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.
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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.
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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.”
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“The treatment of AD mice with the PPAR-γ agonist pioglitazone, a drug used to treat type 2 diabetes, results in enhanced capability of microglia to phagocyte Aβ (Yamanaka et al., 2012) and cognitive improvement.”
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“These effects may be at least partially related to the activation of PPAR nuclear receptors (Fakhfouri et al. 2012; Scuderi et al. 2014), whose classic activators are also active in experimental models of this disease (e.g., pioglitazone: Yamanaka et al. 2012).”
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“…insulin-like growth factor-1 and PPAR signaling; in this screen, expression of RXRc was enhanced with ablation of microglial EP2, and RXRc along with its binding partner PPARc reduce pro-inflammatory gene expression (Heneka et al. 2007) and enhance clearance of Ab peptides (Yamanaka et al. 2012).”
Alzheimer's disease failed clinical trials
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PPARs in the central nervous system: roles in neurodegeneration and neuroinflammation
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“In microglia and macrophages, PPARγ activation inhibits pro-inflammatory gene expression (Yamanaka et al., 2012).”
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“Consistently, evidence for gliosis and central infiltration of peripheral immune cells is often found in histopathological studies in AD mouse models (Yamanaka et al., 2012; Lourenco and Ledo, 2013; Yang et al., 2013; Baik et al., 2014; Ferreira et al., 2014; Monson et al., 2014).”
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“A previous study using an LPS-stimulated murine microglial cell line (BV-2) showed that oleamide suppressed the production of NO and PGE2 [42].”
MethodModulation of inflammation in transgenic models of Alzheimer’s disease
Birch, A. M., Katsouri, L., & Sastre, M. (2014) · Journal of Neuroinflammation · doi:10.1186/1742-2094-11-25 · Cited by 121
Role of docosahexaenoic acid in the modulation of glial cells in Alzheimer’s disease
Heras-Sandoval, D., Pedraza‐Chaverrí, J., & Pérez‐Rojas, J. M. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0525-7 · Cited by 126
“Moreover, activation of heterodimeric PPARγ/RXRα results in increased phagocytosis of Aβ by microglia [89].”
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Pharmacological approaches to mitigate neuroinflammation in Alzheimer’s disease
Uddin, M. S., Kabir, M. T., Mamun, A. A., Barreto, G. E., Rashid, M., Perveen, A., & Ashraf, G. M. (2020) · International Immunopharmacology · doi:10.1016/j.intimp.2020.106479 · Cited by 121
Shibuya, Y., Chang, C. C. Y., Huang, L.-H., Bryleva, E. Y., & Chang, T.-Y. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.2567-14.2014 · Cited by 108
“Scavenger receptors, including scavenger receptor A (SRA) and CD36 (which is a member of the class B scavenger receptor family), are expressed in microglia and are involved in binding and/or phagocytosis of A in cell culture and in vivo (Yang et al., 2011; Yamanaka et al., 2012).”
BackgroundZádori, D., Veres, G., Szalárdy, L., Klivènyi, P., & Vécsei, L. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-170929 · Cited by 108
Soluble apoE/Aβ complex: mechanism and therapeutic target for APOE4-induced AD risk
Tai, L. M., Mehra, S., Shete, V., Estus, S., Rebeck, G. W., Bu, G., & LaDu, M. J. (2014) · Molecular Neurodegeneration · doi:10.1186/1750-1326-9-2 · Cited by 116
Pioglitazone for the treatment of Alzheimer’s disease
Galimberti, D., & Scarpini, E. (2017) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2017.1265504 · Cited by 106
Möhle, L., Israël, N., Paarmann, K., Krohn, M., Pietkiewicz, S., Müller, A. J., Lavrik, I. N., Buguliskis, J. S., Schott, B. H., Schlüter, D., et al. (2016) · Acta Neuropathologica Communications · doi:10.1186/s40478-016-0293-8 · Cited by 103
Microglia-Mediated Neurodegeneration in Perinatal Brain Injuries
Fleiss, B., Steenwinckel, J. V., Bokobza, C., Shearer, I. K., Ross-Munro, E., & Gressèns, P. (2021) · Biomolecules · doi:10.3390/biom11010099 · Cited by 110
Miao, J., Chen, L., Pan, X., Li, L.-Q., Zhao, B., & Lan, J. X. (2023) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-023-01376-y · Cited by 121
Medrano-Jiménez, E., Jiménez-Ferrer, I., Pedraza‐Escalona, M., Ramírez-Serrano, C. E., Álvarez‐Arellano, L., Cortés‐Mendoza, J., Herrera-Ruiz, M. L., Jiménez‐Ferrer, E., Zamilpa, A., Tortoriello, J., et al. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1515-3 · Cited by 100
Nuclear receptors in neurodegenerative diseases
Skerrett, R., Malm, T., & Landreth, G. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.05.019 · Cited by 94
Chang, C.-F., Massey, J., Osherov, A., da Costa, L. H. A., & Sansing, L. H. (2019) · Stroke · doi:10.1161/strokeaha.119.027037 · Cited by 95
“In the AD brain, activation of the RXR/PPAR heterodimer enhance phagocytosis of amyloid-β plaque in a CD36dependent mechanism.(24) We and others have shown that PPAR activation by rosiglitazone promotes macrophage reparative phenotype and hematoma resolution,(3,4,8) and the activation of RXR/PPAR heterodimer is to be…”
BackgroundKhan, M. A., Alam, Q., Haque, A., Ashafaq, M., Khan, M. J., Ashraf, G. M., & Ahmad, M. (2018) · Current Neuropharmacology · doi:10.2174/1570159x16666180828100002 · Cited by 92
PPAR Agonists as Therapeutics for CNS Trauma and Neurological Diseases
Mandrekar-Colucci, S., Sauerbeck, A. D., Popovich, P. G., & McTigue, D. M. (2013) · ASN NEURO · doi:10.1042/an20130030 · Cited by 91
“Also, studies have shown that PPAR and RXR agonists, when used together to simultaneously activate the heterodimer complex, have synergistic effects allowing for maximal stimulation and expanding possible treatment paradigms (Papi et al., 2009; Yamanaka et al., 2012).”
BackgroundSeok, H., Lee, M., Shin, E., Yun, M. R., Lee, Y., Moon, J. H., Kim, E., Lee, P. H., Lee, B., Kang, E. S., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-40736-x · Cited by 92
Metabolic Plasticity of Astrocytes and Aging of the Brain
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Skerrett, R., Pellegrino, M. P., Casali, B. T., Taraboanta, L., & Landreth, G. E. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.652008 · Cited by 91
“LXR (9, 13, 18, 20 –24) and PPAR (27, 36, 46, 48, 50, 52, 55, 59, 60) agonists have been reported to ameliorate memory deficits using a variety of tests in a range of mouse models.”
BackgroundInfluentialTargeting microglia for the treatment of Alzheimer’s disease
McGeer, P. L., & McGeer, E. G. (2014) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2014.988707 · Cited by 92
“Furthermore, transgenic AD mice treated with DSP-8658 not only showed improved phagocytosis of Ab but also some memory improvement [46].”
BackgroundAlternative retinoid X receptor (RXR) ligands
Krężel, W., Rühl, R., & de Lera, Á. R. (2019) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2019.04.016 · Cited by 90
Ano, Y., Dohata, A., Taniguchi, Y., Hoshi, A., Uchida, K., Takashima, A., & Nakayama, H. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.763813 · Cited by 91
CD36 in Alzheimer’s Disease: An Overview of Molecular Mechanisms and Therapeutic Targeting
Dobri, A.-M., Dudău, M., Enciu, A., & Hinescu, M. E. (2020) · Neuroscience · doi:10.1016/j.neuroscience.2020.11.003 · Cited by 83
“This approach increased Ab clearance from the brain parenchyma, reduced amyloid plaques and improved cognitive performance in the tested animals (Yamanaka et al., 2012).”
The Evolving Biology of Microglia in Alzheimer's Disease
Malm, T. M., Jay, T. R., & Landreth, G. E. (2015) · Neurotherapeutics · doi:10.1007/s13311-014-0316-8 · Cited by 85
Candesartan ameliorates brain inflammation associated with Alzheimer's disease
Torika, N., Asraf, K., Apte, R. N., & Fleisher‐Berkovich, S. (2018) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.12802 · Cited by 82
Alhowail, A. H., Alsikhan, R. S., Alsaud, M. M., Aldubayan, M. A., & Rabbani, S. I. (2022) · Drug Design Development and Therapy · doi:10.2147/dddt.s367229 · Cited by 84
“Importantly, the use of pioglitazone improved spatial learning, enhanced AKT signaling, and attenuated tau hyperphosphorylation and neuroinflammation(79) through enhanced microglial uptake of Aβ.(80,81) PD is a neurodegenerative disorder characterized by non-motor and motor symptoms caused by a depletion of striatal d…”
BackgroundMicroglia as a critical player in both developmental and late-life CNS pathologies
Derecki, N. C., Katzmarski, N., Kipnis, J., & Meyer-Luehmann, M. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1321-z · Cited by 78
Migration of blood cells to β-amyloid plaques in Alzheimer's disease
Hohsfield, L. A., & Humpel, C. (2015) · Experimental Gerontology · doi:10.1016/j.exger.2015.03.002 · Cited by 79
“The authors report that treatment of a PPARγ agonist results in the enhanced phagocytosis of Aβ by microglial cells (mediated by increased CD36 expression) as well as the reduction of cortical and hippocampal Aβ levels (Yamanaka et al., 2012).”
Loeffler, D. A. (2023) · Journal of Alzheimer s Disease Reports · doi:10.3233/adr-230025 · Cited by 90
Discovering New Treatments for Alzheimer's Disease by Repurposing Approved Medications
Appleby, B. S., & Cummings, J. L. (2013) · Current Topics in Medicinal Chemistry · doi:10.2174/15680266113136660162 · Cited by 78
Islet amyloid polypeptide: Another key molecule in Alzheimer’s pathogenesis?
Zhang, Y., & Song, W. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.03.001 · Cited by 79
Malm, T., Mariani, M., Donovan, L. J., Neilson, L., & Landreth, G. E. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-014-0229-9 · Cited by 77
Xie, Z., Zhao, J., Wang, H., Jiang, Y., Yang, Q., Fu, Y., Zeng, H., Hölscher, C., Xu, J., & Zhang, Z. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.109886 · Cited by 78
Pinto, M., Nissanka, N., Peralta, S., Brambilla, R., Díaz, F., & Moraes, C. T. (2016) · Molecular Neurodegeneration · doi:10.1186/s13024-016-0090-7 · Cited by 78
Fatty acids, endocannabinoids and inflammation
Witkamp, R. F. (2015) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2015.08.051 · Cited by 78
Martín-Maestro, P., Sproul, A. A., Martínez, H., Paquet, D., Gerges, M., Noggle, S., & Starkov, A. A. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-01665-y · Cited by 77
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
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