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
Forman, B. M., Chen, J., & Evans, R. M. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.9.4312 · Cited by 2,116 · cited 2×
“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).”
BackgroundThe role of apolipoprotein E in Alzheimer's disease
Kim, J., Basak, J. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.06.026 · Cited by 1,661 · cited 3×
“…mainly by astrocytes and plays an isoform-dependent role in modulating A fibrillization and clearance (Holtzman, 2001; Zlokovic et al., 2005; Kim et al., 2009). apoE scaffolds the formation of high-density lipoproteins (HDLs), which traffic cholesterol and phospholipids (Kim et al., 2009).”
BackgroundAmyloid-β–induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networks
Palop, J. J., & Mucke, L. (2010) · Nature Neuroscience · doi:10.1038/nn.2583 · Cited by 1,651 · cited 1×
“A 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).”
BackgroundJankowsky, J. L., Fadale, D. J., Anderson, J., Xu, G. M., Gonzales, V., Jenkins, N. A., Copeland, N. G., Lee, M. K., Younkin, L. H., Wagner, S. L., et al. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh019 · Cited by 1,575 · cited 3×
“Cg-Tg(Gfap-cre)73.12Mvs/J], also obtained from Jackson Laboratories, to generate mice that lacked PPAR expression in astrocytes and cortical neurons.”
MethodSoluble Amyloid β Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease
Lue, L.-F., Kuo, Y.-M., Roher, A. E., Brachova, L., Shen, Y., Sue, L., Beach, T., Kurth, J. H., Rydel, R. E., & Rogers, J. (1999) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)65184-x · Cited by 1,530 · cited 2×
“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).”
BackgroundA PPARγ-LXR-ABCA1 Pathway in Macrophages Is Involved in Cholesterol Efflux and Atherogenesis
Chawla, A., Boisvert, W. A., Lee, C.-H., Laffitte, B. A., Barak, Y., Joseph, S. B., Liao, D., Nagy, L., Edwards, P. A., Curtiss, L. K., et al. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00164-2 · Cited by 1,347 · cited 10×
“These experiments demonstrate that in vivo pioglitazone activates PPAR and induces the expression of LXR and its target genes in the AD brain, solidifying the linkage of a PPAR -LXR signaling pathway in the CNS.”
BackgroundInfluentialWyss-Coray (2006) · doi:10.1038/nm1484 · Cited by 1,284 · cited 2×
“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).”
BackgroundActivation of the Nuclear Receptor LXR by Oxysterols Defines a New Hormone Response Pathway
Lehmann, J. M., Kliewer, S. A., Moore, L. B., Smith-Oliver, T. A., Oliver, B. B., Su, J.-L., Sundseth, S. S., Winegar, D. A., Blanchard, D. E., Spencer, T. A., et al. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.6.3137 · Cited by 1,233 · cited 1×
“LXR activation induces HDL particle formation through apoe and abca1 expression (Lehmann et al., 1997; Tall, 2008).”
BackgroundApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models
Cramer, P. E., Cirrito, J. R., Wesson, D. W., Lee, C. Y. D., Karlo, J. C., Zinn, A. E., Casali, B. T., Restivo, J. L., Goebel, W. D., James, M. J., et al. (2012) · Science · doi:10.1126/science.1217697 · Cited by 1,050 · cited 1×
“…we have shown that activation of the Retinoid X Receptor, the obligate heterodimeric partner of PPAR 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).”
BackgroundSelf-citationRelationship of microglia and astrocytes to amyloid deposits of Alzheimer disease
Itagaki, S., McGeer, P. L., Akiyama, H., Zhu, S., & Selkoe, D. (1989) · Journal of Neuroimmunology · doi:10.1016/0165-5728(89)90115-x · Cited by 940 · cited 1×
“Microglia and astrocytes are found in intimate association with amyloid plaques in both the AD brain and brains of AD mouse models (Itagaki et al., 1989; Wisniewski et al., 1992).”
BackgroundAdult mouse astrocytes degrade amyloid-β in vitro and in situ
Wyss-Coray, T., Loike, J. D., Brionne, T. C., Lu, E., Anankov, R., Yan, F., Silverstein, S. C., & Husemann, J. (2003) · Nature Medicine · doi:10.1038/nm838 · Cited by 909
ApoE Promotes the Proteolytic Degradation of Aβ
Jiang, Q., Lee, C. Y. D., Mandrekar, S., Wilkinson, B., Cramer, P., Zelcer, N., Mann, K., Lamb, B., Willson, T. M., Collins, J. L., et al. (2008) · Neuron · doi:10.1016/j.neuron.2008.04.010 · Cited by 876 · cited 7×
“…pathway Our previous work and that of others has demonstrated a role for LXR activation in stimulating the production of apoE and facilitating the proteolytic degradation of A (Koldamova et al., 2005a; Riddell et al., 2007; Jiang et al., 2008; Donkin et al., 2010; Fitz et al., 2010).”
BackgroundInfluentialSelf-citationAlternative M2 Activation of Kupffer Cells by PPARδ Ameliorates Obesity-Induced Insulin Resistance
Odegaard, J. I., Ricardo-González, R. R., Eagle, A. R., Vats, D., Morel, C. R., Goforth, M. H., Subramanian, V., Mukundan, L., Ferrante, A. W., & Chawla, A. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.04.003 · Cited by 863 · 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).”
BackgroundAPOLIPOPROTEIN E ALLELES AS RISK FACTORS IN ALZHEIMER'S DISEASE
Roses, M. D. (1996) · Annual Review of Medicine · doi:10.1146/annurev.med.47.1.387 · Cited by 707
Risner, M. E., Saunders, A. M., Altman, J. F. B., Ormandy, G. C., Craft, S., Foley, I. M., Zvartau-Hind, M. E., Hosford, D. A., Roses, A. D., & for the Rosiglitazone in Alzheimer's Disease Study Group (2006) · The Pharmacogenomics Journal · doi:10.1038/sj.tpj.6500369 · Cited by 686 · cited 1×
“A larger phase II clinical trial showed improvements in memory retention and attention with the treatment of rosiglitazone (6 months) in patients who did not possess an ApoE4 allele (Risner et al., 2006).”
BackgroundCharacterization of the Drosophila melanogaster genome at the nuclear lamina
Pickersgill, H., Kalverda, B., de Wit, E., Talhout, W., Fornerod, M., & van Steensel, B. (2006) · Nature Genetics · doi:10.1038/ng1852 · Cited by 656
Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells
Glass, C. K., & Saijo, K. (2010) · Nature Reviews Immunology · doi:10.1038/nri2748 · Cited by 619 · cited 1×
“Activation of these nuclear receptors suppresses NF B-mediated inflammatory responses and activates their phagocytic machinery (Zelcer et al., 2007; Mukundan et al., 2009; Glass and Saijo, 2010).”
BackgroundHigh‐yield isolation of murine microglia by mild trypsinization
Saura, J., Tusell, J. M., & Serratosa, J. (2003) · Glia · doi:10.1002/glia.10274 · Cited by 592 · cited 1×
“Microglia were isolated as described by Saura et al. (2003).”
Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-β peptides
Koistinaho, M., Lin, S., Wu, X., Esterman, M., Koger, D., Hanson, J., Higgs, R., Liu, F., Malkani, S., Bales, K. R., et al. (2004) · Nature Medicine · doi:10.1038/nm1058 · Cited by 571 · cited 2×
“, 2003; Lasagna-Reeves and Kayed, 2011), and in vitro this ability was restricted to adult astrocytes (al-Ali and alHussain, 1996; Wyss-Coray et al., 2003; Koistinaho et al., 2004; Pihlaja et al., 2008).”
BackgroundHeneka, M. T., Sastre, M., Dumitrescu-Ozimek, L., Hanke, A., Dewachter, I., Kuiperi, C., O'Banion, K., Klockgether, T., Van Leuven, F., & Landreth, G. E. (2005) · Brain · doi:10.1093/brain/awh452 · Cited by 565 · cited 2×
“…PPAR 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;…”
BackgroundSelf-citationControl of Macrophage Activation and Function by PPARs
Chawla, A. (2010) · Circulation Research · doi:10.1161/circresaha.110.216523 · Cited by 531 · cited 4×
“…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).”
BackgroundInfluentialDynamics of the Microglial/Amyloid Interaction Indicate a Role in Plaque Maintenance
Bolmont, T., Haiss, F., Eicke, D., Radde, R., Mathis, C. A., Klunk, W. E., Kohsaka, S., Jucker, M., & Calhoun, M. E. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.4814-07.2008 · Cited by 526 · cited 2×
“Bolmont et al. (2008) have shown that microglia in the AD brain are capable of taking up Aβs and delivering them to lysosomal compartments.”
BackgroundKoenigsknecht-Talboo, J., & Landreth, G. E. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.1808-05.2005 · Cited by 477 · cited 1×
“The basis of the inactivation of phagocytic function is unknown but is postulated to be the result of autocrine actions of cytokines (Koenigsknecht-Talboo and Landreth, 2005).”
BackgroundSelf-citationWahrle, S. E., Jiang, H., Parsadanian, M., Legleiter, J., Han, X., Fryer, J. D., Kowalewski, T., & Holtzman, D. M. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m407963200 · Cited by 474 · cited 5×
“Pioglitazone treatment of 6 and 12 month animals resulted in a significant induction in cortical protein levels of both ABCA1 and ApoE (Fig.”
BackgroundInfluentialYan, Q., Zhang, J., Liu, H., Babu-Khan, S., Vassar, R., Biere, A. L., Citron, M., & Landreth, G. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-20-07504.2003 · Cited by 469 · cited 3×
“Sustained PPAR 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;…”
BackgroundSelf-citationInflammation, microglia, and alzheimer's disease
Cameron, B., & Landreth, G. E. (2009) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.10.006 · Cited by 452 · cited 1×
“In the AD brain, microglia fail to effectively phagocytose A and are also impaired in their ability to degrade A fibrils (Chung et al., 1999; Cameron and Landreth, 2010).”
BackgroundSelf-citationTall, A. R. (2008) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2007.01898.x · Cited by 436
Neuroinflammatory processes in Alzheimer’s disease
Heneka, M. T., O’Banion, M. K., Terwel, D., & Kummer, M. P. (2010) · Journal of Neural Transmission · doi:10.1007/s00702-010-0438-z · Cited by 433 · cited 2×
“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).”
BackgroundMicroglia and Inflammation in Alzheimers Disease
Mandrekar-Colucci, S., & Landreth, G. E. (2010) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/187152710791012071 · Cited by 421 · cited 3×
“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).”
BackgroundSelf-citationAstrocytes accumulate Aβ42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains
Nagele, R. G., D’Andrea, M. R., Lee, H., Venkataraman, V., & Wang, H.-Y. (2003) · Brain Research · doi:10.1016/s0006-8993(03)02361-8 · Cited by 416 · cited 1×
“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; LasagnaReeves and Kayed, 2011), and in vitro this ability was restricted to adult astrocytes (al-Ali and al-Hussain, 1996; Wyss-Coray et al., 2003;…”
BackgroundExpression profiles for macrophage alternative activation genes in AD and in mouse models of AD.
(2006) · Journal of Neuroinflammation · doi:10.1186/1742-2094-3-27 · Cited by 393
Efficacy of PPAR-γ agonist pioglitazone in mild Alzheimer disease
Sato, T., Hanyu, H., Hirao, K., Kanetaka, H., Sakurai, H., & Iwamoto, T. (2011) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2009.10.009 · Cited by 387
Chinetti-Gbaguidi, G., Baron, M., Bouhlel, M. A., Vanhoutte, J., Copin, C., Sebti, Y., Derudas, B., Mayi, T., Bories, G., Tailleux, A., et al. (2011) · Circulation Research · doi:10.1161/circresaha.110.233775 · Cited by 387 · cited 2×
“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).”
BackgroundJimenez, S., Baglietto-Vargas, D., Caballero, C., Moreno-Gonzalez, I., Torres, M., Sanchez-Varo, R., Ruano, D., Vizuete, M., Gutierrez, A., & Vitorica, J. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.3024-08.2008 · Cited by 383 · cited 1×
“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).”
BackgroundGinderachter, J. A. V., Movahedi, K., Ghassabeh, G. H., Meerschaut, S., Beschin, A., Raes, G., & BAETSELIER, P. D. (2006) · Immunobiology · doi:10.1016/j.imbio.2006.06.002 · Cited by 372
PPAR-δ senses and orchestrates clearance of apoptotic cells to promote tolerance
Mukundan, L., Odegaard, J. I., Morel, C. R., Heredia, J. E., Mwangi, J. W., Ricardo-Gonzalez, R. R., Goh, Y. P. S., Eagle, A. R., Dunn, S. E., Awakuni, J. U. H., et al. (2009) · Nature Medicine · doi:10.1038/nm.2048 · Cited by 368 · cited 5×
“Previous studies have demonstrated a role for PPARγ in polarizing macrophages to an alternative activation phenotype that is anti-inflammatory in nature and induces the phagocytic activity of cells (Mukundan et al., 2009; Chawla, 2010).”
BackgroundInfluentialGold, M., Alderton, C., Zvartau-Hind, M., Egginton, S., Saunders, A. M., Irizarry, M., Craft, S., Landreth, G., Linnamägi, Ü., & Sawchak, S. (2010) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000318845 · Cited by 361 · cited 1×
“However, phase III clinical trials, using rosiglitazone, failed to show efficacy for the treatment of AD (Gold et al., 2010).”
BackgroundSelf-citationAttenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors
Zelcer, N., Khanlou, N., Clare, R., Jiang, Q., Reed-Geaghan, E. G., Landreth, G. E., Vinters, H. V., & Tontonoz, P. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0701096104 · Cited by 358 · cited 5×
“Activation of these nuclear receptors suppresses NF B-mediated inflammatory responses and activates their phagocytic machinery (Zelcer et al., 2007; Mukundan et al., 2009; Glass and Saijo, 2010).”
BackgroundInfluentialSelf-citationLack of ABCA1 Considerably Decreases Brain ApoE Level and Increases Amyloid Deposition in APP23 Mice
Koldamova, R., Staufenbiel, M., & Lefterov, I. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m504513200 · Cited by 350 · cited 3×
“…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,…”
BackgroundAssociation of Microglia with Amyloid Plaques in Brains of APP23 Transgenic Mice
Stalder, M., Phinney, A., Probst, A., Sommer, B., Staufenbiel, M., & Jucker, M. (1999) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)65423-5 · Cited by 345 · cited 2×
“The number of glial cells surrounding a plaque directly increases in proportion to the dimensions of the deposits (Stalder et al., 1999; Sasaki et al., 2002).”
BackgroundMaier, M., Peng, Y., Jiang, L., Seabrook, T. J., Carroll, M. C., & Lemere, C. A. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.0829-08.2008 · Cited by 323 · cited 1×
“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).”
BackgroundLee, G., Elwood, F., McNally, J., Weiszmann, J., Lindstrom, M., Amaral, K., Nakamura, M., Miao, S., Cao, P., Learned, R. M., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200743200 · Cited by 319 · cited 2×
“To determine whether degradation of sAβ was dependent on the actions of PPARγ and LXRs, microglia and astrocytes were pretreated with antagonists of these receptors (T0 and 22HC, respectively; Lee et al., 2002; Kase et al., 2007).”
MethodAmyloid Fibrils Activate Tyrosine Kinase-Dependent Signaling and Superoxide Production in Microglia
McDonald, D. R., Brunden, K. R., & Landreth, G. E. (1997) · Journal of Neuroscience · doi:10.1523/jneurosci.17-07-02284.1997 · Cited by 310 · cited 1×
“Primary microglia and astrocytes were cultured from postnatal day 0 –3 C57BL/6J mice and have been previously described (McDonald et al., 1997).”
MethodSelf-citationCD45: new jobs for an old acquaintance
Penninger, J. M., Irie-Sasaki, J., Sasaki, T., & Oliveira-dos-Santos, A. (2001) · Nature Immunology · doi:10.1038/87687 · Cited by 305 · cited 1×
“We also evaluated the expression by microglia of CD45, a tyrosine phosphatase that plays an integral role in immune signaling (Penninger et al., 2001).”
BackgroundCharacterization of four lipoprotein classes in human cerebrospinal fluid
Koch, S., Donarski, N., Goetze, K., Kreckel, M., Stuerenburg, H.-J., Buhmann, C., & Beisiegel, U. (2001) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)31605-9 · Cited by 298 · cited 2×
“ApoA1 is an HDL-associated apolipoprotein which is lipidated by ABCA1 and acts in a similar fashion to ApoE in the periphery (Koch et al., 2001; Denis et al., 2004; Smith et al., 2004), and has been shown to bind to A (Koldamova et al., 2005b) and promote A degradation (Jiang et al., 2008).”
BackgroundToledo, E. M., & Inestrosa, N. C. (2009) · Molecular Psychiatry · doi:10.1038/mp.2009.72 · Cited by 292 · cited 4×
“…Camacho et al., 2004; Heneka et al., 2005; Nicolakakis et al., 2008; Escribano et al., 2010; Toledo and Inestrosa, 2010; Rodriguez-Rivera et al., 2011); however, there has been no consensus on the mechanisms of action (Pedersen and Flynn, 2004; Escribano et al., 2010; Toledo and Inestrosa, 2010).”
BackgroundInfluentialKoldamova, R. P., Lefterov, I. M., Staufenbiel, M., Wolfe, D., Huang, S., Glorioso, J. C., Walter, M., Roth, M. G., & Lazo, J. S. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m411420200 · Cited by 279
Nicolakakis, N., Aboulkassim, T., Ongali, B., Lecrux, C., Fernandes, P., Rosa-Neto, P., Tong, X.-K., & Hamel, E. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.3348-08.2008 · Cited by 262 · cited 1×
“…levels of A , reduce plaque burden, and improve behavior in some AD mouse models (Yan et al., 2003; Camacho et al., 2004; Heneka et al., 2005; Nicolakakis et al., 2008; Escribano et al., 2010; Toledo and Inestrosa, 2010; Rodriguez-Rivera et al., 2011); however, there has been no consensus on…”
BackgroundCoordination of inflammation and metabolism by PPAR and LXR nuclear receptors
Hong, C., & Tontonoz, P. (2008) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2008.07.016 · Cited by 253 · cited 4×
“Astrocytes greatly outnumber microglia in the CNS, and their ability to remove even modest amounts of A in the brain may have a significant impact on amyloid clear- ance in the brain.”
BackgroundInfluentialSeo, J. B., Moon, H. M., Kim, W. S., Lee, Y. S., Jeong, H. W., Yoo, E. J., Ham, J., Kang, H., Park, M.-G., Steffensen, K. R., et al. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.8.3430-3444.2004 · Cited by 250 · cited 2×
“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).”
BackgroundCell Mediators of Inflammation in the Alzheimer Disease Brain
Akiyama, H., Arai, T., Kondo, H., Tanno, E., Haga, C., & Ikeda, K. (2000) · Alzheimer Disease & Associated Disorders · doi:10.1097/00002093-200000001-00008 · Cited by 245 · cited 2×
“Similarly, the induction of inflammatory mediators parallels amyloid deposition and the phenotypic activation of glial cells in the AD brain (Akiyama et al., 2000a; Wyss-Coray, 2006).”
BackgroundRiddell, D. R., Zhou, H., Comery, T. A., Kouranova, E., Lo, C. F., Warwick, H. K., Ring, R. H., Kirksey, Y., Aschmies, S., Xu, J., et al. (2007) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2007.01.011 · Cited by 244 · cited 2×
“…pathway Our previous work and that of others has demonstrated a role for LXR activation in stimulating the production of apoE and facilitating the proteolytic degradation of A (Koldamova et al., 2005a; Riddell et al., 2007; Jiang et al., 2008; Donkin et al., 2010; Fitz et al., 2010).”
BackgroundEscribano, L., Simón, A.-M., Gimeno, E., Cuadrado-Tejedor, M., López de Maturana, R., García-Osta, A., Ricobaraza, A., Pérez-Mediavilla, A., Del Río, J., & Frechilla, D. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2010.32 · Cited by 235 · cited 4×
“…plaque burden, and improve behavior in some AD mouse models (Yan et al., 2003; Camacho et al., 2004; Heneka et al., 2005; Nicolakakis et al., 2008; Escribano et al., 2010; Toledo and Inestrosa, 2010; Rodriguez-Rivera et al., 2011); however, there has been no consensus on the mechanisms of action…”
BackgroundInfluentialNuclear Receptors in Lipid Metabolism: Targeting the Heart of Dyslipidemia
Beaven, S. W., & Tontonoz, P. (2006) · Annual Review of Medicine · doi:10.1146/annurev.med.57.121304.131428 · Cited by 230 · cited 1×
“ApoE has been shown to play a vital role in amyloid clearance and its expression is directly regulated by LXR activation (Beaven and Tontonoz, 2006; Jiang et al., 2008).”
BackgroundWisniewski, H. M., Wegiel, J., Wang, K. C., & Lach, B. (1992) · Acta Neuropathologica · doi:10.1007/bf00311383 · Cited by 221 · cited 1×
“Microglia and astrocytes are found in intimate association with amyloid plaques in both the AD brain and brains of AD mouse models (Itagaki et al., 1989; Wisniewski et al., 1992).”
BackgroundChung, H., Brazil, M. I., Soe, T. T., & Maxfield, F. R. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.45.32301 · Cited by 212 · cited 1×
“In the AD brain, microglia fail to effectively phagocytose A and are also impaired in their ability to degrade A fibrils (Chung et al., 1999; Cameron and Landreth, 2010).”
BackgroundAβ-Induced Inflammatory Processes in Microglia Cells of APP23 Transgenic Mice
Bornemann, K. D., Wiederhold, K., Pauli, C., Ermini, F., Stalder, M., Schnell, L., Sommer, B., Jucker, M., & Staufenbiel, M. (2001) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63945-4 · Cited by 206 · cited 2×
“The appearance of plaques in the AD brain is associated with a robust induction of astrogliosis and microgliosis (Bornemann et al., 2001; Wegiel et al., 2001).”
BackgroundDonkin, J. J., Stukas, S., Hirsch-Reinshagen, V., Namjoshi, D., Wilkinson, A., May, S., Chan, J., Fan, J., Collins, J., & Wellington, C. L. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.108100 · Cited by 200 · cited 4×
“Results PPAR facilitates the degradation of soluble A through an LXR/ApoE-dependent pathway Our previous work and that of others has demonstrated a role for LXR activation in stimulating the production of apoE and facilitating the proteolytic degradation of A (Koldamova et al., 2005a; Riddell et al., 2007; Jiang et al…”
BackgroundInfluentialTerwel, D., Steffensen, K. R., Verghese, P. B., Kummer, M. P., Gustafsson, J.-Å., Holtzman, D. M., & Heneka, M. T. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.6546-10.2011 · Cited by 190
Lee, C. Y. D., Tse, W., Smith, J. D., & Landreth, G. E. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.295451 · Cited by 178 · cited 1×
“In microglia, apoE facilitates soluble A degradation through reduction of intracellular cholesterol levels and not through direct contact with the A peptide (Lee et al., 2012).”
BackgroundFitz, N. F., Cronican, A., Pham, T., Fogg, A., Fauq, A. H., Chapman, R., Lefterov, I., & Koldamova, R. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.1051-10.2010 · Cited by 175
Peroxisome Proliferator-Activated Receptor γ Induces a Clearance Mechanism for the Amyloid-β Peptide
Espuny-Camacho, I., Serneels, L., Spittaels, K., Merchiers, P., Dominguez, D. I., & Strooper, B. D. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.3987-04.2004 · Cited by 171
Lalonde, R., Kim, H. D., Maxwell, J. A., & Fukuchi, K. (2005) · Neuroscience Letters · doi:10.1016/j.neulet.2005.08.028 · Cited by 170 · cited 1×
“Additionally, pioglitazone treatment reversed noncognitive behavioral deficits seen in APP/PS1 animals and restored distance and speed traveled to levels comparable to wild-type animals in an open field (Lalonde et al., 2005).”
BackgroundPihlaja, R., Koıstınaho, J., Malm, T., Sikkilä, H., Vainio, S. J., & Koistinaho, M. (2007) · Glia · doi:10.1002/glia.20599 · Cited by 165 · cited 2×
“, 2003; Lasagna-Reeves and Kayed, 2011), and in vitro this ability was restricted to adult astrocytes (al-Ali and alHussain, 1996; Wyss-Coray et al., 2003; Koistinaho et al., 2004; Pihlaja et al., 2008).”
BackgroundThe role of microglial cells and astrocytes in fibrillar plaque evolution in transgenic APPSW mice
Wegiel, J. (2001) · Neurobiology of Aging · doi:10.1016/s0197-4580(00)00181-0 · Cited by 159 · cited 2×
“The appearance of plaques in the AD brain is associated with a robust induction of astrogliosis and microgliosis (Bornemann et al., 2001; Wegiel et al., 2001).”
BackgroundHanyu, H., Sato, T., Kiuchi, A., Sakurai, H., & Iwamoto, T. (2008) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.2009.02067.x · Cited by 158 · cited 1×
“Because of the efficacy of PPAR agonist action in mouse models of AD, small clinical trials evaluated the effects of receptor activation and found that pioglitazone treatment improved memory and cognition in patients with mild to moderate AD (Hanyu et al., 2009; Sato et al., 2011).”
Background(1998) · Europe PMC (PubMed Central) · Cited by 146
Holtzman, D. M. (2001) · Journal of Molecular Neuroscience · doi:10.1385/jmn:17:2:147 · Cited by 143 · cited 1×
“…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., 2009). apoE scaffolds the formation of high-density lipoproteins (HDLs), which traffic cholesterol…”
Background(1997) · PubMed · Cited by 139
ABCA1 mediates concurrent cholesterol and phospholipid efflux to apolipoprotein A-I
Smith, J. D., Goff, W. L., Settle, M., Brubaker, G., Waelde, C. A., Horwitz, A. A., & Oda, M. N. (2004) · Journal of Lipid Research · doi:10.1194/jlr.m300336-jlr200 · Cited by 132 · cited 2×
“ApoA1 is an HDL-associated apolipoprotein which is lipidated by ABCA1 and acts in a similar fashion to ApoE in the periphery (Koch et al., 2001; Denis et al., 2004; Smith et al., 2004), and has been shown to bind to A (Koldamova et al., 2005b) and promote A degradation (Jiang et al., 2008).”
BackgroundNuclear receptors as therapeutic targets for Alzheimer's disease
Mandrekar-Colucci, S., & Landreth, G. E. (2011) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2011.594043 · Cited by 126 · cited 1×
“A number of studies of the thiazolidinedione agonists of PPAR , pioglitazone (Actos) and rosiglitazone (Avandia), reported salutary effects of these drugs in murine models of AD (Mandrekar-Colucci and Landreth, 2011).”
BackgroundSelf-citationBrioni, J. D., Esbenshade, T. A., Garrison, T. R., Bitner, S. R., & Cowart, M. (2010) · Cited by 125
Immunoreactivity of CD45, a protein phosphotyrosine phosphatase, in Alzheimer's disease
Masliah, E., Mallory, M., Hansen, L., Alford, M., Albright, T., Terry, R., Shapiro, P., Sundsmo, M., & Saitoh, T. (1991) · Acta Neuropathologica · doi:10.1007/bf00294425 · Cited by 112 · cited 1×
“CD45 expression is elevated in microglia in the AD brain and is associated with classical M1 microglial activation (Masliah et al., 1991; Wilcock et al., 2001).”
BackgroundPEDERSEN, W., & FLYNN, E. (2004) · Neurobiology of Disease · doi:10.1016/j.nbd.2004.08.003 · Cited by 108 · cited 4×
“…Camacho et al., 2004; Heneka et al., 2005; Nicolakakis et al., 2008; Escribano et al., 2010; Toledo and Inestrosa, 2010; Rodriguez-Rivera et al., 2011); however, there has been no consensus on the mechanisms of action (Pedersen and Flynn, 2004; Escribano et al., 2010; Toledo and Inestrosa, 2010).”
BackgroundInfluentialKalinin, S., Richardson, J. C., & Feinstein, D. L. (2009) · Current Alzheimer Research · doi:10.2174/156720509789207949 · Cited by 107 · cited 4×
“Previous work has also suggested that PPAR activation may regulate the expression of key Aβ proteases, insulin-degrading enzyme (IDE) and neprilysin (Du et al., 2009; Kalinin et al., 2009).”
BackgroundInfluentialNeurovascular Pathways and Alzheimer Amyloid β-peptide
Zlokovic, B. V., Deane, R., Sallstrom, J., Chow, N., & Miano, J. M. (2006) · Brain Pathology · doi:10.1111/j.1750-3639.2005.tb00103.x · Cited by 104 · cited 1×
“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).”
BackgroundHemauer, S. J., Patrikeeva, S. L., Nanovskaya, T. N., Hankins, G. D. V., & Ahmed, M. S. (2010) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2010.01.035 · Cited by 103 · cited 1×
“The actions of PPAR 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).”
BackgroundCombs, C. K., Bates, P., Karlo, J. C., & Landreth, G. E. (2001) · Neurochemistry International · doi:10.1016/s0197-0186(01)00052-3 · Cited by 101 · cited 2×
“Since PPARγ activation has been shown to result in potent anti-inflammatory actions and represses microglia-mediated inflammation, we examined the effects of pioglitazone treatment on glial activation status and their association with amyloid deposits (Combs et al., 2001).”
BackgroundSelf-citationDenis, M., Haidar, B., Marcil, M., Bouvier, M., Krimbou, L., & Genest, J. J. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m306963200 · Cited by 90 · cited 2×
“ApoA1 is an HDL-associated apolipoprotein which is lipidated by ABCA1 and acts in a similar fashion to ApoE in the periphery (Koch et al., 2001; Denis et al., 2004; Smith et al., 2004), and has been shown to bind to A (Koldamova et al., 2005b) and promote A degradation (Jiang et al., 2008).”
BackgroundRodriguez-Rivera, J., Denner, L. A., & Dineley, K. T. (2010) · Behavioural Brain Research · doi:10.1016/j.bbr.2010.08.002 · Cited by 88 · cited 2×
“Indeed, PPAR agonists have been shown to effectively lower both soluble levels of A , reduce plaque burden, and improve behavior in some AD mouse models (Yan et al., 2003; Camacho et al., 2004; Heneka et al., 2005; Nicolakakis et al., 2008; Escribano et al., 2010; Toledo and Inestrosa, 2010; Rodriguez-Rivera et al., 2…”
BackgroundWilcock, D. M., Gordon, M. N., Ugen, K. E., Gottschall, P. E., DiCarlo, G., Dickey, C. A., Boyett, K. W., Jantzen, P. T., Connor, K. E., Melachrino, J., et al. (2001) · DNA and Cell Biology · doi:10.1089/10445490152717596 · Cited by 87 · cited 1×
“CD45 expression is elevated in microglia in the AD brain and is associated with classical M1 microglial activation (Masliah et al., 1991; Wilcock et al., 2001).”
BackgroundKase, E. T., Thoresen, G. H., Westerlund, S., Højlund, K., Rustan, A. C., & Gaster, M. (2007) · Diabetologia · doi:10.1007/s00125-007-0760-7 · Cited by 68 · cited 1×
“To determine whether degradation of sA was dependent on the actions of PPAR and LXRs, microglia and astrocytes were pretreated with antagonists of these receptors (T0 and 22HC, respectively; Lee et al., 2002; Kase et al., 2007).”
MethodSasaki, A., Shoji, M., Harigaya, Y., Kawarabayashi, T., Ikeda, M., Naito, M., Matsubara, E., Abe, K., & Nakazato, Y. (2002) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/s00428-002-0643-8 · Cited by 63 · cited 2×
“The number of glial cells surrounding a plaque directly increases in proportion to the dimensions of the deposits (Stalder et al., 1999; Sasaki et al., 2002).”
BackgroundBouhlel, M. A., Staels, B., & Chinetti‐Gbaguidi, G. (2008) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2007.01892.x · Cited by 51 · cited 1×
“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).”
Background(1996) · PubMed · Cited by 49
Yue, L., & Mazzone, T. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m808482200 · Cited by 49 · cited 2×
“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).”
BackgroundAstrocytes contain amyloid-β annular protofibrils in Alzheimer's disease brains
Lasagna‐Reeves, C. A., & Kayed, R. (2011) · FEBS Letters · doi:10.1016/j.febslet.2011.08.027 · Cited by 41
Specific uptake of Aβ1-40 in rat brain occurs in astrocyte, but not in microglia
Matsunaga, W., Shirokawa, T., & Isobe, K. (2003) · Neuroscience Letters · doi:10.1016/s0304-3940(03)00240-4 · Cited by 36
Du, J., Sun, B., Chen, K., Fan, L., & Wang, Z. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.04.148 · Cited by 19 · cited 2×
“Previous work has also suggested that PPAR activation may regulate the expression of key Aβ proteases, insulin-degrading enzyme (IDE) and neprilysin (Du et al., 2009; Kalinin et al., 2009).”
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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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