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
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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.
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Claims the paper makes
15 of 30 cited sources checked · 4 supported · 0 flagged · 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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- 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)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- 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)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesEvery 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)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- 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)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- 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)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesEvery 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)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- 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)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- 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)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. 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)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably 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)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- 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)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably 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)
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- 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
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast 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
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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.
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Tests✗ Asserted: fails✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably 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
Tests✓ Asserted: passes✗ Checkable: fails✓ Load-bearing: passes✓ Based: passesProbably 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
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. 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.
DSP-8658 treatment start age differs between methods and results
MajorThe methods say three-month-old mice were assigned to treatment for three months, whereas the results say APP/PS1 mice received the diet from four to six months of age. These descriptions give different treatment start ages.
“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.”
“APP/PS1 transgenic mice received a DSP-8658-enriched diet from 4 -6 months of age.”
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Items 101–200 of 326
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“…promotes phagocytosis of apoptotic cells, contributing to the resolution of inflammation (Flores et al., 2016; Savage et al., 2015; Villapol, 2018; Yamanaka et al., 2012; Zhao et al., 2015b), although there is a report showing that an antagonist of PPARγ promotes the pro-inflammatory to…”
BackgroundDanger-Sensing/Patten Recognition Receptors and Neuroinflammation in Alzheimer’s Disease
Chiarini, A., Armato, U., Hu, P., & Prà, I. D. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21239036 · Cited by 77
“CD36 Pioglitazone (thiazolidinedione peroxisome-proliferator activated receptor γ [PPARγ] agonist) Mild Cognitive Impairment (Phase 3) Terminated (Lack of efficacy of the drug) [341]”
BackgroundNeuroinflammatory Signaling in the Pathogenesis of Alzheimer’s Disease
Uddin, M. S., Kabir, M. T., Jalouli, M., Rahman, M. A., Jeandet, P., Behl, T., Alexiou, A. T., Albadrani, G. M., Abdel‐Daim, M. M., Perveen, A., et al. (2021) · Current Neuropharmacology · doi:10.2174/1570159x19666210826130210 · Cited by 76
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BackgroundMethodNoh, M., Kwon, H. S., Kwon, M., Nahm, M., Jin, H. K., Bae, J., & Kim, S. H. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00867-4 · Cited by 94
Therapeutic potential of nuclear receptor agonists in Alzheimer's disease
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Microglia as Dynamic and Essential Components of the Amyloid Hypothesis
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“Existing drugs that could be aimed, e.g., at increasing the phagocytic activity of microglia include the peroxisome proliferatoractivated receptor g (PPARg) agonist pioglitazone and a novel selective PPARa/g modulator, DSP-8658 (Yamanaka et al., 2012), as well as the mixed acetylcholinesterase inhibitor-nicotinic agon…”
BackgroundGhosal, K., Haag, M., Verghese, P. B., West, T., Veenstra, T., Braunstein, J. B., Bateman, R. J., Holtzman, D. M., & Landreth, G. E. (2016) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1016/j.trci.2016.06.001 · Cited by 73
Signaling Mechanisms of Selective PPARγ Modulators in Alzheimer’s Disease
Govindarajulu, M., Pinky, P. D., Bloemer, J., Ghanei, N., Suppiramaniam, V. D., & Amin, R. (2018) · PPAR Research · doi:10.1155/2018/2010675 · Cited by 77
“In a recent study utilizing APP/Presenilin-1 mouse model [85], activation of PPARγ enhances the microglial uptake of Aβ resulting in reduced cortical and hippocampal Aβ level.”
BackgroundLandreth, G. E., Cramer, P. E., Lakner, M. M., Cirrito, J. R., Wesson, D. W., Brunden, K. R., & Wilson, D. A. (2013) · Science · doi:10.1126/science.1234114 · Cited by 75
Therapeutic Actions of the Thiazolidinediones in Alzheimer’s Disease
Maria Jose Perez, J., & Quintanilla, R. A. (2015) · PPAR Research · doi:10.1155/2015/957248 · Cited by 75
Rosiglitazone-induced CD36 up-regulation resolves inflammation by PPARγ and 5-LO-dependent pathways
Ballesteros, I., Cuartero, M. I., Pradillo, J. M., de la Parra, J., Pérez‐Ruíz, A., Corbí, A. L., Ricote, M., Hamilton, J. A., Sobrado, M., Vivancos, J., et al. (2013) · Journal of Leukocyte Biology · doi:10.1189/jlb.0613326 · Cited by 70
“In this context, CD36 up-regulation in the CNS by RSG has been linked to improved hematoma resolution [41] and -amyloid peptide clearance in the brain [39, 40].”
BackgroundLourenco, M. V., Ferreira, S. T., & Felice, F. G. D. (2015) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.03.003 · Cited by 74
Multiple inflammatory profiles of microglia and altered neuroimages in APP/PS1 transgenic AD mice
Liu, L., Liu, Y., Li, N., Huang, R., Zheng, X., Huang, L., Hou, S.-X., & Yuan, Q. (2020) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2020.01.003 · Cited by 71
CD 4 T cells in immunity and immunotherapy of A lzheimer's disease
Monsonego, A., Nemirovsky, A., & Harpaz, I. (2013) · Immunology · doi:10.1111/imm.12103 · Cited by 72
Role of PPAR γ in the Differentiation and Function of Neurons
Quintanilla, R. A., Utreras, E., & Cabezas-Opazo, F. (2014) · PPAR Research · doi:10.1155/2014/768594 · Cited by 71
“Acute treatment of 10-month-old APPV717I mice with pioglitazone significantly decreased the number of activated microglia and astrocytes in hippocampus and cortex [18].”
BackgroundKoronyo‐Hamaoui, M., Sheyn, J., Hayden, E. Y., Li, S., Fuchs, D.-T. S., Regis, G. C., Lopes, D. H. J., Black, K. L., Bernstein, K. E., Teplow, D. B., et al. (2019) · Brain · doi:10.1093/brain/awz364 · Cited by 75
“…pruning (Hong et al., 2016; Johnson and Stevens, 2018), while insufficiently clearing misfolded amyloid-b (Morgan et al., 2005; Simard et al., 2006; El Khoury et al., 2007; Hickman et al., 2008; Koronyo-Hamaoui et al., 2009; Yamanaka et al., 2012; Frenkel et al., 2013; Roussos et al., 2015).”
BackgroundMolecular and genetic inflammation networks in major human diseases
Zhao, Y., Forst, C. V., Sayegh, C. E., Wang, I., Yang, X., & Zhang, B. (2016) · Molecular BioSystems · doi:10.1039/c6mb00240d · Cited by 72
TREM2 alters the phagocytic, apoptotic and inflammatory response to Aβ42 in HMC3 cells
Akhter, R., Shao, Y., Formica, S., Khrestian, M., & Bekris, L. M. (2021) · Molecular Immunology · doi:10.1016/j.molimm.2020.12.035 · Cited by 68
Regenerative Capacity of Macrophages for Remyelination
Rawji, K. S., Mishra, M. K., & Yong, V. W. (2016) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2016.00047 · Cited by 70
“Agents which have been shown to modulate macrophage polarization toward a regulatory phenotype include interferon-β1 and the peroxisome proliferator-activated receptor α/γ agonist, DSP-8658 (Yamanaka et al., 2012; Cohen et al., 2014).”
BackgroundDuffy, C. M., Xu, H., Nixon, J. P., Bernlohr, D., & Butterick, T. A. (2017) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2017.02.004 · Cited by 66
“Interestingly, PPARγ antagonists are neuroprotective in models of neurodegenerative diseases such as AD and PD, through a microglial-mediated mechanism (Garrido-Gil et al., 2012; Yamanaka et al., 2012).”
Microglial Function and Regulation during Development, Homeostasis and Alzheimer’s Disease
Casali, B. T., & Reed-Geaghan, E. G. (2021) · Cells · doi:10.3390/cells10040957 · Cited by 70
Casali, B. T., Corona, A. W., Mariani, M. M., Karlo, J. C., Ghosal, K., & Landreth, G. E. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.1000-15.2015 · Cited by 63
“…postulate that provision of DHA as a free fatty acid delivered by oral gavage in our study, either alone, and in combination with bexarotene, may promote clearance of dense-core plaques by catalyzing target genes of LXR and PPAR involved in phagocytosis (Terwel et al., 2011; Yamanaka et al., 2012).”
BackgroundSong, J., Choi, S., & Kim, B. C. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2017.00064 · Cited by 63
PPARγ and Cognitive Performance
d’Angelo, M., Castelli, V., Catanesi, M., Antonosante, A., Dominguez-Benot, R., Ippoliti, R., Benedetti, E., & Cimini, A. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20205068 · Cited by 63
“Moreover, DSP-8658 treatment improves spatial memory performance [40].”
BackgroundCao, Y., Zhao, L.-W., Chen, Z.-X., & Li, S.-H. (2024) · Frontiers in Neuroscience · doi:10.3389/fnins.2024.1430465 · Cited by 65
He, S., Xu, Z., & Han, X. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00803-6 · Cited by 62
Teng, E., Taylor, K. M., Bilousova, T. V., Weiland, D. A., Pham, T., Zuo, X., Yang, F., Chen, P., Glabe, C. G., Takacs, A., et al. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.09.002 · Cited by 65
“…al., 2013), further investigations of the effects of DHA supplementation on CD36 expression (Vallve et al., 2002), which appears to mediate microglial Aβ phagocytosis induced by PPAR-γ and prostaglandin E2 receptor subtype 2 signaling (Li et al., 2015; Yamanaka et al., 2012) appear to be warranted.”
Lecca, D., Janda, E., Mulas, G., Diana, A., Martino, C., Angius, F., Spolitu, S., Casu, M. A., Simbula, G., Boi, L., et al. (2018) · British Journal of Pharmacology · doi:10.1111/bph.14214 · Cited by 62
Menn, G. L., & Neels, J. G. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19061575 · Cited by 61
“In the context of Alzheimer’s disease, in vitro studies demonstrated that PPARγ agonists stimulated Aβ phagocytosis by rat primary microglia through induction of CD36 expression [103].”
BackgroundEffects of pioglitazone on the incidence of dementia in patients with diabetes
Chou, P., Ho, B., & Yang, Y. (2017) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2017.01.006 · Cited by 59
Assaf, N., El-Shamarka, M. E.-S., Salem, N. A., Khadrawy, Y. A., & Sayed, N. S. E. (2019) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2019.109793 · Cited by 58
Yu, Y., Li, X., Blanchard, J., Li, Y., Iqbal, K., Liu, F., & Gong, C. (2014) · Journal of Neural Transmission · doi:10.1007/s00702-014-1294-z · Cited by 60
Wang, Y., Zhu, T., Wang, M., Zhang, F., Zhang, G., Zhao, J., Zhang, Y., Wu, E., & Li, X. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00291 · Cited by 58
“Specifically, PPARγ appears to be linked to stress modulation (Garcia-Bueno et al., 2005) and to mediate the conversion between microglia phenotypes (Yamanaka et al., 2012; Saijo et al., 2013).”
BackgroundBrain Cleanup as a Potential Target for Poststroke Recovery
Ting, S., Zhao, X., Sun, G., Obertas, L., Ricote, M., & Aronowski, J. A. (2020) · Stroke · doi:10.1161/strokeaha.119.027315 · Cited by 57
Kumari, S., Dhapola, R., Sharma, P., Singh, S. K., & HariKrishnaReddy, D. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.102098 · Cited by 58
Nuclear Receptors as Therapeutic Targets for Neurodegenerative Diseases: Lost in Translation
Moutinho, M., Codocedo, J. F., Puntambekar, S. S., & Landreth, G. E. (2018) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010818-021807 · Cited by 57
Dhage, P. A., Sharbidre, A. A., Dakua, S. P., & Balakrishnan, S. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111634 · Cited by 53
Targeting MicroRNA-485-3p Blocks Alzheimer’s Disease Progression
Koh, H., Lee, S., Lee, H., Min, J.-W., Iwatsubo, T., Teunissen, C. E., Cho, H., & Ryu, J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222313136 · Cited by 58
Zolezzi, J. M., Candia, S. B., Santos, M. J., & Inestrosa, N. C. (2014) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2014.00176 · Cited by 56
“Although the main effects resulting from PPAR stimulation have been related to microglial and astrocytic activation as the key events that allow brain Aβ clearance (Mandrekar-Colucci et al., 2012; Yamanaka et al., 2012), additional mechanisms, such as the PPARγ-LXR-mediated increased expression of ApoE (Cramer et al.”
BackgroundWang, C., Wang, Z., Xie, J., Cai, J., Wang, T., Xu, Y., Wang, X., & Li, A. (2014) · Antioxidants and Redox Signaling · doi:10.1089/ars.2014.5845 · Cited by 53
de Retana, S. F., Marazuela, P., Solé, M., Colell, G., Bonaterra‐Pastra, A., Sánchez‐Quesada, J. L., Montaner, J., Maspoch, D., Cano‐Sarabia, M., & Hernández‐Guillamón, M. (2019) · Alzheimer s Research & Therapy · doi:10.1186/s13195-019-0498-8 · Cited by 55
BAD-mediated neuronal apoptosis and neuroinflammation contribute to Alzheimer's disease pathology
Zhang, L., Qian, Y., Li, J., Zhou, X., Xu, H. J., Yan, J., Xiang, J., Yuan, X., Sun, B., Sisodia, S. S., et al. (2021) · iScience · doi:10.1016/j.isci.2021.102942 · Cited by 54
“Ab can be sensed by microglial pattern recognition receptors, such as Toll-like receptor 2 (TLR-2) (Liu et al., 2012) and CD36 (Yamanaka et al., 2012), thereby engulfed by microglia through phagocytosis and degraded by lysosomes (Tarasoff-Conway et al., 2015).”
BackgroundSun, Y., Wei, K., Liao, X., Wang, J., Gao, L., & Pang, B. (2025) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2025.5580 · Cited by 63
“…recognizes oxidized low‑density lipoprotein and A β while facilitating fatty acid transmembrane transport (70,71). cd36 activation triggers Myd88‑dependent signaling via TLR4/6 complexes, promoting pro‑inflammatory cytokine release (e.g., IL‑1 β , TNF‑ α ) and enhancing phagocytic activity (72,73).”
Combination treatment with leptin and pioglitazone in a mouse model of Alzheimer's disease
Fernández-Martos, C. M., Atkinson, R. A. K., Chuah, M. I., King, A. E., & Vickers, J. C. (2016) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1016/j.trci.2016.11.002 · Cited by 52
Kawahara, K., Suenobu, M., Ohtsuka, H., Kuniyasu, A., Sugimoto, Y., Nakagomi, M., Fukasawa, H., Shudo, K., & Nakayama, H. (2014) · Journal of Alzheimer's Disease · doi:10.3233/jad-132720 · Cited by 51
Kitagishi, Y., & Matsuda, S. (2013) · Alzheimer s Research & Therapy · doi:10.1186/alzrt208 · Cited by 48
“Combined treatment with agonists for the heterodimeric binding partners of PPARγ and the RXRs shows additive enhancement of the amyloid-beta (Aβ) uptake that is mediated by RXRα activation [35].”
BackgroundFocke, C., Blume, T., Zott, B., Shi, Y., Deußing, M., Peters, F., Schmidt, C., Kleinberger, G., Lindner, S., Gildehaus, F., et al. (2018) · Journal of Nuclear Medicine · doi:10.2967/jnumed.118.217703 · Cited by 48
Wang, D., Dong, X., & Wang, C. (2018) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.118.248674 · Cited by 47
“PPARg activation has been reported to provoke the conversion of microglia from M1 inflammatory (classic) to M2 anti-inflammatory (alternative) phenotypes and promote Ab clearance, resulting in cognitive improvement in the AD brain (Mandrekar-Colucci et al., 2012; Yamanaka et al., 2012).”
BackgroundDiabetes: Risk factor and translational therapeutic implications for Alzheimer's disease
Cummings, J. L., Ortiz, A. A., Castellino, J., & Kinney, J. W. (2022) · European Journal of Neuroscience · doi:10.1111/ejn.15619 · Cited by 54
“Pioglitazone increased microglial Aβ phagocytosis in the hippocampus in an AD mouse model (Yamanaka et al., 2012).”
BackgroundAPOEgenotype-dependent modulation of astrocyte chemokine CCL3 production
Cudaback, E., Yang, Y. J., Montine, T. J., & Keene, C. D. (2014) · Glia · doi:10.1002/glia.22732 · Cited by 47
“This observation is supported through experimental extrinsic modulation of microglial function, which results in altered Ab clearance and reduced neurotoxicity in transgenic models of AD (Cameron et al., 2012; Cramer et al., 2012; Griciuc et al., 2013; Xue et al., 2012; Yamanaka et al., 2012).”
ResultPan-PPAR Modulation Effectively Protects APP/PS1 Mice from Amyloid Deposition and Cognitive Deficits
Kummer, M. P., Schwarzenberger, R., Sayah‐Jeanne, S., Dubernet, M., Walczak, R., Hum, D. W., Schwartz, S., Axt, D., & Heneka, M. T. (2014) · Molecular Neurobiology · doi:10.1007/s12035-014-8743-4 · Cited by 47
Self-citationAddressing Unmet Medical Needs in Type 2 Diabetes: A Narrative Review of Drugs under Development
Mittermayer, F., Caveney, E. J., OLIVEIRA, C. D. F., Gourgiotis, L., Puri, M., Tai, L.-J., & Turner, J. R. (2015) · Current Diabetes Reviews · doi:10.2174/1573399810666141224121927 · Cited by 48
Piemontese, L., & Hiremathad, A. (2017) · Neural Regeneration Research · doi:10.4103/1673-5374.213541 · Cited by 50
“microglia (Yamanaka et al., 2012) and inhibit pro-inflamma-”
BackgroundMatsumoto, K., Chiba, Y., Fujihara, R., Kubo, H., Sakamoto, H., & Ueno, M. (2015) · Histochemistry and Cell Biology · doi:10.1007/s00418-015-1366-7 · Cited by 46
IKKβ Deficiency in Myeloid Cells Ameliorates Alzheimer's Disease-Related Symptoms and Pathology
Liu, Y., Liu, X., Hao, W., Decker, Y., Schomburg, R., Fülöp, L., Pasparakis, M., Menger, M. D., & Fassbender, K. C. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.1348-14.2014 · Cited by 46
“…ligand (Tan et al., 1999 and 2002), IRAK4 (Cameron et al., 2012), NLRP3 (Heneka et al., 2013), or Mrp14 (a neuroinflammation-amplifying protein; Kummer et al., 2012), by blocking TGF- -SMAD2/3 signaling (Town et al., 2008), or by stimulating PPAR and retinoid X receptors (Yamanaka et al., 2012).”
BackgroundAlzheimer’s Disease, a Lipid Story: Involvement of Peroxisome Proliferator-Activated Receptor α
Sáez-Orellana, F., Octave, J., & Pierrot, N. (2020) · Cells · doi:10.3390/cells9051215 · Cited by 47
CD36 gene polymorphism is associated with Alzheimer's disease
Šerý, O., Janoutová, J., Ewerlingová, L., Hálová, A., Lochman, J., Janout, V., Khan, N. A., & Balcar, V. J. (2017) · Biochimie · doi:10.1016/j.biochi.2017.01.009 · Cited by 44
Genetic risk factors for Alzheimer disease: emerging roles of microglia in disease pathomechanisms
Takatori, S., Wang, W., Iguchi, A., & Tomita, T. (2019) · Advances in Experimental Medicine and Biology · doi:10.1007/978-3-030-05542-4_5 · Cited by 44
Liu, J., Wang, Z., Liang, W., Zhang, Z., Deng, Y., Chen, X., Hou, Z., Xie, Y., Wang, Q., Li, Y., et al. (2025) · Immunity · doi:10.1016/j.immuni.2025.04.018 · Cited by 47
Wang, X., Li, J., Ma, C., Huang, C., & Li, Z. (2019) · Biochemical Pharmacology · doi:10.1016/j.bcp.2019.113674 · Cited by 45
Microglial Phagocytosis—Rational but Challenging Therapeutic Target in Multiple Sclerosis
Pinto, M. V., & Fernandes, A. M. A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21175960 · Cited by 42
Neuroinflammation in Alzheimer’s Disease: Microglia, Molecular Participants and Therapeutic Choices
Wang, H., Shen, Y., Chuang, H.-Y., Chiu, C., Ye, Y., & Zhao, L. (2019) · Current Alzheimer Research · doi:10.2174/1567205016666190503151648 · Cited by 43
Madadi, S., Schwarzenbach, H., Saidijam, M., Mahjub, R., & Soleimani, M. (2019) · Cell & Bioscience · doi:10.1186/s13578-019-0354-3 · Cited by 41
Fang, Y., Yao, L., Li, C., Wang, J., Wang, J., Chen, S., Zhou, X., & Liao, H. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0522-x · Cited by 42
“In thioflavin S (ThioS, Sigma) staining [21], the brain sections were incubated with a 1 % ThioS solution dissolved in distilled water containing 50 % ethanol for 5 min and differentiated in 50 % ethanol thrice.”
MethodAmyloid‐β induces sleep fragmentation that is rescued by fatty acid binding proteins in Drosophila
Gerstner, J. R., Lenz, O., Vanderheyden, W. M., Chan, M. T., Pfeiffenberger, C., & Pack, A. I. (2017) · Journal of Neuroscience Research · doi:10.1002/jnr.23778 · Cited by 40
“PPAR activation has been shown to facilitate the clearance of Ab in AD animal models (Mandrekar-Colucci et al., 2012; Yamanaka et al., 2012), and, because DHA triggers nuclear localization of Fabp7 to regulate PPAR-mediate transcription (Mita et al., 2010), this pathway may represent one mechanism…”
BackgroundRole of insulin resistance in Alzheimer’s disease
Cai, Z., Xiao, M., Chang, L., & Yan, L. (2014) · Metabolic Brain Disease · doi:10.1007/s11011-014-9631-3 · Cited by 38
“…under inhibiting inflammation and oxidative stress (Escribano et al. 2010; Heneka et al. 1999; Kalinin et al. 2009; Lourenco and Ledo 2013; Zolezzi et al. 2013), and benefited reversal of disease-related behavioral impairment (Jiang et al. 2008; Mandrekar-Colucci et al. 2012; Yamanaka et al. 2012).”
BackgroundAlzheimer's disease risk alleles in TREM2 illuminate innate immunity in Alzheimer's disease
Golde, T. E., Streit, W. J., & Chakrabarty, P. (2013) · Alzheimer s Research & Therapy · doi:10.1186/alzrt178 · Cited by 39
Yip, P. K., Bowes, A. L., Hall, J. C. E., Burguillos, M. A., Ip, T. H. R., Baskerville, T., Liu, Z.-H., Mohamed, M. A. E. K., Getachew, F., Lindsay, A. D., et al. (2019) · Human Molecular Genetics · doi:10.1093/hmg/ddz073 · Cited by 38
Abdallah, H. M. I., Ammar, N. M., Abdelhameed, M. F., et al. (2020) · Biology · doi:10.3390/biology9080195 · Cited by 38
“A prior study using an LPS-stimulated murine microglial cell line (BV-2) revealed that oleamide inhibited the production of NO and PGE2 [81].”
MethodEndogenous Generation and Signaling Actions of Omega-3 Fatty Acid Electrophilic Derivatives
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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.
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