The DOI matches its Crossref record; 65 of the 71 references it cites were found in a registry or an index; 54 of the 66 sources its claims cite were checked for support.
Alzheimer's-associated PU.1 expression levels regulate microglial inflammatory response
Open accessAbstract
More than forty loci contribute to genetic risk for Alzheimer's disease (AD). These risk alleles are enriched in myeloid cell enhancers suggesting that microglia, the brain-resident macrophages, contribute to AD risk. We have previously identified SPI1/PU.1, a master regulator of myeloid cell development in the brain and periphery, as a genetic risk factor for AD. Higher expression of SPI1 is associated with increased risk for AD, while lower expression is protective. To investigate the molecular and cellular phenotypes associated with higher and lower expression of PU.1 in microglia, we used stable overexpression and knock-down of PU.1 in BV2, an immortalized mouse microglial cell line. Transcriptome analysis suggests that reduced PU.1 expression suppresses expression of homeostatic genes similar to the disease-associated microglia response to amyloid plaques in mouse models of AD. Moreover, PU.1 knock-down resulted in activation of protein translation, antioxidant action and cholesterol/lipid metabolism pathways with a concomitant decrease of pro-inflammatory gene expression. PU.1 overexpression upregulated and knock-down downregulated phagocytic uptake in BV2 cells independent of the nature of the engulfed material. However, cells with reduced PU.1 expression retained their ability to internalize myelin similar to control albeit with a delay, which aligns with their anti-inflammatory profile. Here we identified several microglial responses that are modulated by PU.1 expression levels and propose that risk association of PU.1 to AD is driven by increased pro-inflammatory response due to increased viability of cells under cytotoxic conditions. In contrast, low expression of PU.1 leads to increased cell death under cytotoxic conditions accompanied by reduced pro-inflammatory signaling that decreased A1 reactive astrocytes signature supporting the protective effect of SPI1 genotype in AD. These findings inform future in vivo validation studies and design of small molecule screens for therapeutic discovery in AD.
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Claims the paper makes
53 Own result · 37 Own interpretation · 24 Partly supported · 16 Supported · 8 Own method · 4 No full text of the sources · 1 Supported so far · 1 No basis given · accuracy not yet measured
Every source the paper cites for this claim was checked and supports it.
In the paper
“We have previously reported that SPI1 is the most likely gene mediating the association of the CELF1 locus with AD risk (Huang et al., 2017).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Introduction
What the sources say
- Supportedcites Huang et al., 2017 source
The Results section ('Conditional and SMR analysis of the SPI1/CELF1 locus') calls SPI1 the most likely candidate gene underlying the disease association at this locus. The Discussion explicitly nominates SPI1 as the gene responsible for the association at the previously reported CELF1 locus. (LLM, conf=0.95)
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.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“The disease-associated phenotype of microglia seems to be shared by aging, as well as neurological and non-neurological diseases with different etiology, e.g. AD and amyotrophic lateral sclerosis (Holtman et al., 2015; Keren-Shaul et al., 2017), atherosclerosis and obesity, characterized by lipid overload (Jaitin et al., 2019; Martinet et al., 2019).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Introduction
What the sources say
- Supportedcites Holtman et al., 2015 source
The Discussion and conclusions report a shared core microglial gene-expression profile in mouse models of physiological aging, Alzheimer’s disease and ALS, suggesting a similarly primed phenotype. In the citing sentence, Holtman et al. is cited for those conditions; the atherosclerosis and obesity examples have separate citations. The source’s evidence is from mouse models, not direct studies of patients. (LLM, conf=0.91)
- Supportedcites Keren-Shaul et al., 2017 source
The Results identify disease-associated microglia in an Alzheimer’s disease mouse model, a highly similar population in an ALS mouse model, and an increased population in aged mice. The Discussion suggests this program is not specific to one disease etiology. In the citing sentence, atherosclerosis and obesity are attached to different citations, not to Keren-Shaul et al. (LLM, conf=0.91)
- Supportedcites Jaitin et al., 2019 source
The Results section reports that lipid-associated macrophages in obese adipose tissue have a gene profile highly similar to disease-associated microglia. The Discussion extends that comparison to aortic macrophages in atherosclerosis and identifies lipid accumulation as a common feature. The sentence cites other works for aging and amyotrophic lateral sclerosis; Jaitin et al. supports the obesity and atherosclerosis portion. (LLM, conf=0.90)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Meta-analysis of genome-wide association studies for AD suggests that genes expressed in microglia modulate risk for late onset AD (Jones et al., 2015; Kunkle et al., 2019).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Introduction
What the sources say
- Supportedcites Jones et al., 2015 source
The Results report that genes shared by an immune/microglia expression module and the paper’s significantly enriched modules were enriched for association with late-onset AD. The Discussion interprets the GWAS-linked expression signature as a possible marker of microglial changes affecting AD susceptibility. This supports the citing sentence’s qualified wording, although the full microglia module was not significantly enriched. (LLM, conf=0.87)
- Supportedcites Kunkle et al., 2019 source
In Results, under “Candidate gene prioritization at genome-wide loci” (page unavailable), the paper reports that genes at GWAS loci include genes preferentially or highly expressed in microglia. It also describes microglial cells as playing a key role in the response associated with late-onset Alzheimer’s disease, supporting the citing sentence’s qualified claim. (LLM, conf=0.90)
hedgedcorrelational- 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.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“This signaling pathway seems to be conserved in human microglia (Zhou et al., 2020)”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Introduction
What the sources say
- Partly supportedcites Zhou et al., 2020 sourceExperimental — accuracy not yet measured
The Results section on TREM2 variants reports a reduced microglial response in human AD, supporting a shared role for TREM2 in mouse and human disease. But the Results section on human AD gene signatures and the Discussion say the human microglial signature is quite distinct from mouse disease-associated microglia (DAM); they do not establish that the DAM signaling pathway is conserved. The indexed passages provide no page numbers. (LLM, conf=0.85)
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“We have previously reported that PU.1 regulates zymosan phagocytosis (Huang et al., 2017) and others reported that PU.1 knock-down reduces Aβ42 uptake in human microglial cells (Smith et al., 2013).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > PU.1 overexpression increased and knock-down decreased microglial phagocytosis
What the sources say
- Supportedcites Huang et al., 2017 source
The Results section reports that PU.1 overexpression increased zymosan uptake in BV2 mouse microglial cells, while PU.1 knock-down decreased it. The Discussion likewise states that changing PU.1 expression altered zymosan engulfment. This supports the cited claim in the cell model studied. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Our data suggest that PU.1 may contribute to this mechanism of innate immune memory in the brain (Wendeln et al., 2018).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
What the sources say
- Supportedcites Wendeln et al., 2018 source
The citation supports the reference to innate immune memory in the brain: the Microglial molecular profiles section says the experiments provide proof of principle for innate immune memory in microglia. The suggestion that PU.1 contributes is explicitly the citing authors’ interpretation of their own data, not a finding attributed to Wendeln et al. (LLM, conf=0.90)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“However, the impaired ability of Trem2−/− or Apoe−/− microglia to remove damaged myelin hinders subsequent remyelination (Cantoni et al., 2015; Cantuti-Castelvetri et al., 2018; Poliani et al., 2015; Yeh et al., 2016).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
What the sources say
- Partly supportedcites Cantoni et al., 2015 sourceExperimental — accuracy not yet measured
The Results section (“Defective myelin degradation by microglia in TREM2−/− mice”; page unavailable) supports impaired myelin breakdown and clearance in TREM2−/− mice, but reports no defect in myelin uptake. Our copy does not establish that this defect hinders subsequent remyelination, and it does not provide evidence about Apoe−/− microglia. (LLM, conf=0.88)
- Partly supportedcites Cantuti-Castelvetri et al., 2018 sourceExperimental — accuracy not yet measured
The main text (p. 2) reports myelin-debris accumulation in APOE-knockout phagocytes and impaired lesion recovery; the Fig. 3 caption (Supplementary Materials, p. 6) describes APOE-knockout microglial clearance and remyelination measurements. Our copy does not report the claimed impairment in Trem2-knockout microglia. (LLM, conf=0.87)
- Partly supportedcites Poliani et al., 2015 sourceExperimental — accuracy not yet measured
The Results and Discussion report impaired myelin-debris removal and remyelination in Trem2−/− mice after cuprizone-induced demyelination. This supports the Trem2−/− portion, but the cited paper does not establish the corresponding claim for Apoe−/− microglia. (LLM, conf=0.88)
plaindirect- 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.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Proliferation of microglia depends on CSF1R signaling through PU.1 and C/EBPα (Gomez-Nicola et al., 2013), and we now show that microglial apoptosis is also modulated by PU.1 (Fig. 3), which in vivo leads to regeneration of white matter after death of pro-inflammatory microglia following demyelination (Lloyd et al., 2019).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
What the sources say
- Supportedcites Lloyd et al., 2019 source
The copy’s Abstract states that efficient remyelination requires death of pro-inflammatory microglia followed by repopulation, and passage [1] describes this as supporting white matter regeneration. The source identifies the death mechanism as necroptosis; the citing authors’ preceding statement about PU.1 and apoptosis is their own finding, not the claim attributed to Lloyd et al. (LLM, conf=0.92)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“This effect was propagated to primary astrocytes inducing a neurotoxic reactive gene signature, which was reduced by PU.1 knock-down in LPS-stimulated microglial cells (Fig. 5g), suggesting reduced PU.1 expression converts microglial cells to a neuroprotective phenotype (Joshi et al., 2019; Yun et al., 2018).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
What the sources say
- Could not verifycites Joshi et al., 2019 sourceExperimental — accuracy not yet measured
The Results sections on microglial activation and astrocyte responses report that P110 inhibits Drp1/Fis1-mediated mitochondrial fission and blunts inflammatory responses. Searches for PU.1, SPI1, and PU.1 knock-down found no passage in our copy linking reduced PU.1 expression to a neuroprotective microglial phenotype. The cited paper therefore does not verify the specific claim. (LLM, conf=0.76)
- Partly supportedcites Yun et al., 2018 sourceExperimental — accuracy not yet measured
The paper reports that inhibiting microglial activation with NLY01 prevents the formation of neurotoxic A1 astrocytes (Abstract; page unavailable). It does not report that reducing PU.1 expression or knocking down PU.1 converts microglia to a neuroprotective phenotype. (LLM, conf=0.82)
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.
- Could not verify
Every source the paper cites for this claim was checked and supports it.
In the paper
“In BV2 microglial cells protective low expression of PU.1 led to decreased phagocytic uptake (Fig. 2), which is in line with previous data showing that siRNA knock-down of PU.1 in human microglia in vitro reduces expression of genes involved in phagocytic and antigen presentation pathways (Rustenhoven et al., 2018).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
What the sources say
- Supportedcites Rustenhoven et al., 2018 source
The citation is attached to the previous-data clause, not the citing authors’ BV2 uptake result. The Methods describe PU.1-specific siRNA transfection, and the Results and Discussion report reduced expression of genes involved in phagocytosis and antigen presentation in human microglia. The cited paper does not need to establish the BV2 result to support this citation. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
- Probably not a substantial claim. 32
- It may state two separate claims as one. 71
Every source the paper cites for this claim was checked and supports it.
In the paper
“The molecular signature of disease-associated microglia (DAM), described in the 5XFAD mouse model of AD, shows repression of microglial homeostatic genes that are expressed in microglia within a healthy brain and upregulation of genes with roles in phagocytosis and lipid metabolism (Keren-Shaul et al., 2017).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Introduction
What the sources say
- Supportedcites Keren-Shaul et al., 2017 source
The Introduction identifies DAM in the 5XFAD mouse model and describes downregulation of microglial checkpoint genes followed by activation of phagocytic and lipid-metabolism activity. The Results report decreasing expression of a homeostatic gene during the transition to DAM and state that DAM express high levels of phagocytic and lipid-metabolism pathways. Page numbers are unavailable in our copy. (LLM, conf=0.94)
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. It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In microglia and macrophages PU.1 is bound to myeloid-specific enhancers sustaining cell response to injury induced by stimulus-dependent transcription factors (Holtman et al., 2017).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Introduction
What the sources say
- Partly supportedcites Holtman et al., 2017 sourceExperimental — accuracy not yet measured
The PU.1 section identifies PU.1 as a myeloid lineage-determining factor that binds most microglial enhancers. The Introduction explains that stimulus-dependent transcription factors act at enhancers established by lineage-determining factors to produce cell-specific responses. It does not specifically establish that PU.1 sustains a response to injury in both microglia and macrophages. (LLM, conf=0.82)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The DAM response is dependent on TREM2 and APOE, two major AD risk genes, in mouse models of AD and metabolic disease (Krasemann et al., 2017; Pimenova et al., 2017a).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Introduction
What the sources say
- Partly supportedcites Krasemann et al., 2017 sourceExperimental — accuracy not yet measured
The Discussion says the disease-associated microglial signature depends on the TREM2–APOE pathway, and the Results demonstrate a TREM2-mediated phenotype switch in APP-PS1 Alzheimer’s-model mice. The Results also find the signature in Mfp2-deficient mice, identified in Methods as a lipid-disorder model, but do not establish that the response in that model depends on both TREM2 and APOE. Page numbers are unavailable in our copy. (LLM, conf=0.84)
- Not matchedcites Pimenova et al., 2017a
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“SPI1/PU.1 is a master regulator of microglial development and homeostasis and the expression of several AD genetic risk genes, e.g. ABCA7, CD33, MS4A4A, MS4A6A, TREM2, APOE and CLU, and small changes in PU.1 expression can significantly affect cell function (Huang et al., 2017; Satoh et al., 2014).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Introduction
What the sources say
- Partly supportedcites Huang et al., 2017 sourceExperimental — accuracy not yet measured
The Results section on the PU.1 cistrome reports binding at several AD-associated genes, and its functional experiments show that altering PU.1 changes gene expression and phagocytosis in mouse microglial cells. The Discussion describes PU.1 as required for myeloid-cell development and function, but the paper does not establish that *small* expression changes significantly affect cell function or specifically characterize PU.1 as a master regulator of microglial homeostasis. (LLM, conf=0.85)
- Partly supportedcites Satoh et al., 2014 sourceExperimental — accuracy not yet measured
The Introduction and Discussion (pages unavailable) support PU.1’s importance for microglial development and function: PU.1-deficient mice lack microglia, and PU.1 knockdown reduces human microglial viability and phagocytosis. The paper identifies Trem2 as a Spi1 target, but does not establish regulation of the other listed Alzheimer’s disease risk genes or show that small changes in PU.1 expression significantly affect cell function. (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“although the mouse DAM transcriptome profile may not be fully present in AD brain, as human microglia show a distinct AD-related gene signature (Jaitin et al., 2019; Mathys et al., 2019).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Introduction
What the sources say
- Could not verifycites Jaitin et al., 2019 sourceExperimental — accuracy not yet measured
The Results and Discussion (page not provided) describe a DAM-like signature shared across macrophages and say it is highly similar to signatures in the brains of mice and humans with neurodegenerative disease. Our copy does not assess whether the mouse DAM transcriptome is fully present in Alzheimer’s disease brain or report a distinct Alzheimer’s-related signature in human microglia (searched for those comparisons). High similarity does not rule out differences, so this is not a contradiction. (LLM, conf=0.73)
- Supportedcites Mathys et al., 2019 source
The ‘Identification of AD-associated cellular subpopulations’ section reports that human AD-associated Mic1 markers overlap significantly with mouse disease-associated microglia markers, but also include AD-associated genes not seen in the animal models. It concludes that the human state shares features with, yet is distinct from, the reported mouse states, supporting the claim’s cautious wording. (LLM, conf=0.92)
hedged- 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.
- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“SPI1/PU.1 is a myeloid lineage-determining transcription factor that together with MEF2C shapes the enhancer landscape specific to microglia in the brain (Lavin et al., 2014).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Introduction
What the sources say
- Partly supportedcites Lavin et al., 2014 sourceExperimental — accuracy not yet measured
The Results (‘Tissue Regulators Define Distinct Sets of Macrophage Enhancers’; page not provided) report MEF2 motif enrichment at microglia-specific enhancers and identify Mef2c as the most differentially expressed MEF2 family member in microglia. The Discussion describes PU.1 as a master regulator but calls Mef2c a candidate regulator; it does not establish that PU.1 and MEF2C together shape the microglial enhancer landscape. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Higher expression of SPI1 is associated with increased risk for AD, while lower expression is protective.”
- Also stated in: § Introduction · plain
“Reduced PU.1 expression confers protection, while increased expression is associated with higher AD risk.”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Abstract
What the sources say
- Supportedcites Huang et al., 2017 source
The Abstract (page unavailable) reports that a protective allele is associated with lower SPI1 expression in myeloid cells and delayed Alzheimer’s onset; it also states that the results suggest lower SPI1 expression reduces AD risk. Higher expression being associated with greater risk is the corresponding direction of that reported association. (LLM, conf=0.87)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Also stated in: § Introduction · plain
Every source the paper cites for this claim was checked and supports it.
In the paper
“Modulation of PU.1 significantly affected the microglial transcriptome with knock-down of PU.1 showing opposing effects to overexpression (Fig. 1), which we further compared to the previously described DAM signature to elaborate on the possible significance of these changes in vivo (Keren-Shaul et al., 2017).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
What the sources say
- Supportedcites Keren-Shaul et al., 2017 source
The citation is attached to the previously described DAM signature, not to the citing authors’ PU.1 modulation results. The source’s Results describe DAM as a distinct microglial state in an Alzheimer’s disease mouse model and report its gene-expression changes; the citing authors’ comparison is therefore to a signature this paper describes. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Phagocytic capability of microglia has been shown to be affected by risk factors for AD, such as TREM2 and CD33 (Griciuc et al., 2013; Kleinberger et al., 2014).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > PU.1 overexpression increased and knock-down decreased microglial phagocytosis
What the sources say
- Supportedcites Griciuc et al., 2013 source
The Introduction reports that CD33 is both required and sufficient to inhibit microglial uptake of Aβ42. The Discussion also identifies TREM2 as an AD risk gene and reports its role in phagocytic clearance. Page numbers are not provided in our copy. (LLM, conf=0.92)
- Not checked — no full text of the sourcecites Kleinberger et al., 2014 source
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.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Activated microglia propagate the inflammatory response to astrocytes, which become reactive and neurotoxic (Liddelow et al., 2017).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > PU.1 overexpression amplifies and knock-down abates microglial inflammatory response
What the sources say
- Supportedcites Liddelow et al., 2017 source
The Introduction states that activated microglia induce A1 reactive astrocytes, which gain a neurotoxic function. The Concluding Remarks specify that microglia induce A1s by secreting Il-1α, TNFα, and C1q. The claim accurately paraphrases this finding, with the qualification that the paper identifies the neurotoxic cells as A1 astrocytes. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Next we tested the effect of Aβ42 and LPS on oxidative stress response in microglial cells as amyloid and inflammation trigger and exacerbate pathological changes in AD brain (Wendeln et al., 2018).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > PU.1 overexpression potentiates and knock-down mitigates microglial oxidative stress response
What the sources say
- Partly supportedcites Wendeln et al., 2018 sourceExperimental — accuracy not yet measured
In “Immune memory shapes neuropathology” (page not provided), the paper reports that amyloid plaques activate microglia and that a single LPS exposure increased amyloid burden in an AD mouse model. The claim is too broad about inflammation exacerbating pathology: four LPS exposures instead decreased amyloid burden. (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The SPI1 locus is one of the few AD risk loci for which a mechanism of action based on the modulation of gene expression by common disease risk alleles has been delineated (Huang et al., 2017).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
What the sources say
- Partly supportedcites Huang et al., 2017 sourceExperimental — accuracy not yet measured
The Results (Cis-eQTL associations and colocalization analysis; page unavailable) link a protective allele to lower SPI1 expression in myeloid cells, and the Discussion proposes expression changes as a route by which the locus may affect AD risk. But the Discussion calls this a hypothesis, and the Results (Conditional and SMR analysis; page unavailable) say the functional variant has not been definitively identified. Saying the mechanism has been delineated is therefore stronger than the paper's conclusion. (LLM, conf=0.84)
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.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Interestingly, DAM and PU.1 overexpression both upregulated TREM1 pathways, while PU.1 knock-down showed decreased activation, which aligns with reduced uptake capacity in BV2 cells after PU.1 downregulation (Huang et al., 2017).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > Knock-down of PU.1 repressed homeostatic microglial gene expression and activated disease-associated microglial signature pathways
What the sources say
- Supportedcites Huang et al., 2017 source
The citation is attached to the reduced-uptake finding, not the citing authors’ transcriptomic comparison of TREM1 pathways. In Results (‘SPI1 (PU.1) cistrome and functional analysis in myeloid cells’), Huang et al. report that PU.1 knock-down decreased zymosan uptake, measured as phagocytic activity in BV2 cells. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“F11349, F12455 and 75.11-IW1A12 (Karch et al., 2019) iPSC lines were used with confirmed normal karyotyping (WiCell).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Methods > iPSCs culture and differentiation
What the sources say
- Partly supportedcites Karch et al., 2019 sourceExperimental — accuracy not yet measured
In Results, “Generation and Characterization of iPSCs” (page unavailable), the paper says chromosomal stability was assessed by karyotyping and all reported iPSC lines met its quality-control criteria. Table 4 identifies 75.11-IW1A12, but the copy does not identify F11349 or F12455 or establish their karyotyping results. It also does not attribute testing to WiCell. (LLM, conf=0.85)
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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Oxidative stress is part of AD pathology as Aβ42 neurotoxicity leads to induction of reactive oxygen species and other free radicals, which in turn may escalate production and deposition of Aβ and phosphorylation and polymerization of tau (Kim et al., 2015).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
What the sources say
- Partly supportedcites Kim et al., 2015 sourceExperimental — accuracy not yet measured
The Alzheimer’s disease section says Aβ accumulation may increase oxidative stress and ROS, while oxidative stress can increase Aβ production and deposition and promote tau phosphorylation. It does not specifically identify Aβ42 as the cause or say that oxidative stress promotes tau polymerization. Page numbers were not provided in our copy. (LLM, conf=0.87)
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. It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“On the other hand, under normal conditions microglia sculpt neuronal brain connections and increased phagocytic activity by PU.1 overexpression may result in elevated removal of dendritic spines contributing to neuronal loss in disease based on studies of microglia depletion in mouse models (Elmore et al., 2018).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
What the sources say
- Partly supportedcites Elmore et al., 2018 sourceExperimental — accuracy not yet measured
The Results section (page unavailable) reports that microglial elimination increased dendritic spine density in aged mice and that replacement microglia sculpted the synaptic landscape. The paper does not connect PU.1 overexpression to increased phagocytosis, excess spine removal, or neuronal loss in disease. (LLM, conf=0.88)
hedgedconditional- 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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The neurodegeneration-related state is controlled by APOE, and agonists of LXR promoted this anti-inflammatory state and microglial phagocytosis of Aβ42 in vitro (Rangaraju et al., 2018).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
What the sources say
- Partly supportedcites Rangaraju et al., 2018 sourceExperimental — accuracy not yet measured
The Discussion identifies Apoe as a hub gene in the anti-inflammatory/phagocytic disease-associated microglia module and describes evidence for its role in regulating these responses. The Results report that LXR agonist treatment increased anti-inflammatory microglia and Aβ42 phagocytosis, but the mice were treated in vivo; phagocytosis was then measured ex vivo, not following LXR treatment in vitro. (LLM, conf=0.88)
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. It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In mouse and human brain turnover of microglia depends on high proliferation rates spatially coupled to efficient apoptosis in order to maintain steady state cell numbers in each brain region (Askew et al., 2017; Füger et al., 2017).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
What the sources say
- Partly supportedcites Askew et al., 2017 sourceExperimental — accuracy not yet measured
The Introduction and Results report high microglial proliferation in mouse and human brains and spatially coupled apoptosis that helps maintain relatively stable cell numbers. However, the Results examined only selected regions and found that microglial numbers increased with age in the mouse thalamus; they do not support steady numbers in each brain region. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites Füger et al., 2017 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Another possibility explaining the protective effect of a reduction in phagocytic uptake is that microglial cells with PU.1 knock-down may continue to maintain a barrier around the amyloid plaques, which has been shown to insulate toxic Aβ42 and improve cognition in mice independent of microglial phagocytic activity based on studies of Trem2−/−mice (Condello et al., 2015; Yuan et al., 2016).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
What the sources say
- Partly supportedcites Condello et al., 2015 sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Not checked — no full text of the sourcecites Yuan et al., 2016 source
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. It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Proliferation of microglia depends on CSF1R signaling through PU.1 and C/EBPα (Gomez-Nicola et al., 2013), and we now show that microglial apoptosis is also modulated by PU.1 (Fig. 3), which in vivo leads to regeneration of white matter after death of pro-inflammatory microglia following demyelination (Lloyd et al., 2019).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
What the sources say
- Supportedcites Gomez-Nicola et al., 2013 source
The Introduction identifies the CSF1R–PU.1–C/EBPα axis as key to controlling microglial proliferation during chronic neurodegeneration. The Discussion likewise identifies CSF1R and both transcription factors as key actors in the regulatory network. (LLM, conf=0.92)
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.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In mouse models of AD genetic or pharmacological depletion of microglia prevented microglia association with amyloid plaques and neuronal loss, which led to improved learning and memory without affecting amyloid plaque load in mouse brain (Dagher et al., 2015; Rice et al., 2015; Spangenberg et al., 2016).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
What the sources say
- Partly supportedcites Dagher et al., 2015 sourceExperimental — accuracy not yet measured
The Results and Discussion report that pharmacological CSF1R inhibition in aged 3xTg-AD mice reduced microglial association with plaques and improved learning and memory without changing Aβ levels or plaque load. This paper does not report that its treatment prevented neuronal loss, and its AD-mouse experiment used pharmacological inhibition rather than genetic depletion. The indexed passages have section labels but no page numbers. (LLM, conf=0.87)
- Partly supportedcites Rice et al., 2015 sourceExperimental — accuracy not yet measured
The Abstract reports improved behavioral outcomes after pharmacological microglial elimination following a genetically induced hippocampal lesion in mice. This was not an amyloid-plaque AD model, and the paper does not report plaque association or plaque load. The Results state the opposite of the neuronal-loss claim: eliminating microglia during lesioning exacerbated neuronal loss. Page numbers were not available in our copy. (LLM, conf=0.90)
- Partly supportedcites Spangenberg et al., 2016 sourceExperimental — accuracy not yet measured
The Introduction and the section on contextual memory report that pharmacological microglial depletion in 5xfAD mice prevented neuronal loss and reduced plaque-associated microglia; the amyloid-pathology section reports no change in plaque load. This paper does not report genetic depletion, and plaque association was reduced rather than prevented. Contextual memory improved only as a statistical trend (P = 0.0813), so the claim overstates that result. (LLM, conf=0.89)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Moreover, microglial repopulation after depletion reversed age-related deficits in long-term potentiation as initial elimination of microglia increased neurogenesis and dendritic spine densities (Elmore et al., 2018).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
What the sources say
- Supportedcites Elmore et al., 2018 source
The Results section, “Microglial repopulation in aged mice rescues deficits in long-term potentiation,” reports that LTP impairments in aged mice were completely rescued after repopulation. The Discussion states that microglial elimination increased both neurogenesis and dendritic spine densities in aged mice. Page numbers are not provided in our copy. (LLM, conf=0.93)
plaindirect- 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.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The AD-associated risk allele of CD33 likely produces the longer more active spliced form of this inhibitory receptor (Pimenova et al., 2017b), which correlates with increased cell surface expression and reduced phagocytic capacity observed in human monocytes (Bradshaw et al., 2013).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
What the sources say
- Not matchedcites Pimenova et al., 2017b
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Supportedcites Bradshaw et al., 2013 source
Bradshaw et al. is cited for the increased CD33 cell-surface expression and reduced phagocytic capacity in human monocytes, not for the preceding claim about a longer splice form. The passages labeled Abstract report that monocytes carrying the rs3865444C risk allele have higher surface expression and reduced uptake of dextran and Aβ42. (LLM, conf=0.93)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Moreover, activation of the DAM signature is dependent on TREM2 suggesting DAM have increased phagocytic clearance ability (Keren-Shaul et al., 2017).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
What the sources say
- Partly supportedcites Keren-Shaul et al., 2017 sourceExperimental — accuracy not yet measured
The Results and Discussion show that full DAM activation, including phagocytic pathways, depends on TREM2. The Results also identify DAM markers in microglia containing Aβ particles, supporting the suggested phagocytic ability. However, the paper explicitly says initial DAM activation is TREM2-independent, so the claim is too broad without specifying full activation. (LLM, conf=0.85)
hedgeddirect- 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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Indeed, genetic variants in several targets of LXR/RXR transcription factors have been associated with risk for AD, e.g. APOE, CLU, ABCA1, ABCA7, ABCG1, TREM2 (A-González and Castrillo, 2011; Pimenova et al., 2017b; Savage et al., 2015).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
What the sources say
- Partly supportedcites A-González and Castrillo, 2011 sourceExperimental — accuracy not yet measured
Section 4 identifies ABCA1 as a direct LXR target and reports LXR-dependent expression of ABCG1 and ApoE. Section 8 discusses LXR activity in models of Alzheimer’s disease, but the paper does not report Alzheimer’s-risk genetic variants in these genes or establish CLU, ABCA7, and TREM2 as LXR/RXR targets. Pages are not specified in our copy. (LLM, conf=0.88)
- Not matchedcites Pimenova et al., 2017b
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Partly supportedcites Savage et al., 2015 sourceExperimental — accuracy not yet measured
The Introduction states that TREM2 variants confer elevated AD risk and that TREM2 expression is regulated by nuclear receptor agonists. The References also identify a study associating ABCA7 variants with AD. Our copy does not establish the claimed AD-risk associations and LXR/RXR-target status for the full list, particularly APOE, CLU, ABCA1, and ABCG1. (LLM, conf=0.88)
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.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Indeed, co-expression network analysis of transcriptomic changes in mouse models of AD revealed distinct states of DAM with pro- and anti-inflammatory profiles (Rangaraju et al., 2018).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
What the sources say
- Supportedcites Rangaraju et al., 2018 source
The Results section on co-expression network analysis reports that transcriptomic analysis of microglia from AD mouse models identified AD-associated Magenta and Yellow modules enriched for pro-inflammatory and anti-inflammatory genes, respectively. The Discussion says network analysis and validation confirmed distinct pro- and anti-inflammatory profiles within disease-associated microglia (DAM). (LLM, conf=0.94)
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.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“TREM2 rare genetic variants associated with AD risk impair microglial lipid sensing and phagocytosis (Kleinberger et al., 2014; Yeh et al., 2016).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
What the sources say
- Not checked — no full text of the sourcecites Kleinberger et al., 2014 source
- Partly supportedcites Yeh et al., 2016 sourceExperimental — accuracy not yet measured
The Summary (page unavailable) reports that AD-associated TREM2 variants reduce binding to lipoproteins and impair their uptake in heterologous cells; it also reports reduced uptake of Aβ–lipoprotein complexes in macrophages from variant carriers. The microglial uptake experiments used Trem2 knockout cells, not cells carrying the AD-associated variants, so the paper does not directly establish that those variants impair microglial phagocytosis. (LLM, conf=0.85)
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 cited sources support only part of this claim — read each source’s verdict below.
In the paper
“This effect was propagated to primary astrocytes inducing a neurotoxic reactive gene signature, which was reduced by PU.1 knock-down in LPS-stimulated microglial cells (Fig. 5g), suggesting reduced PU.1 expression converts microglial cells to a neuroprotective phenotype (Joshi et al., 2019; Yun et al., 2018).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
What the sources say
- Partly supportedcites Joshi et al., 2019 sourceExperimental — accuracy not yet measured
The Results section, “Microglia propagate pro-inflammatory response to activate astrocytes” (page unavailable), reports that signals from activated microglia induced an A1 proinflammatory state in primary astrocytes. It reports that P110 treatment of microglia blunted this response, but does not support the attributed reduction by PU.1 knock-down or establish a neurotoxic reactive gene signature. (LLM, conf=0.88)
- Partly supportedcites Yun et al., 2018 sourceExperimental — accuracy not yet measured
The passage on astrocyte experiments (section labeled Abstract; no page given) reports that conditioned medium from α-syn PFF-treated microglia induces neurotoxic A1 markers in astrocytes. It reports that NLY01 prevents this conversion, not that PU.1 knock-down reduces a reactive gene signature in LPS-stimulated microglia. The latter, more specific part of the attributed claim is unsupported by this paper. (LLM, conf=0.88)
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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Further analyses of single-cell RNA sequencing data identified interferon-related and neurodegeneration-related states of microglia activation that are present in aging and several models of neurodegeneration and inflammation in mice (Friedman et al., 2018; Sala Frigerio et al., 2019).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
What the sources say
- Partly supportedcites Friedman et al., 2018 sourceExperimental — accuracy not yet measured
The Discussion (page not provided) says the authors used single-cell RNA-seq data to distinguish interferon-related and core neurodegeneration-related microglial activation states. It also says the gene modules were derived from profiles spanning aging and multiple mouse disease and inflammatory models, but the single-cell analysis was of an Alzheimer’s disease model; it does not establish that the distinct cell states were present across all those settings. (LLM, conf=0.85)
- Partly supportedcites Sala Frigerio et al., 2019 sourceExperimental — accuracy not yet measured
The Results (‘Aging and Aβ Deposition Induce Similar Responses in Microglia’; page not provided) identify interferon-response and activated-response microglial states that increase with aging and Aβ deposition. Another Results passage finds similar states in a second amyloid mouse model, APP/PS1. The paper does not establish their presence across several models of neurodegeneration and inflammation; its Discussion says that interferon-responsive cells reported in the CK-p25 neurodegeneration model look different from the cells identified here. (LLM, conf=0.85)
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.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“The concept of microglial priming is related to the idea of trained immunity that is controlled by epigenetic mechanisms imprinted after first exposure to a pro-inflammatory stimulus (Haley et al., 2019).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
What the sources say
- Supportedcites Haley et al., 2019 source
The Abstract describes trained immunity as an enhanced inflammatory response involving epigenetic mechanisms mobilised after first exposure to an inflammatory stimulus. The Introduction explicitly proposes that those mechanisms may explain microglial priming, matching the claim’s statement that the concepts are related. (LLM, conf=0.94)
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.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Myelin uptake was accelerated in PU.1 overexpressing cells and delayed in PU.1 knock-down cells, however, both lines with differential PU.1 expression show a similar capacity to internalize myelin over time illustrated by the plateau that is reached by both lines in 60 – 80 hours (Fig. 2b, f).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > PU.1 overexpression increased and knock-down decreased microglial phagocytosis
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A 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
“PU.1 overexpression reduced and PU.1 knock-down increased the population of Annexin V+/DRAQ7− cells describing viable early apoptotic cells positive for phosphatidylserine staining with Annexin V and negative for DRAQ7, which stains nuclei in dead and permeabilized cells (Fig. 3e–f).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > PU.1 overexpression increased resistance and knock-down increased susceptibility of microglia to apoptosis
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A 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 report is the first to show that increased PU.1 expression renders cells more resistant to cell death and increased inflammatory response, which may be detrimental for other cell types of the diseased brain.”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Introduction
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: The BV2 immortalized mouse microglial cell line is a valid model for microglial functions relevant to Alzheimer's disease.
- Rests on an assumption: Stable overexpression and knock-down of PU.1 in BV2 cells mimic the risk and protective SPI1 genotypes.
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
“Interestingly, staurosporine treatment of BV2 cells with PU.1 overexpression reduced PU.1 expression levels, but had no effect on PU.1 in control CTL cells (Supplementary Fig. S4e).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > PU.1 overexpression increased resistance and knock-down increased susceptibility of microglia to apoptosis
plaindirect- 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
“BV2 cells with transient overexpression of PU.1 increased and knock-down of PU.1 decreased phagocytic uptake of all bioparticles independent of their nature as measured by FACS 3 hours after treatment (Supplementary Fig. S3a–e).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > PU.1 overexpression increased and knock-down decreased microglial phagocytosis
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: BV2 cells are a valid model of microglia for studying PU.1-dependent functions relevant to AD.
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
“On the contrary, viability of PU.1 knock-down cells was affected to the same extent as in control SCR cells showing similar levels of early apoptotic cells (Fig. 4f), rate of cell death (Supplementary Fig. S6f) and caspase-3 activation (Fig. 4g–h).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > PU.1 overexpression potentiates and knock-down mitigates microglial oxidative stress response
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The result of this PCA for the overexpression condition reflects the small number of genes affected by PU.1 overexpression – 191 (Spi1 was upregulated by 60%), while there were 3892 genes differentially expressed after PU.1 knock-down (Spi1 was downregulated by 71%) (Fig. 1a–b, Supplementary Tables S2–3).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > Knock-down of PU.1 repressed homeostatic microglial gene expression and activated disease-associated microglial signature pathways
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A 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
“PU.1 overexpression reduced staurosporine-induced cell death as measured by an MTS assay assessing cell proliferation potential, which was enhanced by increased PU.1 (Fig.3a) likely due to increased viability observed with an LDH assay assessing the rate of cell death after staurosporine treatment (Fig. 3a–b).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > PU.1 overexpression increased resistance and knock-down increased susceptibility of microglia to apoptosis
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A 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
“Knock-down of PU.1 also did not affect caspase activation only showing a trend towards increased activation of caspases (Fig. 3g–i).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > PU.1 overexpression increased resistance and knock-down increased susceptibility of microglia to apoptosis
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
“Longitudinal experiments tracking internalization of pHrodo-labeled myelin and zymosan in BV2 cells with stable overexpression or knock-down of PU.1 showed similar results with increased PU.1 expression leading to increased uptake and decreased PU.1 expression inhibiting bioparticle uptake, based on the quantification of uptake half-life (Fig. 2d, h).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > PU.1 overexpression increased and knock-down decreased microglial phagocytosis
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: BV2 cells are a valid model of microglia for studying PU.1-dependent functions relevant to AD.
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
“Interestingly, live imaging of myelin and zymosan internalization showed different kinetics of uptake, while proliferation of PU.1 overexpression and knock-down cells was comparable to control cell lines (Fig. 2a, e).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > PU.1 overexpression increased and knock-down decreased microglial phagocytosis
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 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
“Populations of nonviable phosphatidylserine-negative late apoptotic (Annexin V+/DRAQ7 +) and necrotic (Annexin V−/DRAQ7+) cells seem to be unaffected by PU.1 expression when compared to Z-VAD-FMK, which reduced the number of cells in all three states.”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > PU.1 overexpression increased resistance and knock-down increased susceptibility of microglia to apoptosis
hedged- 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
“This effect was specific to induction of oxidative stress as it could be partially reduced by N-acetyl cysteine (NAC) antioxidant pre-treatment and was due to PU.1-mediated regulation of inducible nitric oxide synthase (iNOS) expression which showed increased levels in PU.1 overexpressing cells and reduced levels in cells with PU.1 knock-down (Fig. 5c–d).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > PU.1 overexpression amplifies and knock-down abates microglial inflammatory response
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A 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
“Indeed, expression levels of PU.1 were unchanged under stimulated conditions compared to baseline, contrary to data after staurosporine treatment (Supplementary Fig. S6g).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > PU.1 overexpression potentiates and knock-down mitigates microglial oxidative stress response
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
“Treatment of primary astrocytes with conditioned medium from LPS-stimulated microglial cells with PU.1 overexpression resulted in increased expression of the astrocytes reactive signature, while PU.1 knock-down negated induction of A1 reactive astrocytes after LPS treatment (Fig. 5g, Supplementary Fig. S7d).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > PU.1 overexpression amplifies and knock-down abates microglial inflammatory response
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A 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
“PU.1 overexpressing cells showed increased zymosan internalization compared to control CTL cells, while PU.1 knock-down cells displayed limited capability to internalize zymosan in comparison to control SCR cells (Fig. 2c, g).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > PU.1 overexpression increased and knock-down decreased microglial phagocytosis
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A 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
“PU.1 overexpression further potentiated NO production after treatment with LPS compared to control cells, while PU.1 knock-down repressed NO production (Fig. 5a–b).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > PU.1 overexpression amplifies and knock-down abates microglial inflammatory response
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In fact, levels of PU.1 were equal under staurosporine treatment in overexpression and knock-down conditions, however, the latter was due to decreased PU.1 expression in control SCR cells, but not in PU.1 knock-down cells (Supplementary Fig. S4f).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > PU.1 overexpression increased resistance and knock-down increased susceptibility of microglia to apoptosis
plaindirect- 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
“Live-imaging of the DRAQ7+ necrotic cells revealed that PU.1 overexpression delayed the onset of BV2 cell death after staurosporine treatment, while PU.1 knock-down cells died at the same rate as control cells (Supplementary Fig. S4c–d).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > PU.1 overexpression increased resistance and knock-down increased susceptibility of microglia to apoptosis
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Moreover, PU.1 knock-down resulted in activation of protein translation, antioxidant action and cholesterol/lipid metabolism pathways with a concomitant decrease of pro-inflammatory gene expression.”
- Also stated in: § Knock-down of PU.1 repressed homeostatic microglial gene expression and activated disease-associated microglial signature pathways · hedged
“Pathway analysis showed activation of LXR/RXR and EIF2 signaling and increased antioxidant action of vitamin C in cells with PU.1 knock-down suggesting a sustained level of oxidative stress response, cholesterol/lipid metabolism and protein translation (Fig. 1e).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The BV2 immortalized mouse microglial cell line is a valid model for microglial functions relevant to Alzheimer's disease.
- Also stated in: § Knock-down of PU.1 repressed homeostatic microglial gene expression and activated disease-associated microglial signature pathways · hedged
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
“PU.1 overexpression upregulated and knock-down downregulated phagocytic uptake in BV2 cells independent of the nature of the engulfed material.”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The BV2 immortalized mouse microglial cell line is a valid model for microglial functions relevant to Alzheimer's disease.
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, knock-down of PU.1 decreased the number of ROS+ cells and ROS production per cell as measured by FACS, while baseline levels of ROS were unaffected (Fig. 4c–d, Supplementary Fig. S6b).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > PU.1 overexpression potentiates and knock-down mitigates microglial oxidative stress response
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A 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
“Pathway analysis showed activation of LXR/RXR and EIF2 signaling and increased antioxidant action of vitamin C in cells with PU.1 knock-down suggesting a sustained level of oxidative stress response, cholesterol/lipid metabolism and protein translation (Fig. 1e).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > Knock-down of PU.1 repressed homeostatic microglial gene expression and activated disease-associated microglial signature pathways
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A 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, cells with reduced PU.1 expression retained their ability to internalize myelin similar to control albeit with a delay, which aligns with their anti-inflammatory profile.”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The BV2 immortalized mouse microglial cell line is a valid model for microglial functions relevant to Alzheimer's disease.
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
“Rotenone treatment of BV2 cells affected cell viability in a similar manner to staurosporine, with PU.1 overexpression showing increased survival upon rotenone treatment (Supplementary Fig. S6e) and a reduced number of early apoptotic cells (Fig. 4e, Supplementary Fig. S6c).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > PU.1 overexpression potentiates and knock-down mitigates microglial oxidative stress response
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A 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
“Rotenone-treated BV2 cells showed an increase in ROS with increased number of cells responding to rotenone treatment and increased production of ROS per cell.”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > PU.1 overexpression potentiates and knock-down mitigates microglial oxidative stress response
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
“Treatment of control CTL cells with Aβ42 or LPS did not produce a robust ROS response, nevertheless, PU.1 overexpression amplified production of ROS in cells exposed to these stimuli (Fig. 4i–j).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > PU.1 overexpression potentiates and knock-down mitigates microglial oxidative stress response
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“While baseline cell viability was not affected by modulation of PU.1, likely because of in vitro cell culture conditions, PU.1 overexpression led to increased resistance and knock-down to increased susceptibility of microglial cells to staurosporine- and rotenone-induced cell death (Figs. 3a–d and 4e–f).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“While baseline cell viability was not affected by modulation of PU.1, likely because of in vitro cell culture conditions, PU.1 overexpression led to increased resistance and knock-down to increased susceptibility of microglial cells to staurosporine- and rotenone-induced cell death (Figs. 3a–d and 4e–f).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
hedged- 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 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
“Interestingly, PU.1 may modulate specificity of microglial phagocytosis towards pro- and anti-inflammatory bioparticles, e.g. amyloid β and zymosan versus myelin, as microglia with PU.1 knock-down specifically showed preserved capacity for storing internalized myelin albeit with a delayed uptake, which was not observed for zymosan (Fig. 2f–g).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
“Indeed, we show here that PU.1 overexpression potentiated and knock-down repressed production of ROS, NO and inflammatory cytokines after treatment with rotenone, Aβ42 or LPS (Figs. 4 and 5).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Specifically, PU.1 overexpression reduced and knock-down increased caspase-activated apoptosis of microglia (Fig. 3e–i), which was corroborated by PU.1 regulation of “organismal death” and “morbidity and mortality” functions (Fig. 1c).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, low expression of PU.1 leads to increased cell death under cytotoxic conditions accompanied by reduced pro-inflammatory signaling that decreased A1 reactive astrocytes signature supporting the protective effect of SPI1 genotype in AD.”
- Also stated in: § Introduction · plain
“PU.1 knock-down makes microglia more susceptible to cell death, but also less pro-inflammatory, which was beneficial in reducing A1 reactive astrocytes signature relevant to diseased brain milieu.”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The BV2 immortalized mouse microglial cell line is a valid model for microglial functions relevant to Alzheimer's disease.
- Rests on an assumption: Stable overexpression and knock-down of PU.1 in BV2 cells mimic the risk and protective SPI1 genotypes.
- Rests on an assumption: In vitro microglial responses to PU.1 modulation reflect in vivo microglial biology and Alzheimer's disease pathogenesis.
- Rests on an assumption: The A1 reactive astrocyte signature induced by conditioned medium from PU.1 knock-down BV2 cells is relevant to the diseased brain milieu.
- Also stated in: § Introduction · plain
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
“iMGLs maturation was confirmed with immunostaining for PU.1 and CD11b after 3–5 days of culture in mature microglial medium.”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Methods > iPSCs culture and differentiation
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.
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
“Interestingly, the effect of PU.1 overexpression on microglial function shows opposing effects to PU.1 knock-down, which supports the mechanism of action for SPI1 contribution to AD pathogenesis based on differential expression.”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Introduction
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Stable overexpression and knock-down of PU.1 in BV2 cells mimic the risk and protective SPI1 genotypes.
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
“Changes in PU.1 expression were confirmed on the mRNA level using qPCR and protein level using western blotting of polyclonal selected lines.”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Methods > Stable cell line generation
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. 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
“In conclusion, PU.1 overexpression potentiates microglial oxidative stress through a direct effect on ROS production and increased survival after treatment with cytotoxic stimuli, while PU.1 knock-down represses the microglial oxidative stress response after rotenone, Aβ42 and LPS treatment.”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > PU.1 overexpression potentiates and knock-down mitigates microglial oxidative stress response
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: BV2 cells are a valid model of microglia for studying PU.1-dependent functions relevant to AD.
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
“Samples passed quality control with Qubit and BioAnalyzer showing RIN = 10.”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Methods > RNA sequencing and analyses
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.
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
“Analysis of mRNA and protein expression of PU.1 showed that we were able to obtain 2-fold overexpression of PU.1 (OE cell line) and 75% knock-down of PU.1 (KD cell line) at the protein level (Supplementary Fig. S2a–c) relative to their respective controls (CTL line for overexpression and SCR line for knock-down).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > Knock-down of PU.1 repressed homeostatic microglial gene expression and activated disease-associated microglial signature pathways
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The achieved 2-fold overexpression and 75% knock-down of PU.1 are sufficient to model the range of PU.1 expression relevant to human AD risk.
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
“Along with reduced phagocytosis we detect reduced activation of IRF by cytosolic pattern recognition receptors in BV2 cells with PU.1 knock-down, suggesting these cells exhibit lower activity and inflammatory response in contrast to DAM.”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > Knock-down of PU.1 repressed homeostatic microglial gene expression and activated disease-associated microglial signature pathways
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.
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
“Routine testing of cell lines using MycoAlert PLUS mycoplasma detection kit (Lonza) showed that all cells were negative for mycoplasma contamination.”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Methods > Reagents, antibodies, plasmids and cell lines
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.
In the paper
“We have previously reported that PU.1 regulates zymosan phagocytosis (Huang et al., 2017) and others reported that PU.1 knock-down reduces Aβ42 uptake in human microglial cells (Smith et al., 2013).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > PU.1 overexpression increased and knock-down decreased microglial phagocytosis
What the sources say
- Not checked — no full text of the sourcecites Smith et al., 2013 source
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.
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
“RNA sequencing results were validated using qPCR on 75 genes with Pearson correlation analysis.”
- Also stated in: § Knock-down of PU.1 repressed homeostatic microglial gene expression and activated disease-associated microglial signature pathways · plain
“Pearson correlation of 75 genes showed good overlap of DEGs from RNA sequencing with qPCR results in BV2 cells (Supplementary Fig. S1b, Supplementary Tables S2–3).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Methods > RNA sequencing and analyses
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.
- Also stated in: § Knock-down of PU.1 repressed homeostatic microglial gene expression and activated disease-associated microglial signature pathways · plain
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
“In conclusion, PU.1 overexpression renders microglial cells resistant to caspase-mediated apoptosis, while PU.1 knock-down cells become more susceptible to caspase-induced cell death.”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > PU.1 overexpression increased resistance and knock-down increased susceptibility of microglia to apoptosis
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: BV2 cells are a valid model of microglia for studying PU.1-dependent functions relevant to AD.
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 researcher was not blinded to sample collection.”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Methods > Statistics
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
“The difference in response of respective control cells may be due to the transformation procedure rendering SCR cells more inflammatory prone than CTL cell line.”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > PU.1 overexpression potentiates and knock-down mitigates microglial oxidative stress response
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: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data suggest that PU.1 regulates the inflammatory response of microglial cells to pathogenic stimuli and that increased PU.1 expression would amplify and propagate it, while decreased PU.1 expression will mitigate microglia-mediated pro-inflammatory responses.”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > PU.1 overexpression amplifies and knock-down abates microglial inflammatory response
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: BV2 cells are a valid model of microglia for studying PU.1-dependent functions relevant to AD.
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
“As we have previously seen with ROS and NO, PU.1 overexpression amplified cytokine secretion suggesting an increased pro-inflammatory response (Fig. 5e).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > PU.1 overexpression amplifies and knock-down abates microglial inflammatory response
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.
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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
“In each analysis three to five independent experiments were performed (n = 3 – 5 biological replicates).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Methods > Statistics
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.
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 pathways are similarly activated in DAM and oppositely inhibited in PU.1 overexpression that is associated with increased risk for AD based on human genetics, suggesting these pathways may be central to”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > Knock-down of PU.1 repressed homeostatic microglial gene expression and activated disease-associated microglial signature pathways
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Changes in the expression of genes mediating immune response and lipid metabolism or direct targets of PU.1 in iMGLs overlapped with BV2 cells suggesting PU.1 affects similar aspects of microglial biology in human and mouse cells (Figure 1c).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > Knock-down of PU.1 repressed homeostatic microglial gene expression and activated disease-associated microglial signature pathways
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: The BV2 immortalized mouse microglial cell line is a valid model for microglial functions relevant to Alzheimer's disease.
In the paper
“This effect may be beneficial in AD considering how microglial uptake of Aβ or lipids may hinder effective debris clearance and result in microglial cell death contributing to seeding of the amyloid plaque core (Baik et al., 2016).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
What the sources say
- Not checked — no full text of the sourcecites Baik et al., 2016 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“SPI1 is a master regulator of this gene network, upregulation of which suggests clearance of lipids and debris may be preserved with PU.1 knock-down.”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
“Based on these observations and our data we propose that PU.1 knock-down may be beneficial in slowing overt neurodegeneration at the onset of disease due to decreased ability of microglia to seed amyloid plaques, possibly without compromising on clearance and maintenance of brain tissue homeostasis at later stages.”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
“PU.1 knock-down dampened stimulus-dependent pro-inflammatory response, which is generally considered protective in neurodegenerative conditions.”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
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.
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 propose that the protective effect of reduced PU.1 expression in AD is mediated through pathways of LXR/RXR signaling, antioxidant action of vitamin C and/or EIF2 protein translation similar to the protective effect of DAM.”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
hedgeddirect- 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: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
In the paper
“Mutations in EIF2B1-5 genes, encoding subunits of eIF2b, responsible for protein translation, lead to leukoencephalopathy with vanishing white matter characterized by progressive degeneration of white matter due to myelination failure and impairments in oligodendrocyte function (Bugiani et al., 2010).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
What the sources say
- Not checked — no full text of the sourcecites Bugiani et al., 2010 source
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.
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
“Since impairments in these pathways contribute to AD progression, counteracting consequences of defects in these pathways will be beneficial in AD, supporting the protective effect of reduced PU.1 expression in microglia.”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: unclear — It is unclear whether it could be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Deletion of PU.1 results in ablation of myeloid lineage cell types in mouse, e.g. macrophages and B cells, suggesting modulation of PU.1 levels in adult brain may affect microglial viability (Kierdorf et al., 2013; McKercher et al., 1996).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
What the sources say
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“PU.1 downregulation reduced phagocytosis, increased apoptotic cell death and inhibited immune response, which promoted the anti-inflammatory state of microglia that is likely protective in AD.”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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, downregulation of PU.1 expression seems to transform microglial cells into an anti-inflammatory state with activated LXR/RXR and reduced IRF signaling that is protective in AD (Fig. 1), albeit distinct from previously described DAM.”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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 studies represent the first step toward investigating PU.1 inhibition/lower expression as a possible therapeutic target for AD treatment.”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check 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. It may be too vague to check against evidence.
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
“As PU.1 is a master regulator of microglial function and several genetic risk factors for AD (APOE, CLU, MS4A4A/MS4A6A, PILRA), it may be possible to modulate several phenotypes at once by targeting a single gene for treatment of AD.”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check 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. It may be too vague to check against evidence. It may state two separate claims as one.
The paper relies on this without support.
The BV2 immortalized mouse microglial cell line is a valid model for microglial functions relevant to Alzheimer's disease.
“we used stable overexpression and knock-down of PU.1 in BV2, an immortalized mouse microglial cell line.”
The paper relies on this without support.
Stable overexpression and knock-down of PU.1 in BV2 cells mimic the risk and protective SPI1 genotypes.
“Using BV2 immortalized mouse microglial cells, we generated lines with stable overexpression and knock-down of PU.1 mimicking the risk and protective genotypes of SPI1.”
The paper relies on this without support.
In vitro microglial responses to PU.1 modulation reflect in vivo microglial biology and Alzheimer's disease pathogenesis.
“To describe how PU.1 affects microglia and predict its role in vivo we compared pathways affected by PU.1 expression and the disease-associated microglia (DAM) (Keren-Shaul et al., 2017) that surround amyloid β (Aβ) plaques in AD and have been reported to be the protective population of microglia in patients’ brains.”
The paper relies on this without support.
The A1 reactive astrocyte signature induced by conditioned medium from PU.1 knock-down BV2 cells is relevant to the diseased brain milieu.
“which was beneficial in reducing A1 reactive astrocytes signature relevant to diseased brain milieu.”
The paper relies on this without support.
BV2 cells are a valid model of microglia for studying PU.1-dependent functions relevant to AD.
“Here we have generated and characterized BV2 microglial cell lines with high and low PU.1 expression to examine changes in and microglial functions, that may be relevant to AD pathogenesis.”
The paper relies on this without support.
The in vitro phenotypes observed in BV2 cells with altered PU.1 expression are relevant to microglial behavior in the AD brain.
“Altogether, PU.1 regulates a plethora of functions in microglial cells that we have evaluated in vitro to begin to describe microglial phenotypes important in supporting the brain milieu that is affected in AD.”
The paper relies on this without support.
Staurosporine- and rotenone-induced cell death in BV2 cells model apoptotic processes relevant to AD.
“To elucidate the contribution of PU.1 to cell death under stimulated conditions we challenged BV2 cells with staurosporine, which induces caspase-dependent cell death.”
The paper relies on this without support.
LPS and Aβ42 stimulation of BV2 cells model pro-inflammatory conditions in AD.
“Next we tested the effect of Aβ42 and LPS on oxidative stress response in microglial cells as amyloid and inflammation trigger and exacerbate pathological changes in AD brain (Wendeln et al., 2018).”
The paper relies on this without support.
The achieved 2-fold overexpression and 75% knock-down of PU.1 are sufficient to model the range of PU.1 expression relevant to human AD risk.
“Analysis of mRNA and protein expression of PU.1 showed that we were able to obtain 2-fold overexpression of PU.1 (OE cell line) and 75% knock-down of PU.1 (KD cell line) at the protein level (Supplementary Fig. S2a–c) relative to their respective controls (CTL line for overexpression and SCR line for knock-down).”
Claims other papers make about this one
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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
“knockdown or overexpression of PU.1 in the BV2 rodent microglia cell line identified a hub of neuroinflammation-related differentially expressed genes (DEGs) (15).”
From Arresting the bad seed: HDAC3 regulates proliferation of different microglia after ischemic stroke (2024) · cites this paper as [15]
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
“which is well known for its pivotal role in microglial development and inflammation (Fig. 7, D to F) (15, 40).”
From Arresting the bad seed: HDAC3 regulates proliferation of different microglia after ischemic stroke (2024) · cites this paper as [15]
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 Alzheimer’s disease, SPI1 downregulation confers protection, whereas its overexpression increases disease risk [26].”
From Inhibition of SPI1 by ADAP Regulates S100A8/A9 Signaling in Macrophages to Control the Development of Colitis (2026) · cites this paper as [26]
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
“Moreover, similar gene expression changes to immune response and lipid metabolism genes were observed in BV-2 cells and human iPSC microglia following PU.1 siRNA knock-down32.”
From Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease (2021) · cites this paper as [32]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“It was recently shown that BV-2 cells with diminished PU.1 expression were more vulnerable to caspase-dependent cell death, while PU.1 over-expressing cells appear to have delayed onset of death. Baseline cell viability did not appear to be impacted by PU.1 modulation in these cells32.”
From Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease (2021) · cites this paper as [32]
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
“On the other hand, PU.1 positively regulates phagocytosis, a potentially beneficial process critical for Aβ clearance in Alzheimer's disease pathology [37, 38].”
From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [37]
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 later stages, it might be beneficial to reduce PU.1 activity while increasing MEF2C activity to inhibit harmful inflammation and support neuroprotective microglial functions”
From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [37]
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
“These results support previous reports demonstrating that higher PU.1 expression in humans is likely to result in earlier AD onset 19,48 .”
From APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints (2023) · cites this paper as [48]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“zymosan particles, which are commonly used to assess general phagocytosis25,26”
From Deletion of SPI1 in microglia exacerbates amyloid pathology by impairing microglial response in Alzheimer’s disease models (2026) · cites this paper as [26]
The cited source says what the claim attributes to it.
In the citing paper
“In the context of Alzheimer’s disease, PU.1 is vital for Aβ clearance (56) and the inflammatory response of microglia (15).”
From Arresting the bad seed: HDAC3 regulates proliferation of different microglia after ischemic stroke (2024) · cites this paper as [15]
The cited source says what the claim attributes to it.
In the citing paper
“In Alzheimer’s disease, SPI1 downregulation confers protection, whereas its overexpression increases disease risk [26].”
From Inhibition of SPI1 by ADAP Regulates S100A8/A9 Signaling in Macrophages to Control the Development of Colitis (2026) · cites this paper as [26]
The cited source says what the claim attributes to it.
In the citing paper
“Together these results suggest that PU.1 dose likely modulates the cytokine response in stimulated BV-2 microglia cells.”
From Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease (2021) · cites this paper as [32]
The cited source says what the claim attributes to it.
In the citing paper
“Basal cytokine expression was higher in BV-2 cells over-expressing PU.1, and was further potentiated by LPS stimulation compared to control samples32.”
From Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease (2021) · cites this paper as [32]
The cited source says what the claim attributes to it.
In the citing paper
“Work in BV-2 cells suggests that reduced PU.1 results in a less reactive phenotype whereas PU.1 over expression primes cells for a more reactive response32.”
From Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease (2021) · cites this paper as [32]
The cited source says what the claim attributes to it.
In the citing paper
“Work in BV-2 cells suggests that reduced PU.1 results in a less reactive phenotype whereas PU.1 over expression primes cells for a more reactive response32.”
From Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease (2021) · cites this paper as [32]
The cited source says what the claim attributes to it.
In the citing paper
“Media taken from LPS treated PU.1 over-expressing BV-2 cells promoted a reactive astrocyte phenotype which was not observed in astrocytes treated with media from LPS treated BV-2 cells with reduced PU.1 expression32.”
From Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease (2021) · cites this paper as [32]
The cited source says what the claim attributes to it.
In the citing paper
“We have previously generated BV2 cells stably overexpressing mouse PU.1 and respective empty frame control, as well as BV2 cells with knockdown of PU.1 with the respective scrambled control39.”
From Lymphoid gene expression supports neuroprotective microglia function (2025) · cites this paper as [39]
The cited source says what the claim attributes to it.
In the citing paper
“Because a previous in vitro study demonstrated that Spi1-knockdown decreased, whereas Spi1-overexpression increased, the microglial immune response in response to Aβ42 and LPS stimulation34, we evaluated whether Spi1 expression affects gliosis in vivo.”
From Effects of SPI1-mediated transcriptome remodeling on Alzheimer's disease-related phenotypes in mouse models of Aβ amyloidosis (2024) · cites this paper as [34]
The cited source says what the claim attributes to it.
In the citing paper
“This finding is particularly relevant to the present review topic because it suggests that PU.1 dosage may influence whether microglia remain homeostatic, become classically inflammatory, or enter an Alzheimer’s-associated response state.”
From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [31]
The cited source says what the claim attributes to it.
In the citing paper
“Pimenova et al. examined Alzheimer’s-associated PU.1 expression levels in microglial models and reported that higher SPI1 expression is associated with increased Alzheimer’s risk, whereas lower expression is associated with protection.”
From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [31]
The cited source says what the claim attributes to it.
In the citing paper
“In their experimental system, reducing PU.1 expression shifted the microglial transcriptome in a way that overlapped with disease-associated microglial responses to amyloid plaques [31].”
From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [31]
The cited source says what the claim attributes to it.
In the citing paper
“Previous studies investigating the therapeutic potential of PU.1 for Alzheimer's disease have relied primarily on in vitro experiments using cell culture systems [22, 37, 38].”
From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [37]
The cited source says what the claim attributes to it.
In the citing paper
“On the one hand, the knockdown of PU.1 in BV‐2 microglia stimulated with LPS reduces the expression of proinflammatory genes and immune response mediators, whereas the overexpression of PU.1 has the opposite effect under the same conditions [22, 37].”
From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [37]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“In comparison, immortalized BV2 cells—despite expressing PU.1—lack key characteristics of primary microglia, such as the capacity to replicate the heterogeneity and functional diversity observed in vivo (He et al., 2018; Pimenova et al., 2021).”
From PU.1 dictates β-amyloid-induced TREM2 expression upregulation in microglia in a transgenic model of Alzheimer’s disease (2025) · cites this paper as Pimenova et al., 2021
Experimental — accuracy not yet measured
Self-check
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Each contradiction between two passages listed here was confirmed by an independent check.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Discussion
“PU.1 overexpression led to increased resistance and knock-down to increased susceptibility of microglial cells to staurosporine- and rotenone-induced cell death (Figs. 3a–d and 4e–f).”
§ Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response > Results > PU.1 overexpression potentiates and knock-down mitigates microglial oxidative stress response
“On the contrary, viability of PU.1 knock-down cells was affected to the same extent as in control SCR cells showing similar levels of early apoptotic cells (Fig. 4f), rate of cell death (Supplementary Fig. S6f) and caspase-3 activation (Fig. 4g–h).”
Citations
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Neurotoxic reactive astrocytes are induced by activated microglia
Liddelow, S. A., Guttenplan, K. A., Clarke, L. E., Bennett, F. C., Bohlen, C. J., Schirmer, L., Bennett, M. L., Münch, A. E., Chung, W.-S., Peterson, T. C., et al. (2017) · Nature · doi:10.1038/nature21029 · Cited by 7,971
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 · cited 6×
“1), which we further compared to the previously described DAM signature to elaborate on the possible significance of these changes in vivo (Keren-Shaul et al., 2017).”
BackgroundMethodResultInfluentialMeta-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
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“The DAM response is dependent on TREM2 and APOE, two major AD risk genes, in mouse models of AD and metabolic disease (Krasemann et al., 2017; Pimenova et al., 2017a).”
BackgroundAlzheimer 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
Macrophages in the Pathogenesis of Atherosclerosis
Moore, K. J., & Tabas, I. (2011) · Cell · doi:10.1016/j.cell.2011.04.005 · Cited by 2,669 · cited 1×
“This process may be similar to how macrophages contribute to atherosclerotic plaques when failure to efficiently eliminate lipids results in the formation of foam cells in cardiovascular disease (Moore and Tabas, 2011).”
BackgroundSingle-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 · cited 1×
“, 2020), although the mouse DAM transcriptome profile may not be fully present in AD brain, as human microglia show a distinct AD-related gene signature (Jaitin et al., 2019; Mathys et al., 2019).”
Tissue-Resident Macrophage Enhancer Landscapes Are Shaped by the Local Microenvironment
Lavin, Y., Winter, D., Blecher-Gonen, R., David, E., Keren-Shaul, H., Merad, M., Jung, S., & Amit, I. (2014) · Cell · doi:10.1016/j.cell.2014.11.018 · Cited by 2,167 · cited 1×
“1 is a myeloid lineage-determining transcription factor that together with MEF2C shapes the enhancer landscape specific to microglia in the brain (Lavin et al., 2014).”
The Cellular Phase of Alzheimer’s Disease
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Disease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration
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“It is hypothesized that DAM are protective in AD because changes in expression of AD risk genes in the DAM signature correlate with reduced disease risk based on human genetics (Deczkowska et al., 2018).”
Cited by
Sorted by citations
Roles of neuropathology-associated reactive astrocytes: a systematic review
Lawrence, J. M., Schardien, K., Wigdahl, B., & Nonnemacher, M. R. (2023) · Acta Neuropathologica Communications · doi:10.1186/s40478-023-01526-9 · Cited by 433
“1 expression may be upregulated, allowing it to facilitate transcriptional changes in microglia and resident macrophages [101].”
BackgroundInfluentialThe neuroimmune axis of Alzheimer’s disease
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“1 transcription factor that has previously been associated with increased AD risk [189, 190].”
BackgroundAPOE mediated neuroinflammation and neurodegeneration in Alzheimer’s disease
Parhizkar, S., & Holtzman, D. M. (2022) · Seminars in Immunology · doi:10.1016/j.smim.2022.101594 · Cited by 255
APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints
Yin, Z., Rosenzweig, N., Kleemann, K. L., Zhang, X., Brandão, W., Margeta, M. A., Schroeder, C., Sivanathan, K. N., Silveira, S., Gauthier, C., et al. (2023) · Nature Immunology · doi:10.1038/s41590-023-01627-6 · Cited by 202
“These results support previous reports demonstrating that higher PU.1 expression in humans is likely to result in earlier AD onset 19,48 .”
ResultGenetics of the human microglia regulome refines Alzheimer’s disease risk loci
Kosoy, R., Fullard, J. F., Zeng, B., Bendl, J., Dong, P., Rahman, S., Kleopoulos, S. P., Shao, Z., Girdhar, K., Humphrey, J., et al. (2022) · Nature Genetics · doi:10.1038/s41588-022-01149-1 · Cited by 168
“SPI1 has previously been associated with increased AD risk 24,42 .”
BackgroundResult
Metadata
- Authors
- Pimenova, A. A., Herbinet, M., Gupta, I., Machlovi, S. I., Bowles, K. R., Marcora, E., & Goate, A. M.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Indian Institute of Technology Delhi (IN)
- Corresponding author
- Goate, Alison M.
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2021-01
- Volume
- 148
- Pages
- 105217
- ISSN
- 0969-9961 (ISSN-L)
- PMC
- PMC7808757
- OpenAlex
- W3112899236
- Cited by
- 120
- References
- 71
- Citations by year
- 2026: 22 · 2025: 24 · 2024: 17 · 2023: 21 · 2022: 29 · 2021: 7
- FWCI
- 6.39
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Neurobiology of Disease (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- BrightFocus Foundation
- National Institute on Aging
- JPB Foundation
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
- Keywords
- Alzheimer's disease, PU.1, microglia, microglial inflammation, genetic susceptibility loci, amyloid plaques, phagocytosis, mRNA translation, antioxidant response, microglial cell death, BV-2 cells
- MeSH terms
- Proto-Oncogene Protein Spi-1, Alzheimer Disease, Animals, Cell Line, Inflammation, Lipopolysaccharides, Nitric Oxide, Peptide Fragments, Proto-Oncogene Proteins, Rotenone, Uncoupling Agents, Trans-Activators, Cytokines, Amyloid beta-Peptides, Apoptosis, Microglia, Staurosporine, Gene Expression Profiling, Mice, Gene Knockdown Techniques
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).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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