > HAM, DAM, and Aging Comparisons in Human AD, Xenograft AD, and Human MS Tissues
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In the paper
“The HAM profile we observe bears little resemblance to the DAM profile.”
- Also stated in: § INTRODUCTION · plain
“which bore almost no resemblance to the damage-associated microglia (DAM) profile defined in mouse AD models.”
- Also stated in: § DISCUSSION · plain
“The DE profile we observed in HAM (the HAM profile) was almost entirely distinct from the DAM profile defined in mouse models.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > Abstract
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In the paper
“However, most AD-related DE genes from our dataset, including APOE and LSR, showed no relationship with age in microglia (Figures 5A and 6A).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > AD Microglia Display an Enhanced Human Aging Phenotype
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In the paper
“In contrast,it was strongly reduced in microglia from MS lesions, being reduced to a similar or even greater extent than in mouse microglia from the Tau-P301S or PS2APP models, respectively (Figure 7).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > HAM, DAM, and Aging Comparisons in Human AD, Xenograft AD, and Human MS Tissues
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In the paper
“However, the RIN of the collected populations was poor, with Bioanalyzer RIN scores in the range of 1–3.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > Defining the HAM Gene Expression Profile Using Frozen Tissues
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In the paper
“most AD risk genes in our cell types purified from frozen brain tissues showed preferential expression in microglia compared with other brain cell types (Figure 2A).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > Defining the HAM Gene Expression Profile Using Frozen Tissues
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In the paper
“the age-related DE scores for AD microglia as a group were significantly higher than the scores for the control group (Figure 5E).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > AD Microglia Display an Enhanced Human Aging Phenotype
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In the paper
“Genome-wide analysis of DE using DESeq2 identified 45 genes increased and 21 genes decreased in AD microglia relative to controls (Figure 3A;”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > Defining the HAM Gene Expression Profile Using Frozen Tissues
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In the paper
“First, the HAM signal was clearly stronger than the DAM signal in AD whole-tissue RNA profiles.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > DISCUSSION
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In the paper
“We did not detect reduced expression of the HAM-Down or Aging-Down gene sets in AD microglial nuclei, perhaps because most of these genes already have low expression and thus are poorly represented in the snRNA-seq data due to extensive gene dropout (Figure S7A), making their further downregulation in AD difficult to detect using this approach.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > HAM, DAM, and Aging Comparisons in Human AD, Xenograft AD, and Human MS Tissues
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In the paper
“expression of the mouse neurodegeneration-related/DAM module was slightly increased in AD microglia, just reaching significance (p = 0.045).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > The HAM Profile Is Unlike Known Mouse Microglial Activation States
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In the paper
“In the myeloid cells, 11/12 DE genes identified by voom+limma were also identified by DESeq2, with CD44 being the only exception (p = 0.113 in DESeq2).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > STAR★METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
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In the paper
“and adding PMI to our statistical model for AD-associated DE gave very similar results.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > STAR★METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
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In the paper
“Sex-associated DE in microglia was almost entirely restricted to X and Y chromosome genes.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > STAR★METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
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In the paper
“there was no overlap between the AD-related DE genes and the PMI-associated genes”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > STAR★METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
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In the paper
“However, the distribution of PMI in our AD and control samples was similar (Figure S2C; Data S4, panel 1A, inset)”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > STAR★METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
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In the paper
“Cell-type-specific marker expression suggested that the RNA-seq profiles we retained represented the intended cell populations with reasonable fidelity (Figure 1D).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > Defining the HAM Gene Expression Profile Using Frozen Tissues
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In the paper
“We validated our overall findings by qRT-PCR using separate preparations of microglia sorted from temporal cortex”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > INTRODUCTION
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In the paper
“AD and control groups had roughly matching distributions of age, sex, and post-mortem interval (PMI).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > Defining the HAM Gene Expression Profile Using Frozen Tissues
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In the paper
“Total RNA extracted from sorted cell populations was subjected to Fluidigm qPCR assay which yielded reliable cell-specific gene expression data, despite poor RNA quality resulting from post-mortem status, freeze/thaw process and fixation.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > STAR★METHODS > METHOD DETAILS
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In the paper
“This did not result from differences in age between our AD and control subjects (Figure 5B).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > AD Microglia Display an Enhanced Human Aging Phenotype
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In the paper
“Despite this caveat, we succeeded in using frozen specimens of human frontal cortex to characterize a human Alzheimer’s microglia (HAM) profile”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > INTRODUCTION
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In the paper
“comparisons with recently published human microglia single-cell RNA sequencing (scRNA-seq) or single-nucleus RNA sequencing (snRNA-seq) datasets suggested that DAM gene induction was more evident in two other neurodegenerative settings.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > INTRODUCTION
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In the paper
“and using whole-tissue RNA-seq datasets from both frontal and temporal cortices.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > INTRODUCTION
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In the paper
“Controls did not have dementia, AD or other neurological disease diagnoses in life.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > STAR★METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
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In the paper
“suggests that its relative lack of induction in AD microglia may be a unique aspect of late-onset AD.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > DISCUSSION
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In the paper
“Overall, our analysis of the snRNA-seq dataset confirmed that the DE we observed in our sorted CD11b+ cell population from AD tissues occurred within the microglial compartment, not in minor populations of co-purifying CD11b+ cells.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > HAM, DAM, and Aging Comparisons in Human AD, Xenograft AD, and Human MS Tissues
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In the paper
“we obtained 113 cell-type-specific expression profiles, including microglia cell profiles from 15 control and 10 AD subjects (Figures 1B and 1C; Data S2).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > Defining the HAM Gene Expression Profile Using Frozen Tissues
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In the paper
“genetic and histological findings suggest that human AD involves impairments in microglial activation (Hansen et al., 2018; Streit et al., 2009).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > DISCUSSION
What the sources say
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In the paper
“This suggests that the enhanced aging profiles we observed in AD microglia are not a direct response to amyloid pathology.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > HAM, DAM, and Aging Comparisons in Human AD, Xenograft AD, and Human MS Tissues
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In the paper
“suggest that the lack of DAM response in human microglia occurs specifically in AD tissues, not other neurodegenerative settings.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > Abstract
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In the paper
“Instead, HAM display an enhanced human aging profile, in addition to other disease-related changes such as APOE upregulation.”
- Also stated in: § AD Microglia Display an Enhanced Human Aging Phenotype · plain
“AD Microglia Display an Enhanced Human Aging Phenotype”
- Also stated in: § INTRODUCTION · plain
“a distinct component of the HAM profile reflected an enhanced human aging phenotype.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > Abstract
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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
“employing a method for prospective isolation of defined cell types from frozen brain tissues that allowed us to survey ~100,000 microglial cells per tissue sample by RNA-seq.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > DISCUSSION
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesWhat 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
“We tested for contributions of age, sex, PMI, and APOE genotype to the DE profile, but none of these covariates accounted for the DE observed between AD and control groups”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > Defining the HAM Gene Expression Profile Using Frozen Tissues
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In the paper
“This seemed to be largely driven by elevated mitochondrial gene expression in a subset of the samples with large PMI.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > STAR★METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
- It may state two separate claims as one. 32
- Probably not a substantial claim. 30
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
“Surprisingly, expression of the resting microglia module defined in mouse microglia was not reduced in microglia from AD tissues (it increased in the snRNA-seq dataset) or even in human xMG from 5xFAD mouse brains.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > HAM, DAM, and Aging Comparisons in Human AD, Xenograft AD, and Human MS Tissues
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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
“RNA was extracted using QIAGEN miRNeasy mini columns, yielding samples with RNA integrity (RIN) scores averaging 6.5.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > STAR★METHODS > METHOD DETAILS
Strength:plain· not yet calibratedn = 289Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“The mouse microglia aging profile, the PS2APP profile, and the PVM profile each showed statistically significant enrichment in AD versus control microglia (Figure 4B).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > The HAM Profile Is Unlike Known Mouse Microglial Activation States
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“A notable caveat of our method is the low quality of the RNA after its purification from the collected cell types because of unavoidable aspects of preparing fixed cell suspensions from frozen and thawed post-mortem tissue samples.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > INTRODUCTION
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Only brief dissociation at 4°C and fixation immediately thereafter permitted cell populations to suitably endure the subsequent immunolabeling and FACS procedures.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > Defining the HAM Gene Expression Profile Using Frozen Tissues
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
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
“Third, we did not observe instances of DAM+ nuclei clustering separately from HAM+ nuclei in the snRNA-seq datasets; instead, these datasets revealed that to whatever extent the DAM signal was induced, it occurred in the same nuclei in which the HAM signal was detected (see Data S4, panel 2).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > DISCUSSION
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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
“However, of more than 100 genes in the module, only APOE was significantly increased in SFG microglia from AD patients (fold change = 4.1, p = 0.0004), and most other genes showed no clear trends in either direction (Figure S5A; Table S1).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > The HAM Profile Is Unlike Known Mouse Microglial Activation States
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None of the sources cited for this claim have been checked yet.
In the paper
“Just as DAM genes induced in neurodegenerative mouse models overlap with those induced by natural aging (Friedman et al., 2018; Holtman et al., 2015), so do many HAM genes induced in human AD tissues (Figure 5A), though the genes involved are distinct between species (Galatro etal.,2017).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > DISCUSSION
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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 contrast, human xMG from 5xFAD mouse brains displayed similar extents of induction for HAM-Up and DAM gene sets, although no changes were observed in the Aging-Up and Aging-Down gene sets (Figure 7).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > HAM, DAM, and Aging Comparisons in Human AD, Xenograft AD, and Human MS Tissues
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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
“In all three whole-tissue datasets, the HAM-Up gene set was significantly increased (Figure 3D); this was most apparent in later Braak stages, which also showed decreased expression of our HAM-Down gene set (Figure S4C).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > Validation of the HAM Profile in Multiple Cortical Regions and Datasets
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“Using these 22 genes to assign a DE score to each sample revealed a clear difference in FuG microglia between AD and control groups, reproducing the signal observed in the SFG RNA-seq data (Figure 3C).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > Validation of the HAM Profile in Multiple Cortical Regions and Datasets
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“None of these attempts were as good as the method described above in terms of cell yield and RNA recovery.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > STAR★METHODS > METHOD DETAILS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“As a point of reference, sorted mouse microglia from the PS2APP and Tau-P301S models showed strong DAM induction and no changes in the HAM-Up gene set.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > HAM, DAM, and Aging Comparisons in Human AD, Xenograft AD, and Human MS Tissues
Strength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“RIN scores for all cell types were typically between 1 and 3.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > STAR★METHODS > METHOD DETAILS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“Most genes with higher expression in microglia from older subjects, including IL15 and the candidate AD risk genes MS4A6A, MS4A4A, NME8, and GPR141, trended toward elevated expression in AD relative to control microglia; conversely, genes with lower expression in microglia from older subjects, like CECR2, tended to be reduced in AD microglia (Figures 5A and 6A).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > AD Microglia Display an Enhanced Human Aging Phenotype
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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
“These samples, which came from new fusiform gyrus tissue blocks, showed very similar sample-by-sample DE profiles as the corresponding samples from the same subjects in GSE95587 (Figure S4A)”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > STAR★METHODS > METHOD DETAILS
Strength:plain· not yet calibratedn = 89Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“All components of the HAM profile—elevated HAM-Up and Aging-Up scores and reduced HAM-Down and Aging-Down scores— were clearly represented in microglia from MS lesions, usually with larger effect sizes and lower p values than the DAM scores in the same cells (Figure 7).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > HAM, DAM, and Aging Comparisons in Human AD, Xenograft AD, and Human MS Tissues
Strength:boosted· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Of 289 total samples, 89 were from subjects that had already been profiled in our previous study, GSE95587.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > STAR★METHODS > METHOD DETAILS
Strength:plain· not yet calibratedn = 89Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Although the fixation adversely affects RNA integrity (RIN), it also permeabilizes the cells and enables labeling of intracellular markers for sorting.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > Defining the HAM Gene Expression Profile Using Frozen Tissues
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“many genes with higher expression in younger subjects in Galatro et al. (2017)’s dataset, like CECR2, were microglia enriched in Gosselin et al. (2017)’s dataset; conversely, many genes with elevated expression in older subjects, like IL15, were monocyte enriched (Figures 6A and 6C).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > AD Microglia Display an Enhanced Human Aging Phenotype
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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 observed that APOE, ABCA7, GPR141, PTK2B, SPI1, and ZYX appeared upregulated in AD microglia, whereas MEF2C appeared downregulated (unadjusted p < 0.05) (Figure 2B).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > Defining the HAM Gene Expression Profile Using Frozen Tissues
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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 included CD44 in our panel of genes tested by qPCR in FuG myeloid cell sorts, and it was again increased in the AD samples (unadjusted p = 0.041), so we consider its DE to be genuine”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > STAR★METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“Differential expression analysis (Data S4, panel 1) revealed that the expression of about 80 genes was significantly increased in microglia from subjects with larger post-mortem interval (PMI).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > STAR★METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“We discarded 1/43 neuron libraries, 19/38 astrocyte libraries, 14/41 endothelial cell libraries, and 18/43 microglia libraries from original frozen tissues, and 16/16 microglia libraries from twice frozen tissues (which underscored the liabilities of the freeze-thaw process).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > STAR★METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“The Cook’s distance filter eliminated 6/10 neuronal DE genes, 9/75 myeloid DE genes, and 382/517 endothelial DE genes from consideration, leaving 4 DE genes in neurons, 66 in myeloid cells, and 135 in endothelial cells.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > STAR★METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. 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
“For APOE genotype, we only detected one DE gene, ACY3, in AD microglia between APOE-e4 carriers versus non-carriers.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > STAR★METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“Compared to”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > STAR★METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Given the highly fragmented condition of our sorted cell RNA preps”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > STAR★METHODS > METHOD DETAILS
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
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
“DE between AD and controls for this study’s sorted cell populations was first attempted using voom+limma, which identified only 12 DE genes (adjusted p ≤ 0.05) in myeloid cells and none in the other cell types.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > STAR★METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, the relative lack of DAM gene induction in human microglia was a peculiar feature of human AD tissues and may be a specific feature of AD pathogenesis.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > INTRODUCTION
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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
“Linear model testing as well as visual exploration revealed no significant correlation between PMI and any of the other variables (diagnosis, see also Figure S2C PMI panel; sex; ApoE4 status; age; or Last MMSE).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > STAR★METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, human microglia are capable of responding in a DAM-like manner, but for some reason this response is blunted in AD patients (at least in the disease stages we examined).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > HAM, DAM, and Aging Comparisons in Human AD, Xenograft AD, and Human MS Tissues
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“our approach allowed us to sample a suitably large number of tissues with known histopathological characteristics while obtaining broad coverage of the transcriptome.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Standard polyA-selected Illumina RNA-Seq analysis was performed as described (Srinivasan et al., 2016) on samples with RNA integrity (RIN) scores at least 5 and post-mortem intervals (PMIs) no greater than 5 hr.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > STAR★METHODS > METHOD DETAILS
What the sources say
- Not checked yetcites Srinivasan et al., 2016 source
Strength:plain· not yet calibratedn = 289Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“provides rich gene expression profiles to enable genome-wide analyses of differential expression (DE)”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > INTRODUCTION
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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
“All AD subjects were clinically diagnosed with AD in life and brains were neuropathologically confirmed to have”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > STAR★METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“The method we developed allows the collection of desired cell types by the tens (or hundreds) of thousands from each tissue sample”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > INTRODUCTION
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably 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
“but were omitted in all other analyses associated with this manuscript to avoid overlap between the two datasets”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > STAR★METHODS > METHOD DETAILS
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably 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
“Although age was not well controlled in the new cohort, the direction of difference was anti-conservative, with the AD cases on average about a half decade younger.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > STAR★METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
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None of the sources cited for this claim have been checked yet.
In the paper
“Several genesassoci-ated with AD incidence (APOE, CLU, ABCA7, SORL1, INPP5D, and PLCG2)(Jansen et al., 2019; Kunkle et al., 2019; Marioni et al., 2018) also function in lipid transport or signaling.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > DISCUSSION
What the sources say
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“These data indicated that the HAM profile in AD microglia reflected a mixture of an enhanced aging process and an age-independent, disease-related activation process.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > AD Microglia Display an Enhanced Human Aging Phenotype
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“We completed this process for 22 AD and 21 control SFG tissues.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > Defining the HAM Gene Expression Profile Using Frozen Tissues
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In the paper
“A third explanation for the dissimilarity could be that the DAM activation state in b-amyloid models is a protective response by healthy microglia (Keren-Shaul et al., 2017)”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > DISCUSSION
What the sources say
- Not checked yetcites Keren-Shaul et al., 2017 source
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✗ Asserted: fails✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The authors may not put it forward as true. 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 sorted cell cohort (GSE125050), controls had either”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > STAR★METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“(The Braak stage analyses did not include the corrective measures for altered cellular makeup of AD tissues, because it was impractical to reduce the sample size.)”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > Validation of the HAM Profile in Multiple Cortical Regions and Datasets
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“Labeling nuclei with DAPI helps ensure that only singlet cell bodies are collected, because doublets with a higher DAPI signal and cell fragments that lack nuclei are easily excluded.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > Defining the HAM Gene Expression Profile Using Frozen Tissues
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“allows the selection of sample cohorts that include a suitably large number of AD and control subjects with desired histopathological or clinical characteristics.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > INTRODUCTION
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“That the DAM activation state—generally considered protective in mouse neurodegeneration models—was more readily observed in microglia from MS lesions and in xMG from 5xFAD mouse brains”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > DISCUSSION
What the sources say
- Not checked yetcites Keren-Shaul et al., 2017 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably 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
“qRT-PCR for specific cell-type markers validated the specificity of the collected populations and was successful for nearly all RNA samples (data not shown).”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > RESULTS > Defining the HAM Gene Expression Profile Using Frozen Tissues
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“After this step cells with less than 800 total transcripts or greater than 30% mitochondrial transcripts were discarded, resulting in 1,738 QC-passing cells for analysis.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > STAR★METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“led us to set these cell types aside (taking a conservative position) and focus on the whether the changes in myeloid cells could be validated.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > STAR★METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
- Rests on an assumption: There was a lack of other human AD datasets available at the time for cross-comparison.
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
“It showed variable expression levels in the Controls (all non-carriers), so it may be a false positive.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > STAR★METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“All assays were performed in duplicate and the average of these two Ct values was kept, except for twelve sample/assay pairs for which the difference was more than 2.82 (corresponding to a standard deviation of 2), which were discarded.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > STAR★METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
Strength:plain· not yet calibratedn = 12Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“We did not use the samples from batches 7 and 8 since, despite restricting to the batch-normalized values, we still saw very strong clustering of these two batches separately from the first 6 on PCA.”
§ Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation > STAR★METHODS > QUANTIFICATION AND STATISTICAL ANALYSIS
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The authors state this as an assumption.
Damage from the freeze-thaw process led to cellular disintegration when cells remained unfixed for too long or were incubated at 37°C.
“We presume that damage from the freeze-thaw process led to cellular disintegration when cells remained unfixed for too long or were incubated at 37°C.”
The paper relies on this without support.
Gray matter atrophy was pronounced in the fusiform gyrus from AD subjects.
“since gray matter atrophy was pronounced in FuG from AD subjects”
The paper relies on this without support.
Activated microglia often display elevated CD45 reactivity.
“since we did not want to exclude activated microglia which often display elevated CD45 reactivity”
The paper relies on this without support.
There was a lack of other human AD datasets available at the time for cross-comparison.
“the lack of other human AD datasets available at the time for cross-comparison”
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 says what the claim attributes to it.
In the citing paper
“Transcriptional profiles of microglia isolated from frozen human AD and control cortical tissue suggest an overall species difference in the disease associated signature, though an increased SPI1 expression was measured in AD samples compared to controls55 validating previous observations by others31.”
From Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease (2021) · cites this paper as [55]
The cited source says what the claim attributes to it.
In the citing paper
“Transcriptional profiles of microglia isolated from frozen human AD and control cortical tissue suggest an overall species difference in the disease associated signature, though an increased SPI1 expression was measured in AD samples compared to controls55 validating previous observations by others31.”
From Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease (2021) · cites this paper as [55]
The cited source says what the claim attributes to it.
In the citing paper
“Human single nucleus RNA sequencing data from Mathys and colleagues [5] and Lake and colleagues [12] were obtained from The Myeloid Landscape 2 portal (http://research-pub.gene.com/BrainMyeloidLandscape) [70].”
From Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease (2024) · cites this paper as [70]
The cited source says what the claim attributes to it.
In the citing paper
“We further compared 832 DEGs with bulk RNA-seq datasets from various brain regions in individuals with AD (80–84), gene members in GO terms related to apoptosis/neurodegeneration, and AD risk genes from Alzgene database, revealing distinct sets of DEGs with overlaps ranging from 8 to 135 genes (Table S7, page 2, 3 and 4).”
From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [84]
The cited source says what the claim attributes to it.
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 Srinivasan et al 2020
The cited source says what the claim attributes to it.
In the citing paper
“Cluster 2 genes were significantly enriched for genes upregulated following in vitro culture34 and in AD-derived microglia33.”
From Genetic analysis of the human microglial transcriptome across brain regions, aging and disease pathologies (2022) · cites this paper as [33]
The cited source says what the claim attributes to it.
In the citing paper
“Cluster 1 contained genes that were upregulated in the cortical regions compared to subcortical regions, such as P2RY12, CD36, and MRC1, and was enriched in genes that were downregulated in AD brain33 and in response to in vitro culture34.”
From Genetic analysis of the human microglial transcriptome across brain regions, aging and disease pathologies (2022) · cites this paper as [33]
The cited source says what the claim attributes to it.
In the citing paper
“The downregulated genes were significantly enriched for cell motility, polarity, IL-6 cytokine signaling (Fig. 3b), and for genes also downregulated following in vitro culture34 and in AD-derived microglia33 (Fig. 3c).”
From Genetic analysis of the human microglial transcriptome across brain regions, aging and disease pathologies (2022) · cites this paper as [33]
The cited source says what the claim attributes to it.
In the citing paper
“While APOE is upregulated in human microglia in AD, the mouse DAM phenotype is absent or only partially overlaps, highlighting species differences between human and mouse and the importance of studying APOE4 in human systems (Galatro et al., 2017; Li et al., 2021; Srinivasan et al., 2020; Zhou et al., 2020).”
From Cholesterol and matrisome pathways dysregulated in astrocytes and microglia (2022) · cites this paper as Srinivasan et al., 2020
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Cluster 1 genes were enriched in genes that were downregulated in AD brain and in response to in vitro culture.”
From Genetic analysis of the human microglial transcriptome across brain regions, aging and disease pathologies (2022) · cites this paper as [33]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Frontal-cortex AD subject count differs between text and table
MinorThe Results state that 22 AD and 21 control SFG tissues were processed, but the sorted-cell cohort table lists 21 AD and 21 control subjects under "All Subjects."
“We completed this process for 22 AD and 21 control SFG tissues.”
“| N | 21 | 21 | | 15 | 10 | |”
Citations
Cites
Neuropathological stageing of Alzheimer-related changes.
Braak, H., & Braak, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00308809 · Cited by 16,123 · cited 2×
“All AD subjects were clinically diagnosed with AD in life and brains were neuropathologically confirmed to have "frequent" CERAD neuritic plaque densities (Mirra et al., 1991) and Braak score V or VI ( Braak and Braak, 1991).”
A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease
Keren-Shaul, H., Spinrad, A., Weiner, A., Matcovitch-Natan, O., Dvir-Szternfeld, R., Ulland, T. K., David, E., Baruch, K., Lara-Astaiso, D., Toth, B., et al. (2017) · Cell · doi:10.1016/j.cell.2017.05.018 · Cited by 5,493
Mirra, S. S., Heyman, A., McKeel, D., Sumi, S. M., Crain, B. J., Brownlee, L. M., Vogel, F. S., Hughes, J. P., Belle, G. V., Berg, L., et al. (1991) · Neurology · doi:10.1212/wnl.41.4.479 · Cited by 4,961
Meta-Analysis of 74,046 Individuals Identifies 11 New Susceptibility Loci for Alzheimer’s Disease
(EADI), E. A. D. I., Lambert, J.-C., (GERAD), G. A. E. R. I. A. D., Alzheimer's Disease Genetic Consortium (ADGC), (CHARGE), C. F. H. A. A. R. I. G. E., Ibrahim-Verbaas, C. A., Harold, D., Naj, A. C., Sims, R., Bellenguez, C., et al. (2013) · Nature Genetics · doi:10.1038/ng.2802 · Cited by 4,336
Host microbiota constantly control maturation and function of microglia in the CNS
Erny, D., Hrabě de Angelis, A. L., Jaitin, D., Wieghofer, P., Staszewski, O., David, E., Keren-Shaul, H., Mahlakoiv, T., Jakobshagen, K., Buch, T., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.4030 · Cited by 3,569
Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq
Zeisel, A., Muñoz-Manchado, A. B., Codeluppi, S., Lönnerberg, P., La Manno, G., Juréus, A., Marques, S., Munguba, H., He, L., Betsholtz, C., et al. (2015) · Science · doi:10.1126/science.aaa1934 · Cited by 3,124
Krasemann, S., Madore, C., Cialic, R., Baufeld, C., Calcagno, N., El Fatimy, R., Beckers, L., O’Loughlin, E., Xu, Y., Fanek, Z., et al. (2017) · Immunity · doi:10.1016/j.immuni.2017.08.008 · Cited by 2,979
Alzheimer Disease Genetics Consortium (ADGC), Kunkle, B. W., The European Alzheimer’s Disease Initiative (EADI), Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE), Genetic and Environmental Risk in AD/Defining Genetic, P. A. E. R. F. A. D. C. (., Grenier-Boley, B., Sims, R., Bis, J. C., Damotte, V., Naj, A. C., et al. (2019) · Nature Genetics · doi:10.1038/s41588-019-0358-2 · Cited by 2,946
Single-cell transcriptomic analysis of Alzheimer’s disease
Mathys, H., Davila-Velderrain, J., Peng, Z., Gao, F., Mohammadi, S., Young, J. Z., Menon, M., He, L., Abdurrob, F., Jiang, X., et al. (2019) · Nature · doi:10.1038/s41586-019-1195-2 · Cited by 2,568
Zhang, Y., Sloan, S. A., Clarke, L. E., Caneda, C., Plaza, C. A., Blumenthal, P. D., Vogel, H., Steinberg, G. K., Edwards, M. S. B., Li, G., et al. (2016) · Neuron · doi:10.1016/j.neuron.2015.11.013 · Cited by 2,295
Flagged first, then by citations
1 of the 52 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Microglia states and nomenclature: A field at its crossroads
Paolicelli, R. C., Sierra, A., Stevens, B., Tremblay, M.-E., Aguzzi, A., Ajami, B., Amit, I., Audinat, E., Bechmann, I., Bennett, M., et al. (2022) · Neuron · doi:10.1016/j.neuron.2022.10.020 · Cited by 1,973
Spatial Transcriptomics and In Situ Sequencing to Study Alzheimer’s Disease
Chen, W.-T., Lu, A., Craessaerts, K., Pavie, B., Sala Frigerio, C., Corthout, N., Qian, X., Laláková, J., Kühnemund, M., Voytyuk, I., et al. (2020) · Cell · doi:10.1016/j.cell.2020.06.038 · Cited by 949
Single cell RNA sequencing of human microglia uncovers a subset associated with Alzheimer’s disease
Olah, M., Menon, V., Habib, N., Taga, M. F., Ma, Y., Yung, C. J., Cimpean, M., Khairallah, A., Coronas-Samano, G., Sankowski, R., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19737-2 · Cited by 722
Neuroinflammation in Alzheimer disease
Heneka, M. T., van der Flier, W. M., Jessen, F., Hoozemanns, J., Thal, D. R., Boche, D., Brosseron, F., Teunissen, C., Zetterberg, H., Jacobs, A. H., et al. (2025) · Nature Reviews Immunology · doi:10.1038/s41577-024-01104-7 · Cited by 638
Molecular characterization of selectively vulnerable neurons in Alzheimer’s disease
Leng, K., Li, E., Eser, R., Piergies, A., Sit, R., Tan, M., Neff, N., Li, S. H., Rodriguez, R. D., Suemoto, C. K., et al. (2021) · Nature Neuroscience · doi:10.1038/s41593-020-00764-7 · Cited by 485
Metadata
- Authors
- Srinivasan, K., Friedman, B. A., Etxeberria, A., Huntley, M. A., van der Brug, M. P., Foreman, O., Paw, J. S., Modrusan, Z., Beach, T. G., Serrano, G. E., & Hansen, D. V.
- Affiliations
- Genentech (US)
- Banner Sun Health Research Institute (US)
- Corresponding author
- Friedman, Brad A.
- Hansen, David V.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2020-06
- Volume
- 31
- Issue
- 13
- Pages
- 107843
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC7422733
- OpenAlex
- W3039072393
- Semantic Scholar
- 161193b958b5ad9f3c708d4d10a0ed89678d1d84
- Cited by
- 427
- References
- 52
- Citations by year
- 2026: 55 · 2025: 60 · 2024: 68 · 2023: 61 · 2022: 74 · 2021: 89 · 2020: 18
- FWCI
- 24.01
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Michael J. Fox Foundation for Parkinson's Research (GSE125050, GSE125583)
- Genentech
- Arizona Department of Health Services (211002)
- Arizona Biomedical Research Commission (0011, 05-901, 1001, 4001)
- National Institute on Aging (P30 AG19610)
- National Institute of Neurological Disorders and Stroke (U24 NS072026)
- 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, human microglia, microglial activation, aging, apolipoprotein E, transcriptome, single-nucleus RNA sequencing, single-cell RNA sequencing, mouse model, neuroinflammation
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Animals, Female, Frontal Lobe, Frozen Sections, Humans, Male, Monocytes, Multiple Sclerosis, Phenotype, Risk Factors, Temporal Lobe, Reproducibility of Results, Transcriptional Activation, Cellular Senescence, Microglia, Genetic Predisposition to Disease, Gene Expression Profiling, Databases, Genetic, Mice, Heterografts
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 2026-10-07, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-07 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
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