The DOI matches its Crossref record; 39 of the 41 references it cites were found in a registry or an index; 15 of the 30 sources its claims cite were checked for support.
PPARγ/RXRα-Induced and CD36-Mediated Microglial Amyloid-β Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice
Open accessAbstract
Alzheimer's disease (AD) is characterized by the extracellular deposition of amyloid-β (Aβ), neurofibrillary tangle formation, and a microglial-driven inflammatory response. Chronic inflammatory activation compromises microglial clearance functions. Because peroxisome proliferator-activated receptor γ (PPARγ) agonists suppress inflammatory gene expression, we tested whether activation of PPARγ would also result in improved microglial Aβ phagocytosis. The PPARγ agonist pioglitazone and a novel selective PPARα/γ modulator, DSP-8658, currently in clinical development for the treatment of type 2 diabetes, enhanced the microglial uptake of Aβ in a PPARγ-dependent manner. This PPARγ-stimulated increase of Aβ phagocytosis was mediated by the upregulation of scavenger receptor CD36 expression. In addition, combined treatment with agonists for the heterodimeric binding partners of PPARγ, the retinoid X receptors (RXRs), showed additive enhancement of the Aβ uptake that was mediated by RXRα activation. Evaluation of DSP-8658 in the amyloid precursor protein/presenilin 1 mouse model confirmed an increased microglial Aβ phagocytosis in vivo , which subsequently resulted in a reduction of cortical and hippocampal Aβ levels. Furthermore, DSP-8658-treated mice showed improved spatial memory performance. Therefore, stimulation of microglial clearance by simultaneous activation of the PPARγ/RXRα heterodimer may prove beneficial in prevention of AD.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
PPARγ activation by pioglitazone or DSP-8658 increases microglial amyloid-β phagocytosis via CD36 upregulation, and combined PPARγ/RXRα activation is additive. In APP/PS1 mice, DSP-8658 increased microglial Aβ uptake, reduced cortical and hippocampal Aβ levels, and improved spatial memory.
Key findings
- DSP-8658 and pioglitazone enhanced Aβ uptake in rat primary microglia in a concentration-dependent manner; PPARγ siRNA suppressed PPARγ gene expression by 50% and abolished the increased phagocytosis.
- The effect required de novo mRNA/protein synthesis, since actinomycin D or cycloheximide abolished it; CD36 mRNA and protein were upregulated, and CD36 antibody or CD36 siRNA blocked PPARγ agonist-stimulated Aβ phagocytosis.
- RXR agonists retinoic acid and bexarotene increased Aβ phagocytosis; combined with pioglitazone or DSP-8658 they showed additive enhancement, and RXRα siRNA suppressed bexarotene-induced uptake while RXRβ siRNA did not.
- In APP/PS1 mice, DSP-8658 treatment increased phagocytosing microglia, produced a 30% increase in Aβ/CD11b colocalization, reduced cortical SDS-soluble Aβ1-42 and Aβ1-40 by 32% and 30%, respectively, decreased hippocampal SDS-soluble Aβ1-42 and cortical plaque load, and improved Morris water maze performance (n = 9 vehicle, n = 10 DSP-8658, p < 0.01).
Methods
- Primary rat and mouse microglia were used for FAM-Aβ1-42 phagocytosis assays, siRNA knockdown of PPARγ, CD36, RXRα, or RXRβ, Western blotting, quantitative PCR, and immunocytochemistry; COS-1 cells were used for PPAR transactivation assays.
- APP/PS1 transgenic mice received a DSP-8658-enriched diet for 3 months (estimated ~150 mg/kg/d); in vivo microglial phagocytosis was measured with methoxy-X04 and flow cytometry, and Aβ levels were measured by sandwich ELISA, with plaque load by thioflavin S and spatial memory by Morris water maze.
- Statistical analyses used Student’s t test, one-way ANOVA followed by Tukey’s post hoc test, or Dunnett’s multiple comparison test.
Limitations
- The paper states that siRNA transfection may have prestimulated microglia, resulting in an overall decreased phagocytic response; RXRβ was not detected or only at minor levels in primary microglia; and the claim that DSP-8658 crosses the blood-brain barrier more effectively than pioglitazone is supported by data not shown.
- Evident from the text: findings rely on primary rodent microglia and one APP/PS1 mouse model, with small sample sizes (n = 3 in vitro; n = 4 for several in vivo assays; n = 9–10 for behavior), and no human AD data or long-term safety data are reported.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
38 Own result · 11 Own interpretation · 7 Partly supported · 6 No full text of the sources · 4 Own method · 3 Supported · 2 Couldn’t confirm · 2 Sources not found · 2 No basis given · 1 Supported so far · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“However, as AD progresses, microglia acquire a chronically activated phenotype through unremitting stimulation by cytokines and A itself, which compromises their clearance function (Bamberger et al., 2003;Hickman et al., 2008;Heneka et al., 2010a) .”
§ PPAR␥/RXR␣-Induced and CD36-Mediated Microglial Amyloid- Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice > Introduction
What the sources say
- Partly supportedcites Bamberger et al., 2003 sourceExperimental — accuracy not yet measured
The Introduction says plaque-associated microglia acquire a reactive proinflammatory phenotype after contact with fibrillar Aβ and links Aβ-stimulated signaling to sustained inflammation. The section on Aβ-stimulated signaling also says IL-1β augments the inflammatory response. Neither passage establishes that microglial activation progressively compromises their clearance function. (LLM, conf=0.86)
- Partly supportedcites Hickman et al., 2008 sourceExperimental — accuracy not yet measured
The Discussion reports that microglia in aging AD-model mice continue producing pro-inflammatory cytokines while losing Aβ-clearing capacity; it also links Aβ-induced inflammation to reduced expression of clearance receptors. The paper does not establish that unremitting stimulation by both cytokines and Aβ causes a chronically activated phenotype, and it frames some cytokine effects as possible mechanisms rather than demonstrated causes. Page numbers were not supplied for these passages. (LLM, conf=0.82)
- Not matchedcites Heneka et al., 2010a
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: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Microglial expression of receptors that promote the clearance and phagocytosis of A, such as CD36, TLR4, and TLR6 (Lee and Landreth, 2010), are mandatory for restricting amyloid plaque formation.”
§ PPAR␥/RXR␣-Induced and CD36-Mediated Microglial Amyloid- Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice > Introduction
What the sources say
- Partly supportedcites Lee and Landreth, 2010 sourceExperimental — accuracy not yet measured
The Fibrillar Aβ clearance section identifies CD36, TLR4 and TLR6 in the microglial receptor complex involved in Aβ uptake and phagocytosis. It does not establish that expression of all three is mandatory for restricting plaques: it calls the effects of TLR inactivation on Aβ deposition confusing and reports differing outcomes across mouse models. (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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Evidence for a important role of microglial phagocytosis comes from studies that show that restricting microglial A uptake leads to increased cerebral A levels (El Khoury et al., 2007;Lee and Landreth, 2010).”
§ PPAR␥/RXR␣-Induced and CD36-Mediated Microglial Amyloid- Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice > Introduction
What the sources say
- Not checked — no full text of the sourcecites El Khoury et al., 2007 source
- Partly supportedcites Lee and Landreth, 2010 sourceExperimental — accuracy not yet measured
The Fibrillar Aβ clearance section reports that mice with inactive TLR4 had greater cortical and hippocampal Aβ burden, and that their microglia were less efficient at taking up Aβ. It describes reduced microglial clearance as the study authors’ proposed explanation, not an established causal finding, and notes differing results for TLR2-deficient mice. The claim states the causal relationship more definitively than this review does. (LLM, conf=0.84)
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.
Every source the paper cites for this claim was checked and supports it.
In the paper
“Of note, a subset of NSAIDs directly regulates gene expression through binding and activating the peroxisome proliferator-activated receptor-␥ (PPAR␥) (Lehmann et al., 1997) that belongs to the nuclear receptor superfamily and forms a heterodimer with the retinoid X receptor (RXR) before binding to PPAR response elements in the promoter region of target genes.”
§ PPAR␥/RXR␣-Induced and CD36-Mediated Microglial Amyloid- Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice > Introduction
What the sources say
- Supportedcites Lehmann et al., 1997 source
The Results report that several NSAIDs activated a PPARγ-dependent gene-expression reporter and competed for binding to PPARγ. The authors conclude that some, but not all, NSAIDs bind and activate PPARγ. Our copy does not provide page numbers for these passages. (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
“Because impaired A clearance is likely to account for the majority of sporadic AD cases (Mawuenyega et al., 2010), identification of factors the regulate microglial A uptake seems to be of upmost importance.”
§ PPAR␥/RXR␣-Induced and CD36-Mediated Microglial Amyloid- Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice > Introduction
What the sources say
- Partly supportedcites Mawuenyega et al., 2010 sourceExperimental — accuracy not yet measured
The paper reports slower Aβ clearance in patients with AD than in controls and says the common late-onset form of AD may involve impaired clearance. It does not establish that impaired clearance accounts for a majority of sporadic cases; the study also cautions that its association does not prove causality (Abstract and study limitations). (LLM, conf=0.86)
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.
- Partly 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
“Because microglia are critical for A phagocytosis, the microglial presence at the A plaque can be interpreted as an attempt to clear this pathological deposit.”
§ PPAR␥/RXR␣-Induced and CD36-Mediated Microglial Amyloid- Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice > Introduction
What the sources say
- Not checked — no full text of the sourcecites El Khoury et al., 2007 source
- Supportedcites Lee and Landreth, 2010 source
The Introduction says microglia play critical roles in the uptake and clearance of Aβ. The Fibrillar Aβ clearance section specifically describes microglia readily phagocytosing fibrillar Aβ, supporting the attributed claim. (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.
Every source the paper cites for this claim was checked and supports it.
In the paper
“However, persisting neuroinflammation and sustained exposure to proinflammatory stimuli compromises microglial clearance functions as AD progresses (Lee and Landreth, 2010).”
§ PPAR␥/RXR␣-Induced and CD36-Mediated Microglial Amyloid- Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice > Discussion
What the sources say
- Supportedcites Lee and Landreth, 2010 source
The Fibrillar Aβ clearance section states that proinflammatory cytokines inhibit microglial degradation of Aβ. It also reports that chronic, unlike acute, inflammatory stimulation increased Aβ deposition in AD mouse models and accelerated pathology. Together with the paper’s discussion of impaired microglial phagocytosis in the proinflammatory AD brain, these passages support the paraphrase. (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.
- Supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“PPAR␥ heterodimerizes with RXRs (Tugwood et al., 1992), and, during ligand activation, the PPAR/RXR heterodimer recruits coactivators and binds to sequence-specific PPAR response elements present in the promoter region of several target genes.”
§ PPAR␥/RXR␣-Induced and CD36-Mediated Microglial Amyloid- Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice > Discussion
What the sources say
- Could not verifycites Tugwood et al., 1992 sourceExperimental — accuracy not yet measured
The Introduction and Discussion describe PPAR binding a response element in the rat ACO promoter. The Discussion mentions RXR only in comparing response-element sequences; it does not say that PPARγ heterodimerizes with RXRs. Searches for RXR heterodimerization and PPARγ found no passage addressing that claim. (LLM, conf=0.76)
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.
- Could not verify
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
“Determination of cortex A levels revealed 32 and 30% decrease of both SDS-soluble A 1-42 and A 1-40 levels, respectively, in response to the DSP-8658 treatment (Fig. 7A).”
§ PPAR␥/RXR␣-Induced and CD36-Mediated Microglial Amyloid- Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice > DSP-8658 reduces brain A levels
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.
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
“Furthermore, DSP-8658-treated mice showed improved spatial memory performance.”
§ PPAR␥/RXR␣-Induced and CD36-Mediated Microglial Amyloid- Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice > 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.
- Probably not a substantial claim. 11
- It may state two separate claims as one. 9
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The recognition that a robust inflammatory response contributes to AD also fuelled the discovery that long-term treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) reduced the risk for AD, delayed disease onset, and slowed cognitive decline (McGeer et al., 1996;Stewart et al., 1997;in t' in t'Veld et al., 2001).”
§ PPAR␥/RXR␣-Induced and CD36-Mediated Microglial Amyloid- Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice > Introduction
What the sources say
- Not checked — no full text of the sourcecites McGeer et al., 1996 source
- Partly supportedcites Stewart et al., 1997 sourceExperimental — accuracy not yet measured
The Results report a lower risk of AD associated with NSAID use, particularly with two or more years of reported use. The Discussion describes delayed onset as a possible benefit requiring trials to establish protection; the paper does not report that NSAIDs slowed cognitive decline. The claim also presents an observed association as a treatment effect. (LLM, conf=0.88)
- Partly supportedcites in t'Veld et al., 2001 sourceExperimental — accuracy not yet measured
The Discussion (page not supplied) reports a significantly lower risk of Alzheimer's disease among people who used NSAIDs for 24 months or more, supporting the risk portion of the claim. This observational study does not establish that NSAIDs caused the reduction, and the passages do not report delayed disease onset or slowed cognitive decline. (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.
Every source the paper cites for this claim was checked and supports it.
In the paper
“In addition to its classical hallmarks, amyloid- (A) deposition and neurofibrillary tangle formation, Alzheimer's disease (AD) is characterized by a neuroinflammatory component (Lucin and Wyss-Coray, 2009).”
§ PPAR␥/RXR␣-Induced and CD36-Mediated Microglial Amyloid- Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice > Introduction
What the sources say
- Supportedcites Lucin and Wyss-Coray, 2009 source
The section “Microglia in neurodegeneration: repairman or reckless killer?” links microglial activation and pro-inflammatory cytokines to neuronal injury in AD. “PAMPs and DAMPs sound the alarm” also describes Aβ triggering microglia to release inflammatory factors. Page numbers are not available in our copy. (LLM, conf=0.92)
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.
Probably not a substantial claim.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Recently, the RXR agonist bexarotene has been reported to facilitate the intracellular degradation of soluble A 1-42 in a PPAR␥-, liver X receptor-, and apolipoprotein E-dependent manner (Cramer et al., 2012).”
§ PPAR␥/RXR␣-Induced and CD36-Mediated Microglial Amyloid- Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice > Discussion
What the sources say
- Partly supportedcites Cramer et al., 2012 sourceExperimental — accuracy not yet measured
In the passage labeled Abstract (page unavailable), the paper reports that bexarotene facilitated degradation of soluble Aβ42 by primary microglia and astrocytes in a PPARγ-, LXR-, and apoE-dependent manner. It does not specify that the degradation was intracellular; a search for “intracellular” found no passage establishing that detail. (LLM, conf=0.86)
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 that could be checked couldn’t confirm or dispute this claim.
In the paper
“PPAR␥ heterodimerizes with RXRs (Tugwood et al., 1992), and, during ligand activation, the PPAR/RXR heterodimer recruits coactivators and binds to sequence-specific PPAR response elements present in the promoter region of several target genes.”
§ PPAR␥/RXR␣-Induced and CD36-Mediated Microglial Amyloid- Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice > Discussion
What the sources say
- Could not verifycites Tugwood et al., 1992 sourceExperimental — accuracy not yet measured
The citation is attached to the statement that PPARγ heterodimerizes with RXRs. The Discussion (page not available in our copy) describes PPAR binding a response element in the ACO promoter and separately mentions an RXR response element, but does not say that PPARγ heterodimerizes with RXR. Searches for heterodimerization and RXR partnership found no supporting passage; the later coactivator statement is not attached to this citation. (LLM, conf=0.75)
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.
- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Thus, microglia interacts with A through a recently characterized cell-surface receptor complex comprising CD36, ␣61 integrin, and CD47 (Lee and Landreth, 2010).”
§ PPAR␥/RXR␣-Induced and CD36-Mediated Microglial Amyloid- Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice > Discussion
What the sources say
- Partly supportedcites Lee and Landreth, 2010 sourceExperimental — accuracy not yet measured
The “Fibrillar Aβ clearance” section identifies CD36, α6β1 integrin, and CD47 as components of a microglial cell-surface receptor complex for fibrillar Aβ. The “Soluble Aβ clearance” section says soluble Aβ is taken up differently, so the claim is too broad when it says Aβ without specifying its fibrillar form. (LLM, conf=0.87)
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
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Using primary microglia transfected with PPAR␥ siRNA, we found that neither pioglitazone nor DSP-8658 were able to increase A phagocytosis, thus confirming PPAR␥ dependency.”
§ PPAR␥/RXR␣-Induced and CD36-Mediated Microglial Amyloid- Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice > 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.
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
“Both substances DSP-8658 and pioglitazone enhanced A phagocytosis in primary microglia without affecting its degradation.”
§ PPAR␥/RXR␣-Induced and CD36-Mediated Microglial Amyloid- Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice > 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 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 and as a positive control, RXR expression was found in BV2 cells (Fig. 5A), indicating that RXR is either not expressed or at levels below detection by Western blot.”
§ PPAR␥/RXR␣-Induced and CD36-Mediated Microglial Amyloid- Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice > Additive effects of combined activation of PPAR␥ and RXR in primary microglia
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
“novel drugs, such as DSP-8658, which acts as a dual PPAR␣/␥ modulator, are currently under clinical development for the treatment of type 2 diabetes and AD.”
§ PPAR␥/RXR␣-Induced and CD36-Mediated Microglial Amyloid- Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice > Discussion
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 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
“Importantly, nontarget siRNA and RXR siRNA did not affect the uptake of A in response to bexarotene (Fig. 5 B, D).”
§ PPAR␥/RXR␣-Induced and CD36-Mediated Microglial Amyloid- Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice > Additive effects of combined activation of PPAR␥ and RXR in primary microglia
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
“Increase in phagocytosis and subsequently reduced levels of A were accompanied by a substantial improvement of spatial memory performance.”
§ PPAR␥/RXR␣-Induced and CD36-Mediated Microglial Amyloid- Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice > Discussion
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 claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“In microglia and macrophages, PPAR␥ activation inhibits proinflammatory gene expression (Jiang et al., 1998;Ricote et al., 1998).”
§ PPAR␥/RXR␣-Induced and CD36-Mediated Microglial Amyloid- Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice > Introduction
What the sources say
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.
In the paper
“In AD, activated microglia are found in close vicinity to A deposits and produce a wide range of cytokines and chemokines (Rogers and Lue, 2001).”
§ PPAR␥/RXR␣-Induced and CD36-Mediated Microglial Amyloid- Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice > Introduction
What the sources say
- Not matchedcites Rogers and Lue, 2001
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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. It may state two separate claims as one.
- Not matched
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
“Quantitative PCR analysis indicated that the siRNA transfection suppressed PPAR␥ gene expression by 50% (Fig. 1F ), resulting in a substantial reduction of PPAR␥ protein levels when compared with the nontarget control siRNA (Fig. 1G).”
§ PPAR␥/RXR␣-Induced and CD36-Mediated Microglial Amyloid- Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice > Effects of PPAR␥ agonist on A phagocytosis in rat primary microglia
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.
In the paper
“The absence of a substantial effect was postulated to be attributable to poor penetration of pioglitazone into the brain (Maeshiba et al., 1997).”
§ PPAR␥/RXR␣-Induced and CD36-Mediated Microglial Amyloid- Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice > Discussion
What the sources say
- Not checked — no full text of the sourcecites Maeshiba et al., 1997
hedgeddirect- Asserted: fails — The authors may not 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. The authors may not put it forward as true.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, we suggest that a combination therapy using agonists of PPAR␥ and RXR␣ may be more effective in AD.”
§ PPAR␥/RXR␣-Induced and CD36-Mediated Microglial Amyloid- Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice > 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.
In the paper
“There are also indications that inhibition of anti-inflammatory stimuli has beneficial effects on A phagocytosis, -amyloidosis, and cognitive function (Town et al., 2008).”
§ PPAR␥/RXR␣-Induced and CD36-Mediated Microglial Amyloid- Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice > Discussion
What the sources say
- Not checked — no full text of the sourcecites Town et al., 2008 source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper relies on this without support.
PPARγ belongs to the nuclear receptor superfamily and forms a heterodimer with RXR before binding to PPAR response elements in the promoter region of target genes.
“Of note, a subset of NSAIDs directly regulates gene expression through binding and activating the peroxisome proliferator-activated receptor-␥ (PPAR␥) (Lehmann et al., 1997) that belongs to the nuclear receptor superfamily and forms a heterodimer with the retinoid X receptor (RXR) before binding to PPAR response elements in the promoter region of target genes.”
The paper relies on this without support.
DSP-8658 is a novel selective PPARα/γ modulator currently developed for type 2 diabetes because the described side effects are absent in relevant preclinical models.
“DSP-8658 is a novel selective PPAR␣/␥ modulator that is currently developed for type 2 diabetes, because the described side effects are absent in relevant preclinical models.”
The paper relies on this without support.
Currently marketed PPARγ ligands modulate insulin sensitivity but cause considerable side effects, including body weight gain and fluid retention.
“Currently marketed PPAR␥ ligands modulate insulin sensitivity but also cause considerable side effects, including body weight gain and fluid retention.”
The paper relies on this without support.
Activation of PPARγ by endogenous or synthetic ligands modulates insulin sensitivity and exerts profound anti-inflammatory effects in peripheral macrophages and microglia.
“Activation of PPAR␥ by endogenous or synthetic ligands modulates insulin sensitivity and exerts profound antiinflammatory effects in peripheral macrophages and microglia.”
The paper relies on this without support.
DSP-8658 passes the blood-brain barrier more effectively than pioglitazone.
“DSP-8658 passes the blood-brain barrier more effectively than pioglitazone (data not shown).”
The paper relies on this without support.
Several synthetic PPARγ ligands execute off-target actions.
“Because several synthetic PPAR␥ ligands execute”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“However, several studies have shown that defects in the phagocytic function of microglia can be restored with Aβ immunization [18, 23] and anti-inflammatory drug treatment [24, 25].”
From IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia (2019) · cites this paper as [24]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated 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
§ PPAR␥/RXR␣-Induced and CD36-Mediated Microglial Amyloid- Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice > RNA preparation and real-time reverse transcription-polymerase chain reaction.
“Three-month-old wild-type and APP/PS1 transgenic mice were divided into control and DSP-8658-treated groups and fed with a standard food not containing substance or containing 0.1% DSP-8658 for 3 months.”
§ PPAR␥/RXR␣-Induced and CD36-Mediated Microglial Amyloid- Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice > DSP-8658 treatment induced in vivo phagocytosis and recruitment of microglia to A plaques
“APP/PS1 transgenic mice received a DSP-8658-enriched diet from 4 -6 months of age.”
Citations
Cites
Microglia: Active sensor and versatile effector cells in the normal and pathologic brain
Hanisch, U.-K., & Kettenmann, H. (2007) · Nature Neuroscience · doi:10.1038/nn1997 · Cited by 3,676
The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation
Ricote, M., Li, A. C., Willson, T. M., Kelly, C. J., & Glass, C. K. (1998) · Nature · doi:10.1038/34178 · Cited by 3,525
PPAR-γ agonists inhibit production of monocyte inflammatory cytokines
Jiang, C., Ting, A. T., & Seed, B. (1998) · Nature · doi:10.1038/34184 · Cited by 2,899
Decreased Clearance of CNS β-Amyloid in Alzheimer’s Disease
Mawuenyega, K. G., Sigurdson, W., Ovod, V., Munsell, L., Kasten, T., Morris, J. C., Yarasheski, K. E., & Bateman, R. J. (2010) · Science · doi:10.1126/science.1197623 · Cited by 2,078
PPARγ Promotes Monocyte/Macrophage Differentiation and Uptake of Oxidized LDL
Tontonoz, P., Nagy, L., Alvarez, J. G. A., Thomázy, V. A., & Evans, R. M. (1998) · Cell · doi:10.1016/s0092-8674(00)81575-5 · Cited by 1,815
McGeer, P. L., Schulzer, M., & McGeer, E. G. (1996) · Neurology · doi:10.1212/wnl.47.2.425 · Cited by 1,367
Microglial Dysfunction and Defective β-Amyloid Clearance Pathways in Aging Alzheimer's Disease Mice
Hickman, S. E., Allison, E. K., & El Khoury, J. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.0616-08.2008 · Cited by 1,329
Nonsteroidal Antiinflammatory Drugs and the Risk of Alzheimer's Disease
in 't Veld, B. A., Ruitenberg, A., Hofman, A., Launer, L. J., van Duijn, C. M., Stijnen, T., Breteler, M. M. B., & Stricker, B. H. C. (2001) · New England Journal of Medicine · doi:10.1056/nejmoa010178 · Cited by 1,196
Risk of Alzheimer's disease and duration of NSAID use
Stewart, W. F., Kawas, C., Corrada, M., & Metter, E. J. (1997) · Neurology · doi:10.1212/wnl.48.3.626 · Cited by 1,132
Lehmann, J. M., Lenhard, J. M., Oliver, B. B., Ringold, G. M., & Kliewer, S. A. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.6.3406 · Cited by 1,110
Cited by
Sorted by citations
Items 201–300 of 326
Inflammatory Cyclooxygenase Activity and PGE2 Signaling in Models of Alzheimer’s Disease
Johansson, J. U., Woodling, N. S., Shi, J., & Andreasson, K. I. (2015) · Current Immunology Reviews · doi:10.2174/1573395511666150707181414 · Cited by 28
The involvement of microglia in Alzheimer's disease: a new dog in the fight
Moore, Z., Taylor, J. M., & Crack, P. J. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14546 · Cited by 29
Ito, F. (2020) · Current Molecular Pharmacology · doi:10.2174/1874467213666200320153410 · Cited by 30
Li, Z., Meng, X., Ma, G., Liu, W., Li, W., Cai, Q., Wang, S., Huang, G., & Zhang, Y. (2022) · Alzheimer s Research & Therapy · doi:10.1186/s13195-022-01092-7 · Cited by 29
Zhou, W., He, J., Shen, G., Liu, Y., Zhao, P., & Li, J. (2024) · Cell Death and Disease · doi:10.1038/s41419-024-07002-z · Cited by 28
Alghamdi, S. S., Suliman, R. S., Aljammaz, N. A., Kahtani, K. M., Aljatli, D., & Albadrani, G. M. (2022) · Plants · doi:10.3390/plants11040549 · Cited by 29
“the suppression of microglial pro-inflammatory activity as well as the promotion of their phagocytic activity [90,91].”
BackgroundMicroglial activation in Alzheimer's disease: The role of flavonoids and microRNAs
Medrano-Jiménez, E., Meza‐Sosa, K. F., Aragon, J. A. U., Secundino, I., Pedraza-Alva, G., & Pérez-Martínez, L. (2022) · Journal of Leukocyte Biology · doi:10.1002/jlb.3mr1021-531r · Cited by 28
El‐Din, S. S., Elwahab, S. A., Rashed, L. A., Fayez, S., Aboulhoda, B. E., Heikal, O. A., Galal, A. F., & Nour, Z. A. (2021) · Metabolic Brain Disease · doi:10.1007/s11011-021-00741-4 · Cited by 25
Muth, C., Schröck, K., Madore, C., Hartmann, K., Fanek, Z., Butovsky, O., Glatzel, M., & Krasemann, S. (2017) · Brain Pathology · doi:10.1111/bpa.12441 · Cited by 23
High-density lipoprotein-related cholesterol metabolism in Alzheimer's disease
Pedrini, S., Chatterjee, P., Hone, E., & Martins, R. N. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15170 · Cited by 22
“…J20), up-regulation of CD36 through the use of peroxisome proliferator-activated receptor-γ agonists such as Rosiglitazone, Pioglitazone and DSP8658, was shown to improve memory deficits and to reduce amyloid plaques by enhancing microglial uptake (Escribano et al., 2010; Yamanaka et al., 2012).”
BackgroundThe role of microRNA-485 in neurodegenerative diseases
Ryu, I. S., Kim, D. H., Cho, H.-J., & Ryu, J.-H. (2023) · Reviews in the Neurosciences · doi:10.1515/revneuro-2022-0039 · Cited by 25
“Pharmacological manipulation of CD36 improved microglial Aβ phagocytosis, resulting in Aβ clearance and cognitive improvement in AD mouse models (Dobri et al. 2021; Yamanaka et al. 2012).”
BackgroundHayashi-Park, E., Ozment, B. N., Griffith, C. M., Zhang, H., Patrylo, P. R., & Rose, G. M. (2016) · Behavioural Brain Research · doi:10.1016/j.bbr.2016.05.020 · Cited by 26
Protein and Peptides for Elderly Health
Shang, N., Chalamaiah, M., Bandara, N., & Wu, J. (2018) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2018.03.003 · Cited by 24
Tan, X., Guan, H., Yang, Y., Luo, S., Hou, L., Chen, H., & Li, J. (2020) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2020.115090 · Cited by 23
Sun, J., Zhu, K., Wang, Y., Wang, D.-J., Zhang, M.-Z., Sarlus, H., Benito‐Cuesta, I., Zhao, X.-Q., Zou, Z., Zhong, Q.-Y., et al. (2022) · Acta Pharmacologica Sinica · doi:10.1038/s41401-022-01000-7 · Cited by 25
“A PPARγ agonist improves the clearance function of microglia, which is mediated by the upregulation of CD36 expression [61].”
BackgroundTargeting Alzheimer's Pathology through PPARγ Signaling: Modulation of Microglial Function
Lourenco, M. V., & Ledo, J. H. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.0172-13.2013 · Cited by 22
“In summary, the study by Yamanaka et al. (2012), in combination with other recent reports, has provided novel insights into how PPAR signaling counteracts amyloid toxicity and cognitive impairment in animal models of AD.”
BackgroundResultInfluentialA Systems View of the Differences between APOE ε4 Carriers and Non-carriers in Alzheimer’s Disease
Jiang, S., Tang, L. Y., Zhao, N., Yang, W., Qiu, Y. L., & Chen, H. (2016) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2016.00171 · Cited by 22
“RXR can form heterodimers with peroxisome proliferator-activated receptor γ (PPARγ), and their combined activation cooperatively enhances the microglial uptake of Aβ (Yamanaka et al., 2012).”
BackgroundMicroglia-Synapse Pathways: Promising Therapeutic Strategy for Alzheimer’s Disease
Xie, J., Wang, H., Lin, T., & Bi, B. (2017) · BioMed Research International · doi:10.1155/2017/2986460 · Cited by 22
Cozza, A., Chinigò, C., Filicetti, E., Greco, G. I., Lappano, R., Marinaro, C., Muglia, L., Soraci, L., Corsonello, A., Lattanzio, F., et al. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102834 · Cited by 20
Araki, W. (2023) · Cells · doi:10.3390/cells12101386 · Cited by 20
“They also demonstrated that oral administration of DSP-8658 for 3 months not only induced Aβ phagocytosis and recruitment of microglia to Aβ plaques in APP/PS1 mice but also reduced Aβ burden and improved spatial memory performance in these mice [89].”
BackgroundSola-Sevilla, N., Mesa-Lombardo, A., Aleixo, M., Expósito, S., Diaz-Perdigón, T., Azqueta, A., Zamani, F., Suzuki, T., Maioli, S., Eroli, F., et al. (2023) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-023-10084-9 · Cited by 19
“It has been described that, in early stage of AD, microglial activation delays disease progression by promoting clearance of Aβ by phagocytosis (Park et al. 2019; Yamanaka et al. 2012).”
BackgroundGarcía‐Bonilla, L., Park, L., & Iadecola, C. (2014) · Experimental Neurology · doi:10.1016/j.expneurol.2014.08.016 · Cited by 19
“PPAR-γ-stimulated microglial phagocytosis, mediated by CD36 upregulation, promotes Aβ clearance from the brain parenchyma and reduces amyloid plaques (Yamanaka et al., 2012).”
BackgroundCai, M., Zhang, Y., Chen, S. X., Wu, Z., & Zhu, L. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.968444 · Cited by 20
“In APP/PS1 transgenic mice, the PPARγ agonists (pioglitazone and rosiglitazone) shifted microglia from the pro-inflammatory phenotype to the phagocytic phenotype and promoted amyloid clearance (Escribano et al., 2010; Yamanaka et al., 2012).”
BackgroundThe β‐adrenergic hypothesis of synaptic and microglial impairment in Alzheimer's disease
Li, S. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.15782 · Cited by 18
Palmitic acid and palmitoylation in cancer: Understanding, insights, and challenges
Song, P., Jiang, Q., Wu, X., Bu, L., Xie, W., Wei, W., Xing, X., & Guo, J. (2025) · The Innovation · doi:10.1016/j.xinn.2025.100918 · Cited by 20
“54 FATPs are a group of integral membrane proteins, also known as solute carrier protein family 27 (SLC27), expressed on the tumor cells’ surface to increase intracellular lipid availability and support cancer progression and therapy resistance.”
Vitória, J. J. M., Trigo, D., & Silva, O. A. B. D. C. E. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-04090-4 · Cited by 19
“Furthermore, RXR activation by bexarotene has been reported to cause Aβ phagocytosis in brain myeloid cells, linked to an increase in the expression of the phagocytic receptors [177].”
BackgroundNLRP3 ‐directed antisense oligonucleotides reduce microglial immunoactivities in vitro
Braatz, C., Komes, M. P., Ravichandran, K. A., de Fragas, M. G., Griep, A., Schwartz, S., McManus, R. M., & Heneka, M. T. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.15778 · Cited by 20
“Based on these markers, it has been shown that NLRP3-deficiency in APP/PS1 mice results in a phenotype shift toward an anti-inflammatory state (Heneka et al., 2013 The mRNA levels of CD68, which plays a key role in A β phagocytosis, were measured (Daria et al., 2017; Yamanaka et al., 2012).”
Self-citationLevistolide A Attenuates Alzheimer's Pathology Through Activation of the PPARγ Pathway
Qu, X., Guan, P., Han, L., Wang, Z., & Huang, X. (2020) · Neurotherapeutics · doi:10.1007/s13311-020-00943-1 · Cited by 18
Šerý, O., Zeman, T., Sheardová, K., Vyhnálek, M., Marková, H., Laczó, J., Lochman, J., Králík, P., Vrzalová, K., Dziedzinská, R., et al. (2022) · Scientific Reports · doi:10.1038/s41598-022-15299-z · Cited by 17
Roles of Cannabidiol in the Treatment and Prevention of Alzheimer’s Disease by Multi-target Actions
Zhang, X. B., Li, J., Gu, J.-H., & Zeng, Y.-Q. (2021) · Mini-Reviews in Medicinal Chemistry · doi:10.2174/1389557521666210331162857 · Cited by 16
Wang, S., Luo, Q., Chen, H., Huang, J., Li, X., Wu, L., Li, B., Wang, Z., Zhao, D., & Jiang, H. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/9343160 · Cited by 15
Lan, T., Xu, T., Fu, Y., Jiang, S., Liang, X., Yu, Z., Pan, L., Rong, X., & Guo, J. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.864703 · Cited by 15
Multitasking Microglia and Alzheimer’s Disease: Diversity, Tools and Therapeutic Targets
Grubman, A., Kanninen, K. M., & Malm, T. (2016) · Journal of Molecular Neuroscience · doi:10.1007/s12031-016-0825-5 · Cited by 14
“Similarly, improving microglial phagocytosis via PPAR-receptor agonism-dependent induction of CD36was found to stimulate amyloid clearance and enhance spatial memory and learning (Yamanaka et al. 2012).”
BackgroundEvaluation of Fluorinated Cromolyn Derivatives as Potential Therapeutics for Alzheimer’s Disease
Shoup, T. M., Griciuc, A., Normandin, M. D., Quinti, L., Walsh, L. V., Dhaynaut, M., Moon, S., Guehl, N. J., Brugarolas, P., Elmaleh, D. R., et al. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-201419 · Cited by 14
Nuclear receptors of NR1 and NR4 subfamilies in the regulation of microglial functions and pathology
Katsuki, H. (2021) · Pharmacology Research & Perspectives · doi:10.1002/prp2.766 · Cited by 14
Corraliza-Gómez, M., Vargas-Soria, M., & Garcı́a-Alloza, M. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00894-1 · Cited by 14
Lai, Y., Yeh, Y., Huang, Y., Almeida, C. D., Chang, G., Chen, W.-J., & Hsu, H. (2024) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.4c00127 · Cited by 14
Ano, Y., Ohya, R., Yamazaki, T., Takahashi, C., Taniguchi, Y., Kondô, K., Takashima, A., Uchida, K., & Nakayama, H. (2020) · Scientific Reports · doi:10.1038/s41598-020-77034-w · Cited by 13
Identification of key genes and pathways associated with spinal cord injury
Zhang, Y., Song, J. T., Wang, L.-G., & Shao, J. (2017) · Molecular Medicine Reports · doi:10.3892/mmr.2017.6192 · Cited by 13
“PPAR, which includes 3 isoforms (PPAR‑ α PPAR-γ PPAR-β / δ ), is involved in the inflammation process (22).”
Metzger, J. M., Matsoff, H. N., Zinnen, A. D., Fleddermann, R. A., Bondarenko, V., Simmons, H. A., Mejia, A. F., Moore, C. F., & Emborg, M. E. (2020) · PLoS ONE · doi:10.1371/journal.pone.0226999 · Cited by 14
Peroxisome proliferator-activated receptors (PPARs) agonists as promising neurotherapeutics
Ghannam, I. A. Y., Hassan, R. M., & Abdel‐Maksoud, M. S. (2025) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2025.108226 · Cited by 13
Zhu, Z., Guan, Y., Gao, S., Guo, F., Liu, D., & Zhang, H. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.117170 · Cited by 12
Jiang, X., Zhao, X., Chen, R., Jiang, Q., & Zhou, B. (2016) · Archives of Medical Science · doi:10.5114/aoms.2016.60821 · Cited by 12
Zubillaga, M., Abadin, X., Ivars, E., Puigròs, M., Trullás, R., Bellini, M. J., Arnal, N., & Colell, A. (2025) · Redox Biology · doi:10.1016/j.redox.2025.103872 · Cited by 17
Quan, Q., Ma, X., Li, M., Li, X., & Yuan, H. (2023) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2023.12319 · Cited by 11
“…activation improved spatial memory in animal models of AD, and it was accomplished by inhibiting β ‑secretase expression and reducing A β production through modulating the responses of the microglia to A β deposition, thereby increasing the phagocytosis of A β and reducing cytokine release (40,41).”
BackgroundMicroglial phagocytosis in epilepsy: Mechanisms and impact
Barath, A. S., & Wu, L. (2025) · The Journal of Physiology · doi:10.1113/jp288573 · Cited by 17
“PPAR γ agonists were found to increase amyloid-β phagocytosis through upregulation of phagocytic receptors Axl, MerTK, TREM2 and CD36 (Savage et al., 2015; Yamanaka et al., 2012).”
Utreras, E., Hamada, R., Prochazkova, M., Terse, A., Takahashi, S., Ohshima, T., & Kulkarni, A. B. (2014) · Journal of Neuroinflammation · doi:10.1186/1742-2094-11-28 · Cited by 11
Piemontese, L. (2018) · Neural Regeneration Research · doi:10.4103/1673-5374.241043 · Cited by 11
Gaspar, J. C., Okine, B. N., Llorente‐Berzal, A., Roche, M., & Finn, D. P. (2020) · Molecules · doi:10.3390/molecules25041007 · Cited by 11
Microglia in Alzheimer’s Disease: A Favorable Cellular Target to Ameliorate Alzheimer’s Pathogenesis
Sumsuzzman, D. M., Uddin, M. S., Kabir, M. T., Hasana, S., Perveen, A., Alanazi, I. S., Albadrani, G. M., Abdel‐Daim, M. M., & Ashraf, G. M. (2022) · Mediators of Inflammation · doi:10.1155/2022/6052932 · Cited by 12
“Moreover, microglia induce Aβ-phagocytosis [194, 195] and senile plaque compaction and limit the Aβ toxicity [196, 197].”
BackgroundDuarte, I. D. A. E., de Souza, M. C. M., Curinga, R. M., Mendonça, H. M., de Oliveira, L. D. L., Milenković, D., Hassimotto, N. M. A., Costa, A. M., Malaquias, J. V., & Borges, T. K. D. S. (2022) · Food & Function · doi:10.1039/d1fo04334j · Cited by 11
Research progress of PPARγ regulation of cholesterol and inflammation in Alzheimer's disease
Gu, L., Ju, Y., Hu, M. S., Miao, Z., Li, Q., & Zhang, X. (2023) · Metabolic Brain Disease · doi:10.1007/s11011-022-01139-6 · Cited by 12
Temporal-logic analysis of microglial phenotypic conversion with exposure to amyloid-β
Anastasio, T. J. (2014) · Molecular BioSystems · doi:10.1039/c4mb00457d · Cited by 11
Topalis, V., Voros, C., & Ziaka, M. (2025) · Journal of Geriatric Psychiatry and Neurology · doi:10.1177/08919887251361578 · Cited by 14
“268 269-272 As an agonist of PPAR γ , pioglitazone plays a signi fi cant role in the regulation of metabolic coupling between astrocytes and neurons, along with promoting dendritic growth and synapse formation.”
Ko, C., Xu, J., Chang, Y.-W. W., Lo, Y.-M. M., Wu, J. S., Huang, W., & Shen, S. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.788723 · Cited by 10
Roles of Microglia in AD Pathology
Gao, R., Wu, H., Li, Q., & Zhao, J. (2023) · Current Alzheimer Research · doi:10.2174/1567205020666230203112351 · Cited by 10
CD36 Deficiency Suppresses Epileptic Seizures
Zheng, F., Yang, Y., Lu, S., Yang, Q. Z., Li, Y., Xu, X., Zhang, Y., Liu, F., Tian, X., & Wang, X. (2017) · Neuroscience · doi:10.1016/j.neuroscience.2017.10.024 · Cited by 10
Avarachan, J., Augustine, A., Shinde, P. M., & Gunasekaran, V. (2021) · Research Journal of Pharmacy and Technology · doi:10.52711/0974-360x.2021.00688 · Cited by 10
Kunze, L. H., Ruch, F., Biechele, G., Eckenweber, F., Wind-Mark, K., Dinkel, L., Feyen, P., Bartenstein, P., Ziegler, S. I., Paeger, L., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241210106 · Cited by 9
“One well-established option to achieve immunomodulation is by targeting the peroxisome proliferator-activated receptor γ (PPARγ) through pioglitazone [9,10].”
BackgroundChronic PPARγ Stimulation Shifts Amyloidosis to Higher Fibrillarity but Improves Cognition
Blume, T., Deussing, M., Biechele, G., Peters, F., Zott, B., Schmidt, C., Franzmeier, N., Wind, K., Eckenweber, F., Sacher, C., et al. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.854031 · Cited by 10
Chen, Z.-X., Xiao, F., Zhu, X., Zhou, W., Rui, K., Lu, L., & Tian, J. (2025) · Metabolism · doi:10.1016/j.metabol.2025.156349 · Cited by 10
Kaiser, S., Henrich, L., Kiessling, I., Loy, B., & Schallner, N. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25031680 · Cited by 10
“In accordance with the findings in this study, microglial CD36 determines phagocytosis after intracerebral hemorrhage [16] and other cerebral injury modalities [17,18,41–43].”
ResultPharmacokinetic properties of MH84, a γ-secretase modulator with PPARγ agonistic activity
Pellowska, M., Stein, C., Pohland, M., Merk, D., Klein, J., Eckert, G. P., Schubert‐Zsilavecz, M., & Wurglics, M. (2014) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2014.10.001 · Cited by 8
Flesch, D., Neß, J., Lamers, C., Dehm, F., Popella, S., Steri, R., Ogorek, I., Hieke, M., Dannhardt, G., Werz, O., et al. (2014) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2014.12.073 · Cited by 7
CB2R activation enhances tumor-associated macrophages-mediated phagocytosis of glioma cell
Lu, S., Chen, X., Yang, Y., & Li, J. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e40806 · Cited by 7
Brain Cancer-Activated Microglia: A Potential Role for Sphingolipids
Bottai, D., Adami, R., Paroni, R. C., & Ghidoni, R. (2019) · Current Medicinal Chemistry · doi:10.2174/0929867326666190506120213 · Cited by 6
Neuroinflammation in Alzheimer's, Parkinson's and Huntington's Diseases
Sastre, M., Katsouri, L., Birch, A. M., Renziehausen, A., Dexter, D. T., Crichton, R. R., & Ward, R. J. (2014) · Wiley eBooks · doi:10.1002/9781118406557.ch6 · Cited by 6
Liu, R., Deng, Q., Gong, L., & Yang, L. (2026) · Neuroscience Bulletin · doi:10.1007/s12264-026-01598-2 · Cited by 5
“However, in AD, microglia often exhibit a reduced ability to clear Aβ, which may be attributed to factors such as trem2 deficiency [312], downregulation of scavenger receptor CD36 expression [313], and impaired recruitment of microglia surrounding amyloid plaques [14].”
Kinoshita, K., Ushida, K., Hirata, Y., et al. (2025) · Neuroscience · doi:10.1016/j.neuroscience.2025.01.062 · Cited by 5
ICA1 affects APP processing through the PICK1‐PKCα signaling pathway
Ji, L., Meng, Z., Dong, X., Wang, Q., Jiang, Y., Zhang, J., Hu, D., Guo, S., Zhou, W., & Song, W. (2024) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14754 · Cited by 5
Chittilla, M., Akimbekov, N. S., & Razzaque, M. S. (2021) · Current Research in Physiology · doi:10.1016/j.crphys.2021.09.004 · Cited by 5
TERC Stimulates Fatty Acid Metabolism to Promote Bladder Cancer Progression
Chen, C., Gao, Y., Lu, R., et al. (2025) · Cancer Research · doi:10.1158/0008-5472.can-24-3439 · Cited by 4
Gao, M., Zhou, J., Shi, N., Yan, X., & Liang, L. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1742677 · Cited by 5
ZHAO, J.-F., JIANG, Y.-R., GUO, T.-L., JIAO, Y.-Q., & WANG, X. (2024) · Biocell · doi:10.32604/biocell.2024.050120 · Cited by 4
“In addition, SCARA-1 can enhance the ability of microglia to bind and phagocytize A β [27], whereas CD36 can promote A β phagocytosis through peroxisome proliferator-activated receptor (PPAR γ ) signaling [28].”
HPGD: An Intermediate Player in Microglial Polarization and Multiple Sclerosis Regulated by Nr4a1
Sun, M., Liu, Y., Wang, X., & Wang, L. (2024) · Molecular Neurobiology · doi:10.1007/s12035-024-04280-8 · Cited by 6
Wang, M., Jin, B., Xu, J., & Wang, C. (2025) · Nutrients · doi:10.3390/nu17162679 · Cited by 4
“Conventional anti-inflammatory agents such as sulindac and ibuprofen have been investigated in AD, but their application is constrained by long-term side effects [47,48].”
Low-Concentrations of Fatty Acids Induce an Early Increase in IL-8 Levels in Normal Human Astrocytes
Dobri, A.-M., Codrici, E., Popescu, I. D., Albulescu, L., Fertig, T. E., Enciu, A., Tănase, C., & Hinescu, M. E. (2022) · Metabolites · doi:10.3390/metabo12040329 · Cited by 4
Yoon, S., & Kim, Y. (2015) · Global Medical Genetics · doi:10.3934/genet.2015.3.230 · Cited by 5
Prospects and Challenges for Alzheimer Therapeutics
Wolfe, M. S. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-802173-6.00023-x · Cited by 5
CD36 gene polymorphisms and Alzheimer's disease
Šerý, O., Goswami, N., & Balcar, V. J. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-815868-5.00004-9 · Cited by 4
The significance of dysregulated serine metabolism in depression
Lu, Y., Lv, M., Zhao, C., Pei, J., & Zhou, M. (2025) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2025.118458 · Cited by 3
Huang, N., Hong, R., Cui, X., Cao, L., Shi, L., Chen, B., Su, Y., Xu, X., Hua, C., & Ying, T. (2026) · Journal of Nanobiotechnology · doi:10.1186/s12951-026-04297-2 · Cited by 5
“CD36-related Aβ clearance by phagocytosis is another focus of microglia [72].”
Mitochondrial Dysfunction in Neurodegenerative Diseases
Chen, C., Zhao, Y., Wang, J., Pan, D., Wang, X., Xu, Y., Yan, J., Wang, L., Yang, X., Lu, M., et al. (2025) · MedComm · doi:10.1002/mco2.70326 · Cited by 3
“PPAR γ /PGC-1 α signaling agonists are likewise effective in the treatment of neurodegenerative disorders such as AD and HD [250, 251].”
Pezeshki, S. P., Darabi, M. K., Nazeri, Z., Sarkaki, A., Rashidi, M., Babaahmadi‐Rezaei, H., Kheirollah, A., & Cheraghzadeh, M. (2023) · PubMed Central · doi:10.22088/ijmcm.bums.12.2.108 · Cited by 3
PPARs (Peroxisome Proliferator-activated Receptors) and Their Agonists in Alzheimer's Disease
Kumar, M., Sharma, A. A., Datusalia, A. K., & Khatik, G. L. (2024) · Medicinal Chemistry · doi:10.2174/0115734064295063240422100615 · Cited by 3
Witkamp, R. F. (2014) · AAPS advances in the pharmaceutical sciences series · doi:10.1007/978-3-319-06151-1_9 · Cited by 3
Design of Novel PPAR Agonist for Neurodegenerative Disease
Steinke, I., & Amin, R. (2021) · Springer eBooks · doi:10.1007/978-3-030-78315-0_10 · Cited by 3
Xin, X., Zong, T., Hu, Z., Jin, L., Zhou, W., Sun, J., & Gao, L. (2025) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2025.108934 · Cited by 2
Neuroprotective role of rice bran extract and its constituents in a neuroinflammatory mouse model
El-Nagah, S. M. A., Abdel‐Halim, M., Heikal, O. A., & Abdel-Kader, R. M. (2025) · BMC Complementary Medicine and Therapies · doi:10.1186/s12906-025-05097-1 · Cited by 3
“Moreover, since CD36 causes phagocytosis of the Aβ protein [30], we examined the effect of RBE on Aβ levels in the brains of RBE-treated mice.”
Liu, Z., Wang, J., Ge, Y., Wang, Y., Ling, H., Liu, Y., Zhang, J., You, Z., & Han, Y. (2026) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2026.106483 · Cited by 2
Suzuki, K., Koyama, H., Nakamura, N., Kimura, Y., Ogata, A., Ikenuma, H., Ishii, H., Zhang, M., Kawamura, K., Minamimoto, T., et al. (2023) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2023.129212 · Cited by 2
Parekh, J., Shende, H., Kumar, A., Tuli, H. S., & Kaur, G. (2024) · Current Pharmacology Reports · doi:10.1007/s40495-024-00354-2 · Cited by 2
“The study shows that thiazolidinedione can induce the overexpression of the ApoE which helps in the clearance of the Aβ [67].”
Chua, H. E., Bhowmick, S. S., & Tucker‐Kellogg, L. (2014) · ACM International Conference on Bioinformatics, Computational Biology, and Health Informatics (ACM-BCB) · doi:10.1145/2649387.2649424 · Cited by 2
“[507] M.”
BackgroundCD36, CD44, and CD83 Expression and Putative Functions in Neural Tissues
Glezer, I., Rivest, S., & Xavier, A. M. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-800781-5.00003-7 · Cited by 2
Chronic PPARγ Stimulation Shifts Amyloidosis to Higher Fibrillarity but Improves CognitionPreprint
Blume, T., Deußing, M., Biechele, G., Peters, F., Zott, B., Schmidt, C., Franzmeier, N., Wind-Mark, K., Eckenweber, F., Sacher, C., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.05.30.446348 · Cited by 2
Comerota, M. M., Gedam, M., Xiong, W., Jin, F., Deng, L., Wang, M. C., Wang, J., & Zheng, H. (2023) · Research Square · doi:10.21203/rs.3.rs-2484513/v1 · Cited by 4
Xu, X., Song, H., Zhang, L., Chen, C., Zhang, X., Liu, Y., Li, C., & Fu, Q. (2025) · Genes · doi:10.3390/genes16040392 · Cited by 2
Hu, D., Li, X., Li, Y., Zhang, Q., Dai, Y., Teng, X., Hou, H., & Li, J. (2025) · ChemBioChem · doi:10.1002/cbic.202500515 · Cited by 1
Cottrell, S., Yoon, S., Wei, X., Dickson, A., & Wei, G.-W. (2026) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c02862 · Cited by 1
Brandys, N., & Chadzińska, M. (2021) · Postępy Higieny i Medycyny Doświadczalnej · doi:10.2478/ahem-2021-0014 · Cited by 1
Metadata
- Authors
- Yamanaka, M., Ishikawa, T., Griep, A., Axt, D., Kummer, M. P., & Heneka, M. T.
- Affiliations
- University of Bonn (DE)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-11-28
- Volume
- 32
- Issue
- 48
- Pages
- 17321-17331
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6621845
- OpenAlex
- W2033726284
- Semantic Scholar
- 5c8c1b6a5899ab2fa9e28907cc0054b1337bb79d
- Cited by
- 326
- References
- 41
- Citations by year
- 2026: 9 · 2025: 26 · 2024: 15 · 2023: 20 · 2022: 24 · 2021: 24 · 2020: 32 · 2019: 25 · 2018: 19 · 2017: 24 · 2016: 32 · 2015: 32 · 2014: 31 · 2013: 13
- FWCI
- 14.33
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion, other-oa)
- PubMed Central (submittedVersion)
- DZNE Pub (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (KFO177)
- Dainippon Sumitomo Pharma
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- Alzheimer's disease, amyloid-beta phagocytosis, microglia, PPARγ, RXRα, CD36, pioglitazone, spatial memory, neuroinflammation, amyloid-beta clearance
- MeSH terms
- Pioglitazone, Alzheimer Disease, Animals, Behavior, Animal, Brain, Cognition, Disease Models, Animal, Hypoglycemic Agents, Phagocytosis, Amyloid beta-Protein Precursor, Microglia, Maze Learning, Thiazolidinediones, PPAR gamma, Mice, Presenilin-1
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 2026-10-20, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-20 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
