The DOI matches its Crossref record; 98 of the 99 references it cites were found in a registry or an index; 28 of the 70 sources its claims cite were checked for support.
Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease
Open accessAbstract
Alzheimer's disease is associated with a disruption of amyloid β (Aβ) homeostasis, resulting in the accumulation and subsequent deposition of Aβ peptides within the brain. The peroxisome proliferator-activated receptor-γ (PPARγ) is a ligand-activated nuclear receptor that acts in a coupled metabolic cycle with Liver X Receptors (LXRs) to increase brain apolipoprotein E (apoE) levels. apoE functions to promote the proteolytic clearance of soluble forms of Aβ, and we found that the synthetic PPARγ agonist, pioglitazone, stimulated Aβ degradation by both microglia and astrocytes in an LXR and apoE-dependent manner. Remarkably, a brief 9 d oral treatment of APPswe/PS1Δe9 mice with pioglitazone resulted in dramatic reductions in brain levels of soluble and insoluble Aβ levels which correlated with the loss of both diffuse and dense-core plaques within the cortex. The removal of preexisting amyloid deposits was associated with the appearance of abundant Aβ-laden microglia and astrocytes. Pioglitazone treatment resulted in the phenotypic polarization of microglial cells from a proinflammatory M1 state, into an anti-inflammatory M2 state that was associated with enhanced phagocytosis of deposited forms of amyloid. The reduction in amyloid levels was associated with a reversal of contextual memory deficits in the drug-treated mice. These data provide a mechanistic explanation for how PPARγ activation facilitates amyloid clearance and supports the therapeutic utility of PPARγ agonists for the treatment of Alzheimer's disease.
Overview
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Written from the paper’s full text.
TL;DR
Pioglitazone, a PPARγ agonist, rapidly cleared soluble and deposited amyloid-β in APP/PS1 mice through PPARγ–LXRα–apoE-dependent degradation and M2 microglial polarization. A 9 d treatment reversed contextual memory deficits, supporting PPARγ agonists as a therapeutic approach for Alzheimer’s disease.
Key findings
- In primary microglia and astrocytes, pioglitazone stimulated dose-dependent intracellular degradation of soluble Aβ42; this was blocked by PPARγ antagonist T0070907 and LXR antagonist 22HC, impaired in apoe−/− cells, and restored by exogenous ApoE or ApoA1.
- PPARγ conditional knockout mice showed >70% lower cortical pparγ mRNA and >50% reductions in cortical ABCA1 and ApoE protein, demonstrating a PPARγ–LXR linkage in brain.
- In 6- and 12-month-old APP/PS1 mice, 9 d oral pioglitazone (80 mg·kg−1·d−1) reduced 6E10 plaque area by ~40% and ~30%, and thioS+ dense-core plaques by ~40% and ~30%, respectively; at 6 months soluble and insoluble Aβ fell by ~50%, while at 12 months soluble Aβ40 fell 40% and insoluble Aβ40/Aβ42 fell 50%/40%, with no significant change in soluble Aβ42.
- Treatment increased M2 markers (Ym1 at 6 months; Fizz1, Ym1, Arg1 at 12 months), reduced Il-1β and tnfα at 12 months, and reversed contextual memory deficits to wild-type levels; >90% of cortical microglia in drug-treated animals internalized amyloid by qualitative assessment.
Methods
- Primary microglia and astrocytes from postnatal C57BL/6J or apoe−/− pups were treated with pioglitazone ± T0070907, 22HC, ApoE, or ApoA1; Aβ levels were measured by ELISA, with Western blot and qPCR for related genes/proteins.
- APP/PS1 and wild-type littermates at 6 and 12 months were gavaged with pioglitazone (80 mg·kg−1·d−1) or vehicle for 9 d; PPARγ fl/fl × GFAP-cre mice were used for conditional knockout. Brains were analyzed by immunohistochemistry (6E10, thioflavin S, Iba1, CD45, GFAP), Aβ ELISA, qPCR, and Western blot.
- Contextual fear conditioning was performed in 12-month-old mice after 9 d treatment, with open-field testing for noncognitive behavior; plaque counts were done by a blinded observer and qPCR used the ΔΔCT method normalized to GAPDH.
Limitations
- The paper states pioglitazone is poorly blood-brain barrier permeable, necessitating 80 mg·kg−1·d−1, a dose higher than previously administered and ~8 times the clinically approved dose, with a very short 9 d treatment interval.
- The paper notes astrocyte Aβ quantification was limited by the GFAP marker, astrocyte cell numbers surrounding plaques could not be determined, and Aβ-positive astrocytes represented only a minor subset that was not quantitatively evaluated; microglial Aβ uptake at 6 months was difficult to assess due to few Iba1+ cells.
- Evident from the text: the mechanistic and behavioral conclusions derive from an APP/PS1 mouse model and primary rodent glia, with several microglial/astrocytic findings based on qualitative imaging rather than fully quantitative causal assays.
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Claims the paper makes
62 Own result · 31 Own interpretation · 15 Partly supported · 10 No full text of the sources · 4 Supported · 4 Sources not found · 3 Own method · 2 Not checked yet · 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
“Alzheimer's disease (AD) is characterized by the accumulation and deposition of amyloid β (Aβ) within the brain because of inefficient clearance of these peptides (Mawuenyega et al., 2010; Querfurth and LaFerla, 2010).”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Introduction
What the sources say
- Partly supportedcites Mawuenyega et al., 2010 sourceExperimental — accuracy not yet measured
The paper reports increased amyloid-β in Alzheimer’s disease and slower clearance of Aβ42 and Aβ40 in patients than in controls (Abstract and study results; page not supplied). But it explicitly says the association of impaired clearance with Alzheimer’s disease does not prove causality, so the claim’s unqualified “because of” goes beyond its findings. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites Querfurth and LaFerla, 2010 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Aβ accumulation is associated with perturbations in synaptic function, neuronal loss, and memory and cognitive impairments (Lue et al., 1999; Akiyama et al., 2000b; Palop and Mucke, 2010).”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Introduction
What the sources say
- Partly supportedcites Lue et al., 1999 sourceExperimental — accuracy not yet measured
The Abstract reports that soluble Aβ concentrations were strongly associated with synapse loss, supporting the synaptic part of the claim. But it says insoluble Aβ deposits were poor correlates of synaptic change, so the finding does not apply to Aβ accumulation indiscriminately. The Patient Samples section says the study focused on synapse loss rather than dementia itself; it does not establish an association with neuronal loss or measured memory and cognitive impairment. (LLM, conf=0.88)
- Not matchedcites Akiyama et al., 2000b
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Partly supportedcites Palop and Mucke, 2010 sourceExperimental — accuracy not yet measured
The Introduction and “Modulation of synaptic transmission by Aβ” sections link elevated Aβ to impaired synaptic function and synaptic loss. “Elevated Aβ destabilizes neural network activity” links these changes to learning, memory, and cognitive deficits. The passages describe loss of synapses, not loss of neurons, so they do not support that part of the claim; page numbers were not provided in our copy. (LLM, conf=0.86)
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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Aβ deposition elicits a robust “M1” microglia-mediated inflammatory response contributing to disease pathogenesis (Gordon, 2003; Mosser and Edwards, 2008; Mandrekar-Colucci and Landreth, 2010).”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Introduction
What the sources say
- Not checked — no full text of the sourcecites Gordon, 2003 source
- Partly supportedcites Mosser and Edwards, 2008 sourceExperimental — accuracy not yet measured
The ‘Classically activated macrophages’ section says their pro-inflammatory cytokines can damage the host and contribute to inflammatory pathology. The paper also mentions CNS microglia in ‘The origin and maintenance of macrophages,’ but does not say that Aβ deposition triggers an M1 microglial response or that such a response contributes to disease pathogenesis. No page numbers are available in our copy. (LLM, conf=0.85)
- Supportedcites Mandrekar-Colucci and Landreth, 2010 source
The Introduction describes amyloid deposition as associated with a robust inflammatory response, and “Microglia and Inflammation in AD” describes pro-inflammatory molecules released by microglia in response to Aβ. “Alternative Activation of Microglial Cells” identifies M1 as the pro-inflammatory phenotype and links Aβ recognition to M1 activation. The paper also says inflammation contributes to AD progression, while noting that microglia can have protective roles. (LLM, conf=0.87)
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.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Sustained PPARγ or LXR activation results in amelioration of AD-related pathophysiology in AD mouse models (Yan et al., 2003; Pedersen and Flynn, 2004; Heneka et al., 2005; Koldamova et al., 2005a; Riddell et al., 2007; Zelcer et al., 2007; Jiang et al., 2008; Donkin et al., 2010; Fitz et al., 2010; Toledo and Inestrosa, 2010).”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Introduction
What the sources say
- Partly supportedcites Yan et al., 2003 sourceExperimental — accuracy not yet measured
The Results report that four months of treatment with the PPARγ agonist pioglitazone significantly reduced SDS-soluble Aβ40 in Tg2576 mice. The Introduction and Discussion say it did not significantly reduce plaque burden or microglial activation, so the broader claim of ameliorated AD-related pathology overstates this study. The paper does not assess LXR activation; page numbers were not provided for these passages. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites Pedersen and Flynn, 2004 source
- Partly supportedcites Heneka et al., 2005 sourceExperimental — accuracy not yet measured
The Introduction (page unavailable) reports that pioglitazone, a PPARγ agonist, reduced inflammatory measures and Aβ deposition in APP-overexpressing mice. But the Animals section (page unavailable) specifies only seven days of treatment, so this paper supports an acute effect, not the claimed sustained activation. It does not report LXR activation. (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
“Peripherally, LXRs and PPARγ participate in a coupled metabolic pathway, whereby activation of PPARγ induces expression of LXRα and its target genes abca1 and apoE (Chawla et al., 2001; Seo et al., 2004; Yue and Mazzone, 2009).”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Introduction
What the sources say
- Partly supportedcites Chawla et al., 2001 sourceExperimental — accuracy not yet measured
The Introduction and Figures 1–3 (page numbers unavailable) support a PPARγ–LXRα pathway in macrophages: PPARγ activation induces LXRα, and PPARγ and LXR ligands cooperate to induce ABCA1. The passages identify ABCG1, not apoE, as the other induced gene; our copy does not support the attributed apoE induction. (LLM, conf=0.88)
- Partly supportedcites Seo et al., 2004 sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) says PPARγ regulates LXRα expression and describes a positive-feedback pathway between the two receptors. An introductory passage indexed as Abstract (page unavailable) says LXR activation promotes cholesterol efflux through ABCA1 and apoE in macrophages. The paper does not establish the full claimed sequence—that activating PPARγ induces expression of LXRα, ABCA1, and apoE. (LLM, conf=0.82)
- Not checked — no full text of the sourcecites Yue and Mazzone, 2009 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“It has recently been appreciated that PPARs act as master regulators governing the polarization of macrophages and microglia into “M2” or “alternative” activation states associated with the suppression of inflammation and promotion of phagocytosis and tissue repair (Chawla, 2010; Chinetti-Gbaguidi et al., 2011).”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Introduction
What the sources say
- Partly supportedcites Chawla, 2010 sourceExperimental — accuracy not yet measured
The ‘PPARs and alternative macrophage activation’ section (page not supplied) says PPARγ and PPARδ are required to acquire and maintain the alternative macrophage phenotype and links PPARδ to anti-inflammatory effects. ‘Macrophage activation and functional heterogeneity’ (page not supplied) associates that phenotype with phagocytic receptors and reparative functions. But the paper identifies IL-4 and IL-13 as the instructive cues, rather than PPARs as master regulators, and the passages found do not extend the claim to microglia. (LLM, conf=0.87)
- Not checked — no full text of the sourcecites Chinetti-Gbaguidi et al., 2011 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The actions of PPARγ in the brain of murine models of AD have been controversial, largely due to the poor penetrance of its agonists into the brain and active P-glycoprotein-mediated efflux mechanisms (Maeshiba et al., 1997; Hemauer et al., 2010).”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Discussion
What the sources say
- Not matchedcites Maeshiba et al., 1997
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Partly supportedcites Hemauer et al., 2010 sourceExperimental — accuracy not yet measured
The COMMENT section (page not available) says P-glycoprotein transports rosiglitazone from brain to blood, supporting an efflux mechanism for that agonist. The paper does not establish poor brain penetration of PPARγ agonists generally or link that mechanism to controversy about PPARγ actions in murine Alzheimer’s disease models. (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.
- Not matched
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Thus, modulating microglial activation status by targeting nuclear receptors appears to restore the competence of these cells to phagocytose and clear amyloid in the AD brain (Mukundan et al., 2009; Chinetti-Gbaguidi et al., 2011).”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Discussion
What the sources say
- Partly supportedcites Mukundan et al., 2009 sourceExperimental — accuracy not yet measured
The Results section ('PPAR-δ regulates opsonin gene expression in macrophages'; page unavailable) reports that activating the nuclear receptor PPAR-δ increased macrophage uptake of apoptotic cells. The paper does not establish that targeting nuclear receptors restores microglial clearance of amyloid in an Alzheimer’s disease brain; its experiments concern macrophages and apoptotic cells. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites Chinetti-Gbaguidi et al., 2011 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Nuclear receptors have only recently been appreciated to play an crucial role in promoting the phenotypic change of macrophages from a “classically” M1 activated to alternatively activated M2 states (Odegaard et al., 2007, 2008; Zelcer et al., 2007; Bouhlel et al., 2008; Kalinin et al., 2009; Chawla, 2010).”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Discussion
What the sources say
- Not matchedcites Odegaard et al., 2007, 2008
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Partly supportedcites Zelcer et al., 2007 sourceExperimental — accuracy not yet measured
The Abstract says LXRs are nuclear receptors that inhibit inflammatory responses in macrophages, and the Results show that LXR activation suppresses inflammatory responses in microglia. Neither passage establishes the claimed phenotypic change of macrophages from M1 to M2 states. (LLM, conf=0.82)
- Not checked — no full text of the sourcecites Bouhlel et al., 2008 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Not matched
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“However, phase III clinical trials, using rosiglitazone, failed to show efficacy for the treatment of AD (Gold et al., 2010).”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Discussion
What the sources say
- Partly supportedcites Gold et al., 2010 sourceExperimental — accuracy not yet measured
The Introduction describes one phase III rosiglitazone trial in people with mild-to-moderate AD, and the Conclusion reports no evidence of efficacy. The cited paper supports that result for its trial, but not the claim that multiple phase III trials failed to show efficacy. (LLM, conf=0.86)
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.
- Partly supported
- Probably not a substantial claim. 14
- It may state two separate claims as one. 25
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“apoE is synthesized mainly by astrocytes and plays an isoform-dependent role in modulating Aβ fibrillization and clearance (Holtzman, 2001; Zlokovic et al., 2005; Kim et al., 2009).”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Introduction
What the sources say
- Not checked — no full text of the sourcecites Holtzman, 2001 source
- Could not verifycites Zlokovic et al., 2005 sourceExperimental — accuracy not yet measured
The matching passages are in the References section (page not provided): they list studies about apoE and Aβ metabolism or degradation, but do not state the claim as a finding of this paper. Searches for apoE, astrocytes, fibrillization, and apoE isoforms found no passage establishing that apoE is synthesized mainly by astrocytes or that its effects on Aβ fibrillization and clearance are isoform-dependent. (LLM, conf=0.72)
- Partly supportedcites Kim et al., 2009 sourceExperimental — accuracy not yet measured
The Physiological Function of ApoE section identifies astrocytes as the main source of apoE in the brain, and the Aβ Aggregation section reports isoform-dependent effects on fibrillization. The Aβ Clearance section reports an isoform-dependent difference in one mouse study, but also describes a study finding no difference and says whether isoform-specific clearance effects exist remains unresolved. The claim presents that clearance effect more definitively than the review does; page numbers were not available in our copy. (LLM, conf=0.84)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The nuclear receptors, peroxisome proliferator-activated receptor-γ (PPARγ) and Liver X receptors (LXRs) are ligand-activated transcription factors that act as fatty acid and cholesterol sensors (Forman et al., 1997; Kersten et al., 2000).”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Introduction
What the sources say
- Partly supportedcites Forman et al., 1997 sourceExperimental — accuracy not yet measured
The Discussion says PPARγ responds to metabolic cues and appears to promote fatty-acid storage; the Results describe PPARs as nuclear fatty-acid and eicosanoid receptors. But the paper identifies PPARα, rather than PPARγ, as sensing broad changes in fatty-acid status, and the passages do not address LXRs as cholesterol sensors (searched: LXR, cholesterol sensors). (LLM, conf=0.85)
- Not checked — no full text of the sourcecites Kersten et al., 2000 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Activation of these nuclear receptors suppresses NFκB-mediated inflammatory responses and activates their phagocytic machinery (Zelcer et al., 2007; Mukundan et al., 2009; Glass and Saijo, 2010).”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Discussion
What the sources say
- Partly supportedcites Zelcer et al., 2007 sourceExperimental — accuracy not yet measured
The Results report that LXR activation suppresses inflammatory responses and restores fibrillar Aβ-stimulated phagocytosis in microglia when inflammation has inhibited it. The Discussion says this restoration occurs most likely through inhibition of NFκB activity. The claim overstates that proposed mechanism as established and describes restored phagocytosis as activation of phagocytic machinery. (LLM, conf=0.84)
- Partly supportedcites Mukundan et al., 2009 sourceExperimental — accuracy not yet measured
The Results section reports that PPAR-δ activation increases opsonin expression and apoptotic-cell uptake, and that PPAR-δ is required for the observed suppression of pro-inflammatory cytokines after apoptotic-cell feeding. The cited paper does not establish that this suppression is NFκB-mediated. Page numbers are unavailable in our copy. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites Glass and Saijo, 2010 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“While this pathway has been well documented in the periphery, it was not recognized to be operative in the brain until now (Chawla et al., 2001).”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Discussion
What the sources say
- Supportedcites Chawla et al., 2001 source
The Introduction describes a PPARγ–LXRα pathway regulating cholesterol efflux in macrophages, and Figure 1 documents PPARγ-responsive LXRα expression in those cells. This supports the citation's point that the pathway was known outside the brain. The statement about its recognition in the brain is the citing authors' own framing, not a finding attributed to Chawla et al.; page numbers are unavailable in our copy. (LLM, conf=0.88)
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“A number of studies of the thiazolidinedione agonists of PPARγ, pioglitazone (Actos) and rosiglitazone (Avandia), reported salutary effects of these drugs in murine models of AD (Mandrekar-Colucci and Landreth, 2011).”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Discussion
What the sources say
- Supportedcites Mandrekar-Colucci and Landreth, 2011 source
Section 5 identifies pioglitazone (Actos) and rosiglitazone (Avandia) as thiazolidinedione PPARγ agonists and reviews multiple studies reporting benefits in AD mouse models. It also reports some null findings, but those do not negate the claim that a number of studies reported salutary effects. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Recently, we have shown that activation of the Retinoid X Receptor, the obligate heterodimeric partner of PPARγ and LXRs, rapidly reverses AD pathology in mouse models of AD, and many of the beneficial effects seen in that study may occur through activation of PPAR signaling pathways (Cramer et al., 2012).”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Discussion
What the sources say
- Supportedcites Cramer et al., 2012 source
The paper reports that the RXR agonist bexarotene rapidly reduced soluble Aβ and plaques and reversed behavioral deficits in AD mouse models (Abstract; passages 1, 5, 6, and 8). It also proposes activation of PPARγ:RXR as a mechanism and reports PPARγ-dependent Aβ degradation in treated cells (passage 4), consistent with the citing sentence’s hedged suggestion about PPAR signaling. (LLM, conf=0.92)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The 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
“Macrophages/microglia are capable of exhibiting a spectrum of phenotypic activation states which dictate their activities (Gordon, 2003; Mosser and Edwards, 2008; Mandrekar-Colucci and Landreth, 2010).”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Discussion
What the sources say
- Not checked — no full text of the sourcecites Gordon, 2003 source
- Supportedcites Mosser and Edwards, 2008 source
The Abstract describes macrophages as plastic cells whose environmental responses produce populations with distinct functions and various ‘shades’ of activation. This supports the macrophage portion of the multiply cited sentence. (LLM, conf=0.91)
- Supportedcites Mandrekar-Colucci and Landreth, 2010 source
The ‘Alternative Activation of Microglial Cells’ section describes a continuum of macrophage activation states and says microglia can adopt a variety of activation states with different functions. It also distinguishes pro-inflammatory and tissue-repair activities associated with those states. The supplied passages have no page numbers. (LLM, conf=0.91)
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.
Every source the paper cites for this claim was checked and supports it.
In the paper
“Terwel et al. (2011) have recently reported similar findings upon activation of LXRs in a mouse model of AD.”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Discussion
What the sources say
- Supportedcites Terwel et al. (2011) source
In “Pharmacological treatment of APP23 mice with the LXR agonist TO901317,” Terwel et al. report activating LXRs in APP23 mice, a mouse model of AD. “Behavioral effects of TO901317 in AD models” reports reduced plaque load and a minor behavioral improvement in the present study. The citing sentence does not specify which findings were similar, but its attribution of findings following LXR activation in an AD mouse model is supported. (LLM, conf=0.88)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Indeed, PPARγ agonists have been shown to effectively lower both soluble levels of Aβ, reduce plaque burden, and improve behavior in some AD mouse models”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Discussion
What the sources say
- Partly supportedcites Yan et al., 2003 sourceExperimental — accuracy not yet measured
The Results report that pioglitazone significantly lowered SDS-soluble Aβ40 in Tg2576 mice, supporting the soluble-Aβ portion. The same Results say pioglitazone produced no significant change in plaque burden; the reported plaque reduction was with ibuprofen. The paper does not report behavioral improvement. (LLM, conf=0.88)
- Not matchedcites Camacho et al., 2004
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Partly supportedcites Heneka et al., 2005 sourceExperimental — accuracy not yet measured
The Results section (page unavailable) reports that pioglitazone reduced soluble Aβ1–42 and Aβ1–42-positive plaque area in APPV717I mice. The paper does not report a behavioral improvement; its methods and results address drug treatment, inflammation, and amyloid measures, not behavioral testing. (LLM, conf=0.90)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In the AD brain, microglia fail to effectively phagocytose Aβ and are also impaired in their ability to degrade Aβ fibrils (Chung et al., 1999; Cameron and Landreth, 2010).”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Discussion
What the sources say
- Partly supportedcites Chung et al., 1999 sourceExperimental — accuracy not yet measured
The Abstract (page unavailable) reports that microglia took up fibrillar Aβ but degraded it only partly, then released intact Aβ. This supports poor degradation, not a failure to phagocytose Aβ. The study examined uptake and degradation by microglial cells; it does not establish that microglia in the AD brain are impaired in either ability. (LLM, conf=0.88)
- Not matchedcites Cameron and Landreth, 2010
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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.
- 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
“We found that GFAP was elevated in APP/PS1 animals, but was significantly reduced in both age groups after pioglitazone treatment (Fig. 5N,O).”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Results > Pioglitazone suppresses glial activation and enhances amyloid clearance
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
“The PPARγ conditional knock-out (PPARγ CKO) mice display significantly lower levels of pparγ mRNA which was reduced in the cortices of these animals by >70% (data not shown).”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Results > PPARγ facilitates the degradation of soluble Aβ through an LXR/ApoE-dependent pathway
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
“mRNA levels of app, bace1, or psen1 or protein levels of APP and APP C-terminal fragments were not altered in response to drug treatment compared with vehicle-treated littermates, suggesting that PPARγ activation does not alter the expression or processing of APP (Fig. 4I,J,M,N).”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Results > PPARγ activation rapidly stimulates the clearance of Aβ in a mouse model of AD
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The mRNA levels for iba1 were significantly lower in pioglitazone-treated animals compared with vehicle-treated animals at 6 months of age and a trend toward a reduction was seen at 12 months of age (Fig. 6S,T).”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Results > Pioglitazone suppresses glial activation and enhances amyloid clearance
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
“Microglia containing small amounts of Aβ were visualized in ~60% of microglial cells in vehicle-treated animals; however, the amount of Aβ internalized by microglia in vehicle-treated animals paled compared with microglia in the cortex of pioglitazone-treated animals (Fig. 7A–D)”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Results > Pioglitazone suppresses glial activation and enhances amyloid clearance
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In vehicle-treated animals, we observed astrocytes in close association with 6E10-positive amyloid plaques (Fig. 5C,I). However, after pioglitazone treatment, astrocytes were seen diffusely surrounding Aβ deposits and very little contact was observed between GFAP-positive cells and amyloid plaques (Fig. 5F,L).”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Results > Pioglitazone suppresses glial activation and enhances amyloid clearance
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We demonstrate that PPARγ activation in the APP/PS1 animals provoked the conversion of at least a subset of microglia from a classical to alternative activation states, suppressing proinflammatory gene expression (IL-1β, TNFα) and inducing the expression of anti-inflammatory genes (YM1, Fizz1, Arg1, TGF-β) associated with tissue repair (Fig. 7).”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Discussion
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Moreover, pioglitazone treatment resulted in intracellular Aβ accumulation in astrocytes, coincident with the reduction in plaque burden (Fig. 5).”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > 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
“This latter function is accompanied by expression of genes necessary for phagocytosis and induction of phagocytic activity and this is consistent with our observation of enhanced phagocytosis of fAβ by microglia.”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > 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 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
“Arg1 and TGF-β mRNA expression remained constant under all treatment paradigms while Ym1 or Fizz1 were not detected in the cultured microglia under any treatment condition (data not shown), suggesting that apoE does not play a role in the M2 polarization of microglial cells that is seen in vivo.”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Results > Pioglitazone suppresses glial activation and enhances amyloid clearance
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 claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Apolipoprotein E (apoE) is the principal genetic risk factor for sporadic, late-onset AD (Corder et al., 1993; Roses, 1996).”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Introduction
What the sources say
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.
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
“This striking result suggests that short-term pioglitazone treatment not only reduces levels of sAβ but also results in the clearance of predeposited insoluble dense-core Aβ plaques in 12-month-old transgenic animals.”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Results > PPARγ activation rapidly stimulates the clearance of Aβ in a mouse model of AD
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These experiments demonstrate that in vivo pioglitazone activates PPARγ and induces the expression of LXRα and its target genes in the AD brain, solidifying the linkage of a PPARγ-LXRα signaling pathway in the CNS.”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Results > PPARγ activation rapidly stimulates the clearance of Aβ in a mouse model of AD
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“LXR activation induces HDL particle formation through apoe and abca1 expression (Lehmann et al., 1997; Tall, 2008).”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > 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: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“It should be noted that pioglitazone is poorly blood-brain barrier permeable, necessitating administration of the drug at 80 mg · kg−1 · d−1, a dose higher than previously administered (Maeshiba et al., 1997).”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Results > PPARγ activation rapidly stimulates the clearance of Aβ in a mouse model of AD
What the sources say
- Not matchedcites Maeshiba et al., 1997
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: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We demonstrate that PPARγ activation induces lxrα, apoe, and abca1 expression, promoting Aβ clearance by both microglia and astrocytes.”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Introduction
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A 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
“demonstrating the requirement for PPARγ in LXR actions in the brain and the normal expression of its target genes apoe and abca1 (Fig. 2G,H).”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Results > PPARγ facilitates the degradation of soluble Aβ through an LXR/ApoE-dependent pathway
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“These cells undergo a classical M1 inflammatory activation in response of amyloid deposition, leading to a proinflammatory milieu in the brain (Wyss-Coray, 2006; Heneka et al., 2010).”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Discussion
What the sources say
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.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The numbers of thioS+ plaques were counted by a blinded observer.”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Materials and Methods > Tissue collection and immunohistochemistry
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“however, there has been no consensus on the mechanisms of action”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Discussion
What the sources say
- Not checked — no full text of the sourcecites Pedersen and Flynn, 2004 source
- Not matchedcites Escribano et al., 2010
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites Toledo and Inestrosa, 2010
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We were unable to quantitatively evaluate this given the limitations of our astroglial marker, GFAP.”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Results > Pioglitazone suppresses glial activation and enhances amyloid clearance
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“In microglia, apoE facilitates soluble Aβ degradation through reduction of intracellular cholesterol levels and not through direct contact with the Aβ peptide (Lee et al., 2012).”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Discussion
What the sources say
- Not matchedcites Lee et al., 2012
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data suggest a conversion of microglial phenotype in APP/PS1 animals, from the classical M1 to an alternative M2 state following PPARγ activation, promoting the phagocytic removal of amyloid deposits by microglial cells.”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Results > Pioglitazone suppresses glial activation and enhances amyloid clearance
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Several studies have shown that astrocytes are capable of taking up amyloid peptides (Funato et al., 1998; Matsunaga et al., 2003; Nagele et al., 2003; Lasagna-Reeves and Kayed, 2011), and in vitro this ability was restricted to adult astrocytes (al-Ali and al-Hussain, 1996; Wyss-Coray et al., 2003; Koistinaho et al., 2004; Pihlaja et al., 2008).”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Discussion
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In this paper we have demonstrated yet another mechanism through which PPARγ activation may ameliorate AD pathophysiology.”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Discussion
boostedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We have shown a mechanistic linkage between the PPARγ and LXR pathways, which had not previously been documented in the brain, and results in the production of lipidated ApoE particles, facilitating the degradation of soluble Aβ species (Fig. 9).”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Discussion
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In this study we have demonstrated the rapid effects of PPARγ activation on amyloid clearance, microglial polarization, and the reversal of cognitive deficits associated with AD.”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Discussion
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
The relationship between PPARγ and LXRs has not been explored in the brain.
“However, these relationships have yet to be explored in the brain.”
The paper relies on this without support.
Little is known about the mechanisms modulating the M2 phenotypic conversion in the AD brain.
“While M2 gene expression has been detected in the AD brain, little is known about the mechanisms modulating this phenotypic conversion (Colton et al., 2006; Jimenez et al., 2008; Maier et al., 2008).”
The paper relies on this without support.
APP/PS1 transgenic mice begin depositing fibrillar thioflavin S+ plaques at approximately 5–6 months of age.
“The APP/PS1 transgenic mice begin depositing fibrillar thioS+ plaques at ~5–6 months of age.”
The paper relies on this without support.
Robust amyloid phagocytosis in response to drug treatment, as seen in this study, has never been observed before.
“However, robust amyloid phagocytosis in response to drug treatment, as seen here, has to our knowledge never been observed before.”
The paper relies on this without support.
Astrocytes greatly outnumber microglia in the CNS.
“Astrocytes greatly outnumber microglia in the CNS, and their ability to remove even modest amounts of Aβ in the brain may have a significant impact on amyloid clearance in the brain.”
The paper relies on this without support.
Microglia are the principal immune effector cells in the CNS and the only professional phagocytes in the CNS.
“Microglia are the principal immune effector cells in the CNS and are the only professional phagocyte in the CNS.”
The paper relies on this without support.
In AD, microglia are competent phagocytes but fail to effectively clear deposited Aβ from the brain.
“An enigmatic feature of AD is that although microglia are competent phagocytes, they fail to effectively clear deposited Aβ from the brain.”
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 source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Pioglitazone, which belongs to the TZD class of compounds, has been shown to reduce the amyloid load in an ApoE and/ or IDE-dependent process, neurofibrillary tangle formation and decline in cognitive function in 3xTgAD mice (Mandrekar-Colucci et al., 2012; Mansour et al., 2021; Searcy et al., 2012; Zhong et al., 2023).”
From Inhibition of the mitochondrial pyruvate carrier in astrocytes reduces amyloid and tau accumulation in the 3xTgAD mouse model of Alzheimer's disease (2024) · cites this paper as Mandrekar-Colucci et al., 2012
Experimental — accuracy not yet measuredThe 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 [25]
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 minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Materials and Methods > Reagents
“The Aβ1–42 peptide was purchased from American Peptide Company, dissolved in DMSO to a final concentration of 1 μg/ml.”
§ Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease > Materials and Methods > Aβ ELISAs
“Cells were then treated with 2 μg/ml soluble Aβ42 in serum-free medium for 24 h with the specified treatments.”
Citations
Cites
Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., & Pericak-Vance, M. A. (1993) · Science · doi:10.1126/science.8346443 · Cited by 9,429 · cited 2×
“Apolipoprotein E (apoE) is the principal genetic risk factor for sporadic, late-onset AD (Corder et al., 1993; Roses, 1996). apoE is synthesized mainly by astrocytes and plays an isoform-dependent role in modulating A fibrillization and clearance (Holtzman, 2001; Zlokovic et al., 2005; Kim et al.,…”
BackgroundExploring the full spectrum of macrophage activation
Mosser, D. M., & Edwards, J. P. (2008) · Nature Reviews Immunology · doi:10.1038/nri2448 · Cited by 9,144 · cited 4×
“mote tissue repair as well as phagocytosis (Gordon, 2003; Mantovani et al., 2004; Mosser and Edwards, 2008).”
BackgroundMethodInfluentialThe chemokine system in diverse forms of macrophage activation and polarization
MANTOVANI, A., SICA, A., SOZZANI, S., ALLAVENA, P., VECCHI, A., & LOCATI, M. (2004) · Trends in Immunology · doi:10.1016/j.it.2004.09.015 · Cited by 6,534 · cited 2×
“mote tissue repair as well as phagocytosis (Gordon, 2003; Mantovani et al., 2004; Mosser and Edwards, 2008).”
BackgroundMethodAlternative activation of macrophages
Gordon, S. (2003) · Nature Reviews Immunology · doi:10.1038/nri978 · Cited by 6,189 · cited 4×
“mote tissue repair as well as phagocytosis (Gordon, 2003; Mantovani et al., 2004; Mosser and Edwards, 2008).”
BackgroundMethodInfluentialQuerfurth, H. W., & LaFerla, F. M. (2010) · New England Journal of Medicine · doi:10.1056/nejmra0909142 · Cited by 4,569
Inflammation and Alzheimer’s disease
Akiyama, H. (2000) · Neurobiology of Aging · doi:10.1016/s0197-4580(00)00124-x · Cited by 4,514
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“The nuclear receptors, peroxisome proliferator-activated receptor- (PPAR ) and Liver X receptors (LXRs) are ligandactivated transcription factors that act as fatty acid and cholesterol sensors (Forman et al., 1997; Kersten et al., 2000).”
BackgroundMacrophage-specific PPARγ controls alternative activation and improves insulin resistance
Odegaard, J. I., Ricardo-Gonzalez, R. R., Goforth, M. H., Morel, C. R., Subramanian, V., Mukundan, L., Eagle, A. R., Vats, D., Brombacher, F., Ferrante, A. W., et al. (2007) · Nature · doi:10.1038/nature05894 · Cited by 2,107 · cited 1×
“…have only recently been appreciated to play an crucial role in promoting the phenotypic change of macrophages from a “classically” M1 activated to alternatively activated M2 states (Odegaard et al., 2007, 2008; Zelcer et al., 2007; Bouhlel et al., 2008; Kalinin et al., 2009; Chawla, 2010).”
BackgroundDecreased Clearance of CNS β-Amyloid in Alzheimer’s Disease
Mawuenyega, K. G., Sigurdson, W., Ovod, V., Munsell, L., Kasten, T., Morris, J. C., Yarasheski, K. E., & Bateman, R. J. (2010) · Science · doi:10.1126/science.1197623 · Cited by 2,078 · cited 2×
“Alzheimer's disease (AD) is characterized by the accumulation and deposition of amyloid β (Aβ) within the brain because of inefficient clearance of these peptides (Mawuenyega et al., 2010; Querfurth and LaFerla, 2010).”
BackgroundRoles of PPARs in health and disease
Kersten, S., Desvergne, B., & Wahli, W. (2000) · Nature · doi:10.1038/35013000 · Cited by 1,956 · cited 1×
“The nuclear receptors, peroxisome proliferator-activated receptor- (PPAR ) and Liver X receptors (LXRs) are ligandactivated transcription factors that act as fatty acid and cholesterol sensors (Forman et al., 1997; Kersten et al., 2000).”
Background
Cited by
Sorted by citations
Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?
Leng, F., & Edison, P. (2021) · Nature Reviews Neurology · doi:10.1038/s41582-020-00435-y · Cited by 3,179
Microglia Function in the Central Nervous System During Health and Neurodegeneration
Colonna, M., & Butovsky, O. (2017) · Annual Review of Immunology · doi:10.1146/annurev-immunol-051116-052358 · Cited by 2,894
Neuroinflammation and M2 Microglia: The Good, the Bad, and the Inflamed
Cherry, J. D., Olschowka, J. A., & O’Banion, M. K. (2014) · Journal of Neuroinflammation · doi:10.1186/1742-2094-11-98 · Cited by 1,748
“Several groups have observed that prolonged treatment with PPARγ agonists can reduce Alzheimer’s disease pathology, demonstrating its potential therapeutic efficacy [102,136,137].”
BackgroundInfluentialSleep and Alzheimer disease pathology--a bidirectional relationship
Ju, Y.-E. S., Lucey, B. P., & Holtzman, D. M. (2014) · Nature Reviews Neurology · doi:10.1038/nrneurol.2013.269 · Cited by 996
Innate immunity in Alzheimer's disease
Heneka, M. T., Golenbock, D. T., & Latz, E. (2015) · Nature Immunology · doi:10.1038/ni.3102 · Cited by 902
Microglia: Scapegoat, saboteur, or something else?
Aguzzi, A., Barres, B. A., & Bennett, M. L. (2013) · Science · doi:10.1126/science.1227901 · Cited by 836
Microglia in the TBI brain: The good, the bad, and the dysregulated
Loane, D. J., & Kumar, A. (2015) · Experimental Neurology · doi:10.1016/j.expneurol.2015.08.018 · Cited by 850
“PPARγ activation produces similar effects inmicroglia (Storer et al., 2005), and PPAR activation ofmicroglia promotes increased phagocytic uptake of amyloid-β plaques and is neuroprotective in mouse models of AD (Mandrekar-Colucci et al., 2012; Yamanaka et al., 2012).”
BackgroundMacrophage activation and its role in repair and pathology after spinal cord injury
Gensel, J. C., & Zhang, B. (2015) · Brain Research · doi:10.1016/j.brainres.2014.12.045 · Cited by 792
“For example, activation of PPARγ attenuates neuroinflammation and increases M2 macrophages in the model of Alzheimer's disease (AD), suggesting that administration of PPAR agonists may create an inflammatory milieu in the CNS favoring regeneration and recovery (Mandrekar Colucci et al., 2012).”
BackgroundChiu, I. M., Morimoto, E. T. A., Goodarzi, H., Liao, J. T., O’Keeffe, S., Phatnani, H. P., Muratet, M., Carroll, M. C., Levy, S., Tavazoie, S., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.06.018 · Cited by 651
“Furthermore, this is likely mediated through the suppression of proinflammatory pathways and induction of anti-inflammatory pathways in microglia (Mandrekar-Colucci et al., 2012).”
Microglial cell dysregulation in brain aging and neurodegeneration
von Bernhardi, R., Eugenín-von Bernhardi, L., & Eugenín, J. (2015) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2015.00124 · Cited by 556
Yin, F. (2023) · The FEBS Journal · doi:10.1111/febs.16344 · Cited by 441
Butterfield, D. A., Di Domenico, F., & Barone, E. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2014.06.010 · Cited by 402
“and tau pathology (3xTg-AD, 18 mg/kg/d, for 4 months), promoted multiple beneficial effects, including improved learning, reduced serum cholesterol, decreased hippocampal amyloid-β and tau deposits, and enhanced short- and long-term plasticity [169,170].”
Apolipoprotein E in Alzheimer's Disease: An Update
Yu, J.-T., Tan, L., & Hardy, J. (2014) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-071013-014300 · Cited by 394
“APOE4 carriers are consistently found with higher tau, phosphorylated tau, and tau/Aβ ratios at every disease stage (Mattsson et al. 2009, Vemuri et al. 2010).”
BackgroundTargeting Microglial Activation States as a Therapeutic Avenue in Parkinson’s Disease
Subramaniam, S., & Federoff, H. J. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00176 · Cited by 353
Microglia Phenotypes in Aging and Neurodegenerative Diseases
Wendimu, M. Y., & Hooks, S. B. (2022) · Cells · doi:10.3390/cells11132091 · Cited by 336
Astrocytes: Role and Functions in Brain Pathologies
Siracusa, R., Fusco, R., & Cuzzocrea, S. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.01114 · Cited by 361
“Aβ accumulation from astrocytes can also be decreased using IL-1β or TNF-α/TNF-α, PPAR-γ receptor agonists, minocycline or nicergoline, and tyrosine kinase inhibitors (Von Bernhardi et al., 2010; Kitazawa et al., 2011; Mandrekar-Colucci et al., 2012; Tweedie et al., 2012).”
BackgroundSharma, P., Srivastava, P., Seth, A., Tripathi, P. N., Banerjee, A. G., & Shrivastava, S. K. (2019) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2018.12.006 · Cited by 331
Insulin resistance and Parkinson’s disease: A new target for disease modification?
Athauda, D. S., & Foltynie, T. (2016) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2016.10.001 · Cited by 340
“These effects were associated with reduced deposition of AB, thought to be due to suppression of BACE1 and modulation of phagocytic clearance of AB by microglia (MandrekarColucci et al., 2012; Sastre et al., 2003; Yamanaka et al., 2012).”
Exploring the Role of Neuroplasticity in Development, Aging, and Neurodegeneration
Marzola, P., Melzer, T., Pavesi, E., Gil-Mohapel, J., & Brocardo, P. S. (2023) · Brain Sciences · doi:10.3390/brainsci13121610 · Cited by 281
“Microglia can assume phagocytic phenotypes and release inflammatory cytokines in response to various stimuli, including protein aggregates and pathogens [285].”
BackgroundFernandez, C. G., Hamby, M. E., McReynolds, M. L., & Ray, W. J. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00014 · Cited by 277
“For example, computer simulations of neuron/astrocyte energetics, based on fMRS data, support a model in which neurons readily metabolize glucose and export lactate, which is taken up by astrocytes, and not the other way around (Simpson et al., 2007; Mangia et al., 2009).”
MethodThe Immune System, Cytokines, and Biomarkers in Autism Spectrum Disorder
Masi, A., Glozier, N., Dale, R. C., & Guastella, A. J. (2017) · Neuroscience Bulletin · doi:10.1007/s12264-017-0103-8 · Cited by 274
PPARγ as a therapeutic target to rescue mitochondrial function in neurological disease
Corona, J. C., & Duchen, M. R. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.06.023 · Cited by 271
Labandeira-García, J. L., Rodriguez-Perez, A. I., Garrido‐Gil, P., Rodríguez‐Pallares, J., Lanciego, J. L., & Guerra, M. J. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00129 · Cited by 259
“PPARγ agonists have been suggested as promising therapy for neurodegenerative diseases enhanced by neuroinflammation such as AD and PD (Schintu et al., 2009; Mandrekar-Colucci et al., 2012).”
BackgroundThawkar, B. S., & Kaur, G. (2018) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2018.11.010 · Cited by 254
PPARγand the Innate Immune System Mediate the Resolution of Inflammation
Croasdell, A., Duffney, P. F., Kim, N., Lacy, S. H., Sime, P. J., & Phipps, R. P. (2015) · PPAR Research · doi:10.1155/2015/549691 · Cited by 246
“Pioglitazone promoted a shift from M1 to M2 macrophages and enhanced Aβ amyloid phagocytosis in the brain [74].”
BackgroundJamwal, S., Blackburn, J. K., & Elsworth, J. D. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107705 · Cited by 236
Benarroch, E. E. (2013) · Neurology · doi:10.1212/wnl.0b013e3182a4a577 · Cited by 232
Jang, E., Kim, J., Lee, S., Kim, J., Seo, J.-W., Jin, M., Lee, M., Jang, I., Lee, W., & Suk, K. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1301637 · Cited by 230
Transcriptional control of microglia phenotypes in health and disease
Holtman, I. R., Skola, D., & Glass, C. K. (2017) · Journal of Clinical Investigation · doi:10.1172/jci90604 · Cited by 218
“It has been suggested that the beneficial effects of PPAR γ agonist are produced by inhibition of the proinflammatory activity of microglia and promotion of their phagocytic activity (115–117).”
BackgroundLan, X., Han, X., Li, Q., Li, Q., Gao, Y., Cheng, T., Wan, J., Zhu, W. M., & Wang, J. (2016) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2016.12.012 · Cited by 214
Clearance of Amyloid Beta and Tau in Alzheimer’s Disease: from Mechanisms to Therapy
Xin, S.-H., Tan, L., Cao, X., Yu, J.-T., & Tan, L. (2018) · Neurotoxicity Research · doi:10.1007/s12640-018-9895-1 · Cited by 222
“Moreover, pioglitazone seems to be an effective therapeutic approach targeting Aβ clearance via similar mechanisms to those of rosiglitazone (Mandrekar-Colucci et al. 2012).”
BackgroundJi, J., Xue, T., Guo, X., Yang, J., Guo, R., Wang, J., Huang, J., Zhao, X., & Sun, X. (2018) · Aging Cell · doi:10.1111/acel.12774 · Cited by 208
Pharmacological Modulation of Functional Phenotypes of Microglia in Neurodegenerative Diseases
Song, G. J., & Suk, K. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00139 · Cited by 206
“PPAR activation increases phagocytic uptake of amyloid-β plaques, and is neuroprotective in an AD mouse model (Mandrekar-Colucci et al., 2012; Yamanaka et al., 2012).”
BackgroundChallenges for Alzheimer's Disease Therapy: Insights from Novel Mechanisms Beyond Memory Defects
Frozza, R. L., Lourenco, M. V., & Felice, F. G. D. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00037 · Cited by 213
“Increased pro-inflammatory signaling resulting from reactive microglial reduces Aβ clearance, promotes aberrant synaptic pruning (Lee and Landreth, 2010;Mandrekar-Colucci et al., 2012; Heneka et al., 2015a,b; Hong et al., 2016b), prompts Aβ and tau pathologies, and contributes to impaired synapse function (Wang W.”
BackgroundPan, J., Jin, J., Ge, H. M., Yin, K., Chen, X. '., Han, L., Chen, Y., Qian, L., Li, X., & Xu, Y. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0270-3 · Cited by 192
“One of the important roles of PPARγ in the control of inflammation may be related with regulation of M1/M2 phenotype as demonstrated in a post-incisional pain study [31] and Alzheimer’s disease model [29].”
BackgroundAhmad, M. H., Fatima, M., & Mondal, A. C. (2018) · Journal of Clinical Neuroscience · doi:10.1016/j.jocn.2018.10.034 · Cited by 201
The Role of APOE and TREM2 in Alzheimer′s Disease—Current Understanding and Perspectives
Wolfe, C. M., Fitz, N. F., Nam, K. N., Lefterov, I. M., & Koldamova, R. P. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms20010081 · Cited by 201
Effect of pioglitazone medication on the incidence of dementia
Heneka, M. T., Fink, A., & Doblhammer, G. (2015) · Annals of Neurology · doi:10.1002/ana.24439 · Cited by 187
“In preclinical models, PPARc activation has been shown to prevent the deposition of beta-amyloid by transcriptional suppression of BACE1,(35,36) the rate-limiting enzyme of the amyloidogenic pathway, and by positively regulating phagocytic clearance of beta-amyloid by microglia.(37,38) In murine AD models, pioglitazon…”
BackgroundAgarwal, S., Yadav, A., & Chaturvedi, R. K. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.08.043 · Cited by 183
Porcu, P., Barron, A. M., Frye, C. A., Walf, A. A., Yang, S., He, X., Morrow, A. L., Panzica, G., & Melcangi, R. C. (2015) · Journal of Neuroendocrinology · doi:10.1111/jne.12351 · Cited by 186
Nuclear Receptors License Phagocytosis by Trem2+Myeloid Cells in Mouse Models of Alzheimer's Disease
Savage, J. C., Jay, T., Goduni, E., Quigley, C., Mariani, M. M., Malm, T., Ransohoff, R. M., Lamb, B. T., & Landreth, G. E. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.4586-14.2015 · Cited by 154
“We demonstrated that acute (3–9 d) treatment with PPAR (Mandrekar-Colucci et al., 2012) or RXR agonists (Cramer et al.”
BackgroundSelf-citationNeurosteroids as regenerative agents in the brain: therapeutic implications
Brinton, R. D. (2013) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2013.31 · Cited by 169
Sato, N., & Morishita, R. (2015) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2015.00199 · Cited by 167
“In patients with AD, gray matter loss occurs in the temporal lobe, hippocampus, entorhinal and parietal lobes (Braak and Braak, 1991; Thompson et al., 2003; Andrade-Moraes et al., 2013), and white matter loss occurs in the temporal region (Mann, 1991).”
BackgroundIntegrated expression profiles of mRNA and miRNA in polarized primary murine microglia
Freilich, R. W., Woodbury, M. E., & Ikezu, T. (2013) · PLoS ONE · doi:10.1371/journal.pone.0079416 · Cited by 160
Oral glycotoxins are a modifiable cause of dementia and the metabolic syndrome in mice and humans
Cai, W., Uribarri, J., Zhu, L., Chen, X., Swamy, S., Zhao, Z., Grosjean, F., Simonaro, C. M., Kuchel, G. A., Beeri, M. S., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1316013111 · Cited by 160
“Additionally, PPARγ, which promotes amyloid clearance and suppresses glial activation (37), was decreased in MG and Reg compared with MG brains.”
ResultProstaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models
Johansson, J. U., Woodling, N. S., Wang, Q., Panchal, M., Liang, X., Trueba-Saiz, A., Brown, H. D., Mhatre, S. D., Loui, T., & Andreasson, K. I. (2015) · Journal of Clinical Investigation · doi:10.1172/jci77487 · Cited by 161
“…the cholesterol transporter ABCA1 (36) and apolipoprotein E (ApoE) (37), proteins that enhance proteolytic degradation of soluble A β peptides (38, 39); recent studies indicate that administration of the FDA-approved RXR agonist bexarotene (Targretin) reduces interstitial levels of soluble A β…”
Han, L., Cai, W., Mao, L., Liu, J., Li, P., Leak, R. K., Xu, Y., Hu, X., & Chen, J. (2015) · Stroke · doi:10.1161/strokeaha.115.010091 · Cited by 155
“In agreement with our results, another PPAR-γ agonist, pioglitazone, has been reported to promote the M1 to M2 switch in animal models of Alzheimer disease.(36) Therefore, it is likely that PPAR-γ agonists also regulate oligodendrogenesis indirectly through the modulation of microglial polarization after stroke.”
ResultBao, J., Zheng, L., Zhang, Q., Li, X., Zhang, X., Li, Z., Bai, X., Zhang, Z., Huo, W., Zhao, X., et al. (2016) · Protein & Cell · doi:10.1007/s13238-016-0269-2 · Cited by 159
Liu, Z., Li, Z., Liu, L., Tang, W., Wang, Y., Dong, M., & Xiao, C. (2016) · Frontiers in Pharmacology · doi:10.3389/fphar.2016.00261 · Cited by 155
“Treatment with PPARγ agonist lead to the reduced Aβ production, neuroinflammation, and improvement of cognitive function (Sodhi et al., 2011; Mandrekar-Colucci et al., 2012).”
BackgroundAmyloid-β-Induced Astrocytic Phagocytosis is Mediated by CD36, CD47 and RAGE
Jones, R. S., Minogue, A. M., Connor, T. J., & Lynch, M. A. (2013) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-012-9427-3 · Cited by 147
Zhang, M., Cheng, Q., Zheng, Z., Qian, F., Wang, Y., Thu, P. M., Zhang, X., Zhou, Y., Tu, L., Liu, Q., et al. (2018) · Theranostics · doi:10.7150/thno.26164 · Cited by 148
“In the CNS, Tyro3 is abundant in neurons [68], whereas Mer and Axl are present in microglia [69-71].”
BackgroundInfluentialMicroglial polarization: novel therapeutic mechanism against Alzheimer’s disease
Yao, K., & Zu, H. (2019) · Inflammopharmacology · doi:10.1007/s10787-019-00613-5 · Cited by 150
“Additionally, PPARγ agonists have been considered to efficiently provide neuroprotective properties via increasing mRNA levels of the M2 marker, YM1 (Mandrekarcolucci et al.”
BackgroundInfluentialZhao, Q., Wu, X., Yan, S., Xie, X., Fan, Y., Zhang, J., Peng, C. Y., & You, Z. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0728-y · Cited by 142
“In recent years, researchers have found that PPARγ agonists might be useful in a number of central nervous system diseases that have a microglia-induced anti-inflammatory response [19, 20].”
BackgroundTherapeutic Strategies Targeting Amyloid-β in Alzheimer’s Disease
Pinheiro, L. M. V., & Faustino, C. M. C. (2019) · Current Alzheimer Research · doi:10.2174/1567205016666190321163438 · Cited by 144
Metabolic and inflammatory adaptation of reactive astrocytes: role of PPARs
Iglesias, J., Morales, L., & Barreto, G. E. (2017) · Molecular Neurobiology · doi:10.1007/s12035-016-9833-2 · Cited by 137
Blackman, J., Swirski, M., Clynes, J., Harding, S., Leng, Y., & Coulthard, E. (2021) · Journal of Sleep Research · doi:10.1111/jsr.13229 · Cited by 141
“This precipitates further plaque formation through recognised positive feedback loops (Mandrekar-Colucci et al., 2012).”
BackgroundFu, W., Wang, X., & Ip, N. Y. (2018) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.8b00402 · Cited by 138
Microglial activation states and their implications for Alzheimer's Disease
Valiukas, Z., Tangalakis, K., Apostolopoulos, V., & Feehan, J. (2025) · The Journal of Prevention of Alzheimer s Disease · doi:10.1016/j.tjpad.2024.100013 · Cited by 167
Miró‐Mur, F., Pérez-de-Puig, I., Ferrer-Ferrer, M., Urra, X., Justicia, C., Chamorro, Á., & Planas, A. M. (2015) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2015.08.010 · Cited by 137
“Moreover, monocytes progressively acquired the expression of typical markers of alternatively activated macrophages, like arginase-1 and YM-1.”
BackgroundIn vivo measurement of apolipoprotein E from the brain interstitial fluid using microdialysis
Ulrich, J. D., Burchett, J. M., Restivo, J. L., Schuler, D. R., Verghese, P. B., Mahan, T. E., Landreth, G. E., Castellano, J. M., Jiang, H., Cirrito, J. R., et al. (2013) · Molecular Neurodegeneration · doi:10.1186/1750-1326-8-13 · Cited by 128
“receptor agonists may be an effective therapeutic target for AD [8,17].”
BackgroundSelf-citationIs Alzheimer’s Disease a Liver Disease of the Brain?
Bassendine, M. F., Taylor-Robinson, S. D., Fertleman, M., Khan, M., & Neely, D. (2020) · Journal of Alzheimer's Disease · doi:10.3233/jad-190848 · Cited by 124
Kurapati, K. R. V., Atluri, V. S. R., Samikkannu, T., & Nair, M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0077624 · Cited by 130
“The peroxisome proliferator-activated receptor-γ (PPARγ) is a ligand-activated nuclear receptor and its activation is associated with clearance of β-amyloid and ameliorating the pathologic and behavioral deficits in AD [70].”
BackgroundThe Polarization States of Microglia in TBI: A New Paradigm for Pharmacological Intervention
Xu, H., Wang, Z., Li, J., Wu, H., Peng, Y., Fan, L., Chen, J., Gu, C., Yan, F., Wang, L., et al. (2017) · Neural Plasticity · doi:10.1155/2017/5405104 · Cited by 134
Piirainen, S., Youssef, A. M., Song, C., Kalueff, A. V., Landreth, G. E., Malm, T., & Tian, L. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.01.046 · Cited by 130
Self-citationBrain Iron Homeostasis: A Focus on Microglial Iron
Nnah, I. C., & Wessling‐Resnick, M. (2018) · Pharmaceuticals · doi:10.3390/ph11040129 · Cited by 131
The Gut-Microglia Connection: Implications for Central Nervous System Diseases
Wang, Y., Wang, Z., Wang, Y., Li, F., Jia, J., Song, X., Qin, S., Wang, R., Jin, F., Kitazato, K., et al. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02325 · Cited by 130
Alzheimer's disease failed clinical trials
Asher, S., & Priefer, R. (2022) · Life Sciences · doi:10.1016/j.lfs.2022.120861 · Cited by 124
Teter, B., Morihara, T., Lim, G. P., Chu, T., Jones, M. R., Zuo, X., Paul, R. M., Frautschy, S. A., & Cole, G. M. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.02.015 · Cited by 127
“One approach to identifying a therapeutic target is to increase expression of selected M2related microglial genes (Mandrekar-Colucci et al., 2012).”
BackgroundInsulin resistance in Alzheimer's disease
Dineley, K. T., Jahrling, J. B., & Denner, L. A. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.09.001 · Cited by 125
PPARs in the central nervous system: roles in neurodegeneration and neuroinflammation
Zolezzi, J. M., Santos, M. J., Candia, S. B., Pinto, C., Godoy, J. A., & Inestrosa, N. C. (2017) · Biological reviews/Biological reviews of the Cambridge Philosophical Society · doi:10.1111/brv.12320 · Cited by 123
“…outcomes in several models of neurodegenerative disorders, including improved cognitive performance in animals (Landreth, 2007; Cramer et al., 2012; Mandrekar-Colucci et al., 2012; Inestrosa et al., 2013; Skerrett et al., 2015) and patients (Landreth, 2007; Bernardo & Minghetti, 2008;…”
BackgroundMicroglia in neurodegenerative diseases
Xu, Y., Jin, M.-Z., Yang, Z., & Jin, M.-Z. (2020) · Neural Regeneration Research · doi:10.4103/1673-5374.290881 · Cited by 121
“Microglia produce APOE, which can moderate the inflammatory response (Xu et al., 2000; Cudaback et al., 2011; Terwel et al., 2011; Mandrekar-Colucci et al., 2012).”
BackgroundAno, Y., Ozawa, M., Kutsukake, T., Sugiyama, S., Uchida, K., Yoshida, A., & Nakayama, H. (2015) · PLoS ONE · doi:10.1371/journal.pone.0118512 · Cited by 121
Modulation 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
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Neuroinflammatory changes negatively impact on LTP: A focus on IL-1β
Lynch, M. A. (2015) · Brain Research · doi:10.1016/j.brainres.2014.08.040 · Cited by 115
“A role for PPARγ in switching cells from an M1 to an M2 phenotype has been reported (Chawla, 2010; Mandrekar-Colucci et al., 2012), and it has been shown that rosiglitazone, the PPARγ activator, partially reversed the age-related deficit in LTP (Cowley et al., 2012; Loane et al., 2009) and it also…”
Pharmacological approaches to mitigate neuroinflammation in Alzheimer’s disease
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Polymeric nanoparticle system to target activated microglia/macrophages in spinal cord injury
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Cognitive Enhancement with Rosiglitazone Links the Hippocampal PPARγ and ERK MAPK Signaling Pathways
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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
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“TO901317 or GW3965) or the PPAR-γ agonist, pioglitazone, results in coordinated up-regulation of apoE, ABCA1 and ABCG1 in brain [80-84].”
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Nuclear receptors in neurodegenerative diseases
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Self-citationda Costa, I. M., Lima, F. O. V., Fernandes, L. C. B., Norrara, B., Neta, F. I., Alves, R. D. A. M., Cavalcanti, J. R. L. D. P., Lucena, E. E. D. S., Cavalcante, J. S., do Rêgo, A. C. M., et al. (2018) · Current Neuropharmacology · doi:10.2174/1570159x16666180911123341 · Cited by 96
“Drugs used in the treatment of DM II such as thiazolidinediones (TZDs) act as agonists in the nuclear receptor and peroxisome proliferatoractivated receptor gamma (PPARγ), tested as potential drugs for treating neurodegenerative disorders such as AD [58, 59].”
BackgroundPolarization of macrophages and microglia in inflammatory demyelination
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“The presence of M1/M2 phenotypic polarization has also been suggested for microglia([17-21]).”
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“PPARc- agonists [54], indicating that if IGF2 acted by accelerating plaque clearance, this too could be observed within the time period of IGF2 administration.”
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“Significantly, it has recently been reported that APP/PS1 mice of 6 and 12 months of age showed significant improvement in the level of ABCA1 and ApoE and as a functional consequence of this reduces the soluble and insoluble levels of Aβ by 50% with treatment of pioglitazone [36].”
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“Pioglitazone also reversed behavioral deficits in AD model mice by decreasing hippocampal Aβ and tau proteins deposits, enhancing short- and long-term plasticity, attenuating neuroinflammation, activating phosphorylated ERK (p-ERK) during memory consolidation (Jahrling et al. 2014; Mandrekar-Colucci et al. 2012; Searc…”
BackgroundPPAR 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
“…characterized by chronic neuroinflammation, PPARγ activation attenuates neuroinflammation and augments expression of M2 macrophage markers, indicating that peripheral administration of PPAR agonists can influence an active and chronic inflammatory milieu in the CNS (Mandrekar-Colucci et al., 2012).”
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Ginsenoside Re reduces Aβ production by activating PPARγ to inhibit BACE1 in N2a/APP695 cells
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Seok, 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
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
“Importantly, PPAR agonists have been shown to not only reduce inflammation but also to increase phagocytosis of A in vitro and in vivo (27, 36).”
BackgroundResultInfluentialSelf-citationTargeting 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
“Pioglitazone (synthetic PPAR-g agonist) H H [45]”
Background
Metadata
- Authors
- Mandrekar-Colucci, S., Karlo, J. C., & Landreth, G. E.
- Affiliations
- Case Western Reserve University (US)
- Case Comprehensive Cancer Center
- ORCID
- Landreth, Gary E.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-07-25
- Volume
- 32
- Issue
- 30
- Pages
- 10117-10128
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3433721
- OpenAlex
- W2006505402
- Cited by
- 355
- References
- 99
- Citations by year
- 2026: 6 · 2025: 16 · 2024: 16 · 2023: 18 · 2022: 22 · 2021: 32 · 2020: 20 · 2019: 27 · 2018: 36 · 2017: 25 · 2016: 34 · 2015: 28 · 2014: 35 · 2013: 34 · 2012: 6
- FWCI
- 19.42
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion)
- PubMed Central (submittedVersion)
- Funders
- Case Western Reserve University
- National Institutes of Health (5r01ag030482-05, 5-R01-)
- National Institute on Aging (5-R01-AG030482, R01-AG030482)
- National Institute of Neurological Disorders and Stroke (F31NS061445)
- 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 clearance, PPARγ agonists, pioglitazone, liver X receptor, apolipoprotein E, microglial polarization, M2 microglia, astrocytes, amyloid plaques, cognitive impairment, APPswe/PS1ΔE9 mice, phagocytosis, anti-inflammatory therapy
- MeSH terms
- Liver X Receptors, Pioglitazone, Alzheimer Disease, Animals, Apolipoproteins E, Astrocytes, Brain, Cells, Cultured, Cognition, Disease Models, Animal, Peptide Fragments, Signal Transduction, Amyloid beta-Peptides, Microglia, Maze Learning, Thiazolidinediones, PPAR gamma, Mice, Orphan Nuclear Receptors
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