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

Alzheimer's disease is characterized by the accumulation and deposition of amyloid β within the brain because of inefficient clearance of these peptides.

“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).”

• cites Mawuenyega et al., 2010 sourcePartly supported

  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)

  Experimental — accuracy not yet measured
• cites Querfurth and LaFerla, 2010 sourceNot checked — no full text of the source

Aβ accumulation is associated with perturbations in synaptic function, neuronal loss, and memory and cognitive impairments.

“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).”

• cites Lue et al., 1999 sourcePartly supported

  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)

  Experimental — accuracy not yet measured
• cites Akiyama et al., 2000bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Palop and Mucke, 2010 sourcePartly supported

  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)

  Experimental — accuracy not yet measured

Aβ deposition elicits a robust M1 microglia-mediated inflammatory response contributing to disease pathogenesis.

“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).”

• cites Gordon, 2003 sourceNot checked — no full text of the source
• cites Mosser and Edwards, 2008 sourcePartly supported

  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)

  Experimental — accuracy not yet measured
• cites Mandrekar-Colucci and Landreth, 2010 sourceSupported

Sustained PPARγ or LXR activation results in amelioration of AD-related pathophysiology in AD mouse models.

“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).”

• cites Yan et al., 2003 sourcePartly supported

  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)

  Experimental — accuracy not yet measured
• cites Pedersen and Flynn, 2004 sourceNot checked — no full text of the source
• cites Heneka et al., 2005 sourcePartly supported

  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)

  Experimental — accuracy not yet measured

Peripherally, LXRs and PPARγ participate in a coupled metabolic pathway in which activation of PPARγ induces expression of LXRα and its target genes abca1 and apoE.

“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).”

• cites Chawla et al., 2001 sourcePartly supported

  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)

  Experimental — accuracy not yet measured
• cites Seo et al., 2004 sourcePartly supported

  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)

  Experimental — accuracy not yet measured
• cites Yue and Mazzone, 2009 sourceNot checked — no full text of the source

PPARs act as master regulators governing the polarization of macrophages and microglia into M2 or alternative activation states associated with suppression of inflammation and promotion of phagocytosis and tissue repair.

“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).”

• cites Chawla, 2010 sourcePartly supported

  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)

  Experimental — accuracy not yet measured
• cites Chinetti-Gbaguidi et al., 2011 sourceNot checked — no full text of the source

The actions of PPARγ in the brain of murine models of AD have been controversial, largely due to poor penetrance of its agonists into the brain and active P-glycoprotein-mediated efflux mechanisms.

“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).”

• cites Maeshiba et al., 1997Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Hemauer et al., 2010 sourcePartly supported

  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)

  Experimental — accuracy not yet measured

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.

“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).”

• cites Mukundan et al., 2009 sourcePartly supported

  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)

  Experimental — accuracy not yet measured
• cites Chinetti-Gbaguidi et al., 2011 sourceNot checked — no full text of the source

Nuclear receptors play a crucial role in promoting the phenotypic change of macrophages from classically M1 activated to alternatively activated M2 states.

“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).”

• cites Odegaard et al., 2007, 2008Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Zelcer et al., 2007 sourcePartly supported

  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)

  Experimental — accuracy not yet measured
• cites Bouhlel et al., 2008 sourceNot checked — no full text of the source

Phase III clinical trials using rosiglitazone failed to show efficacy for the treatment of AD.

“However, phase III clinical trials, using rosiglitazone, failed to show efficacy for the treatment of AD (Gold et al., 2010).”

• cites Gold et al., 2010 sourcePartly supported

  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)

  Experimental — accuracy not yet measured

A brief 9 d oral treatment of APPswe/PS1Δe9 mice with pioglitazone resulted in reductions in brain levels of soluble and insoluble Aβ.

“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.”

Pioglitazone stimulates Aβ degradation by both microglia and astrocytes in an LXR- and apoE-dependent manner.

“we found that the synthetic PPARγ agonist, pioglitazone, stimulated Aβ degradation by both microglia and astrocytes in an LXR and apoE-dependent manner.”

At 6 months of age, Fizz1 levels were significantly reduced in vehicle- and pioglitazone-treated APP/PS1 animals.

“At 6 months of age, Fizz1 levels were significantly reduced in vehicle- and pioglitazone-treated APP/PS1 animals.”

At 12 months of age, soluble levels of Aβ40 were reduced by 40%.

“soluble levels of Aβ40 were reduced by 40%”

At 12 months of age, no significant change was seen in levels of soluble Aβ42.

“At 12 months of age, no significant change was seen in levels of soluble Aβ42; however, soluble levels of Aβ40 were reduced by 40% and insoluble levels of both Aβ40 and Aβ42 were reduced by 50% and 40%, respectively (Fig. 4K,L).”

The reduction in amyloid levels was associated with a reversal of contextual memory deficits in the drug-treated mice.

“The reduction in amyloid levels was associated with a reversal of contextual memory deficits in the drug-treated mice.”

Loss of apoe resulted in a significant impairment of intracellular sAβ degradation by both microglia and astrocytes in response to pioglitazone treatment.

“Loss of apoe resulted in a significant impairment of intracellular sAβ degradation by both cell types in response to pioglitazone treatment (Fig. 2C,D).”

At 12 months of age, most microglia in pioglitazone-treated APP/PS1 animals exhibited robust internalization of Aβ.

“Remarkably, at 12 months of age, we found that most microglia in pioglitazone-treated APP/PS1 animals exhibited robust internalization of Aβ (Fig. 7C,D).”

Pioglitazone dramatically increased levels of the alternative activation marker Ym1 mRNA in 6-month-old APP/PS1 animals.

“Pioglitazone, however, dramatically increased levels of the alternative activation marker, Ym1 mRNA in 6-month-old APP/PS1 animals (Fig. 7E).”

The removal of preexisting amyloid deposits was associated with the appearance of abundant Aβ-laden microglia and astrocytes.

“The removal of preexisting amyloid deposits was associated with the appearance of abundant Aβ-laden microglia and astrocytes.”

Exogenous ApoE or ApoA1 stimulated the clearance of Aβ peptides from the media.

“Exogenous ApoE or ApoA1 stimulated the clearance of Aβ peptides from the media (Fig. 2E,F).”

In vehicle-treated animals, abundant microglia were closely associated with plaque cores.

“Based on qualitative immunohistological evaluation, we found abundant microglia closely associated with plaque cores in vehicle-treated animals (Fig. 6A–C,G–I).”

The M2 polarization was associated with enhanced phagocytosis of deposited forms of amyloid.

“into an anti-inflammatory M2 state that was associated with enhanced phagocytosis of deposited forms of amyloid.”

At 12 months of age, insoluble levels of Aβ40 were reduced by 50%.

“insoluble levels of both Aβ40 and Aβ42 were reduced by 50% and 40%, respectively (Fig. 4K,L).”

Internalized Aβ peptides were found only in astrocytes of pioglitazone-treated animals.

“Surprisingly, internalized Aβ peptides were found only in astrocytes of pioglitazone-treated animals, as seen in z-stack images obtained by confocal microscopy (Fig. 5M).”

At 6 months of age, 9 d of pioglitazone treatment reduced soluble and insoluble levels of Aβ by approximately 50%.

“Remarkably, at 6 months of age, only 9 d of pioglitazone treatment reduced soluble and insoluble levels of Aβ by ~50% (Fig. 4G,H).”

It is the authors' qualitative assessment that more than 90% of the microglia in the cortex of drug-treated animals internalized vast quantities of amyloid.

“It is our qualitative assessment that >90% of the microglia in the cortex of drug-treated animals internalized vast quantities of amyloid.”

At 12 months of age, pioglitazone treatment elevated the expression of all M2 markers assayed, Fizz1, Ym1, and Arg1.

“At 12 months of age, pioglitazone treatment elevated the expression of all M2 markers assayed, Fizz1, Ym1, and Arg1.”

Six-month-old PPARγ CKO animals displayed more than a 50% reduction in cortical protein levels of abca1 and apoe.

“Six-month-old PPARγ CKO animals displayed more than a 50% reduction in cortical protein levels of abca1 and apoe, 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).”

In 12-month animals, CD45+ microglia were associated with all amyloid deposits regardless of treatment.

“In 12 month animals, CD45+ microglia were associated with all amyloid deposits regardless of treatment (Fig. 6M–R).”

Only approximately 50% of 6E10-positive deposits were associated with CD45+ microglia in pioglitazone-treated animals.

“However, only ~50% of 6E10-positive deposits were associated with CD45+ microglia in pioglitazone-treated animals (data not shown).”

Pioglitazone treatment of primary microglia and astrocytes resulted in the induction of the LXR target genes abca1 and apoe in both cell types.

“Importantly, pioglitazone treatment of primary microglia and astrocytes resulted in the induction of the LXR target genes, abca1 and apoe in both cell types (Fig. 1B–F).”

Both PPARγ and LXR antagonist treatment of microglia and astrocytes inhibited PPARγ-facilitated degradation of sAβ.

“Both PPARγ and LXR antagonist treatment of microglia and astrocytes inhibited PPARγ-facilitated degradation of sAβ, suggesting that the activation of both PPAR and LXR pathways”

Fizz1 levels remained reduced in 12-month-old APP/PS1 animals.

“Fizz1 levels remained reduced in 12-month-old APP/PS1 animals (Fig. 7F).”

Six-month-old APP/PS1 animals showed no differences in levels of Ym1 or Arg1 compared with WT animals.

“Six-month-old APP/PS1 animals showed no differences in levels of Ym1 or Arg1 compared with WT animals.”

Addition of ApoE or ApoA1 to pioglitazone-treated microglia or astrocytes did not have additive or synergistic effects on intracellular sAβ degradation.

“Addition of ApoE or ApoA1 to pioglitazone-treated microglia or astrocytes (wild-type or ApoE−/−) did not have additive or synergistic effects on intracelluar sAβ degradation (Fig. 2E,F).”

Pioglitazone treatment of 6- and 12-month-old APP/PS1 mice resulted in a significant induction in cortical protein levels of both ABCA1 and ApoE.

“Pioglitazone treatment of 6 and 12 month animals resulted in a significant induction in cortical protein levels of both ABCA1 and ApoE (Fig. 3A–D).”

Immunohistochemical analysis of 6E10-immunoreactive plaques in cortical slices from 6- and 12-month-old animals revealed approximately 40% and 30% reductions in total levels of deposited Aβ compared with vehicle-treated APP/PS1 littermates.

“Immunohistochemical analysis of 6E10-immunoreactive plaques in cortical slices from animals of both ages revealed ~40% and 30% (6 and 12 months, respectively) reduction in total levels of deposited Aβ compared with vehicle-treated APP/PS1 littermates (Fig. 4A–E).”

The association of Iba1+ microglial cells with amyloid plaques was reduced at both 6 and 12 months of age after pioglitazone treatment.

“The association of Iba1+ microglial cells with amyloid plaques was reduced at both 6 and 12 months of age after pioglitazone treatment (Fig. 6D–F,J–L).”

The reduction in amyloid levels was associated with the loss of both diffuse and dense-core plaques within the cortex.

“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.”

In 6-month-old vehicle-treated animals, CD45 immunoreactivity was seen surrounding all 6E10-positive amyloid deposits.

“In 6-month-old vehicle-treated animals, CD45 immunoreactivity was seen surrounding all 6E10-positive amyloid deposits (data not shown).”

Treatment of primary microglia or astrocytes with pioglitazone stimulated the intracellular degradation of soluble Aβ42 in a dose-dependent manner.

“Treatment of primary microglia or astrocytes with the synthetic agonist pioglitazone stimulated the intracellular degradation of soluble Aβ42 in a dose-dependent manner (Fig. 1A,D).”

There was a parallel loss in the number of thioflavin S+ dense-core amyloid plaques, with an approximately 40% and 30% decrease in the number of thioS+ plaques in 6- and 12-month animals, respectively.

“There was a parallel loss in the number of thioflavin S+ dense-core amyloid plaques, with an ~40% and 30% decrease in the number of thioS+ plaques in 6 and 12 month animals, respectively (Fig. 4F).”

Pioglitazone treatment of 6- and 12-month-old APP/PS1 mice showed a statistically significant increase in levels of mRNA for abca1, apoE, and lxrα.

“Additionally, the assessment of LXR target genes by quantitative real-time PCR showed a statistically significant increase in levels of mRNA for abca1, apoE, and lxrα (Fig. 3E,F).”

Pioglitazone treatment resulted in the phenotypic polarization of microglial cells from a proinflammatory M1 state into an anti-inflammatory M2 state.

“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 impairment of sAβ degradation in apoe−/− microglia and astrocytes was restored by the addition of exogenously supplied ApoE or human apolipoprotein A1.

“This was restored by the addition of exogenously supplied ApoE (a mixture of all human ApoE isoforms) or human apolipoprotein A1 (ApoA1) (Fig. 2C,D).”

A trend for a reduction in cd45 mRNA levels was observed in pioglitazone-treated animals of both age groups.

“However, a trend for a reduction in cd45 mRNA levels was observed in pioglitazone-treated animals of both age groups (Fig. 6S,T).”

Pioglitazone treatment significantly reduced the levels of GFAP-immunoreactive astrocytes surrounding amyloid plaques in transgenic animals at both 6 and 12 months of age.

“Pioglitazone treatment significantly reduced the levels of GFAP-immunoreactive astrocytes surrounding amyloid plaques in transgenic animals at both 6 and 12 months of age and seen by immunohistochemistry (Fig. 5A–L).”

Brain levels of the inflammatory cytokines Il-1β and tnfα were reduced in 12- but not 6-month-old treated animals.

“Brain levels of the inflammatory cytokines, Il-1β and tnfα, were also reduced in 12- but not 6-month-old treated animals, verifying the anti-inflammatory effects of PPARγ activation after amyloid deposition (Fig. 7E,F).”

Pioglitazone treatment did not change mRNA levels of IDE and neprilysin.

“We monitored mRNA levels of IDE and neprilysin to determine whether pioglitazone treatment enhanced expression of these proteases and observed no change (data not shown).”

Pioglitazone-treated 12-month-old animals showed an increase in levels of cortical pparγ mRNA.

“Pioglitazone-treated 12 month animals additionally showed an increase in levels of cortical pparγ mRNA (Fig. 3F).”

Aβ-positive astrocytes were never detected in vehicle-treated animals.

“We never detected Aβ-positive astrocytes in vehicle-treated animals (data not shown).”

At 12 months of age, insoluble levels of Aβ42 were reduced by 40%.

“insoluble levels of both Aβ40 and Aβ42 were reduced by 50% and 40%, respectively (Fig. 4K,L).”

Astrocytes have the capacity to take up sAβ and degrade it in an apoE-dependent manner, similar to microglia.

“We report that astrocytes have the capacity to take up sAβ and degrade it in an apoE-dependent manner, similar to microglia (Figs. 1, 2; Jiang et al., 2008).”

• cites Jiang et al., 2008 sourceNot checked — no full text of the source

Amyloid-laden astrocytes were found only in the cortex of pioglitazone-treated animals and not in vehicle-treated APP/PS1 mice.

“Amyloid-laden astrocytes were only found in the cortex of pioglitazone-treated animals and not in vehicle-treated APP/PS1 mice (Fig. 5).”

Pioglitazone treatment of APP/PS1 mice resulted in significant behavioral improvement that was not different from wild-type animals.

“Treatment of APP/PS1 mice with pioglitazone resulted in significant behavioral improvement that was not different from wild-type animals.”

An increase in levels of Tgf-β was monitored in 12-month-old, but not 6-month-old, APP/PS1 mice.

“Additionally, we monitored an increase in levels of Tgf-β in 12-month-old, but not 6-month-old, APP/PS1 mice.”

All groups of APP/PS1 and wild-type animals exhibited learning across four consecutive training sessions in the contextual fear conditioning assay.

“Animals were trained for four consecutive training sessions and all groups exhibited learning (Fig. 8B).”

Pioglitazone has an extraordinary ability to stimulate microglia to phagocytose amyloid deposits from transgenic mice.

“One striking finding in this study was the extraordinary ability of pioglitazone to stimulate microglia to phagocytose amyloid deposits from the transgenic mice (Fig. 7).”

The dramatic changes from PPARγ activation were elicited after a short 9 d period of drug treatment.

“Importantly, these dramatic changes were elicited after a short 9 d period of drug treatment.”

Pioglitazone treatment restored distance and speed traveled in an open field to levels comparable to wild-type animals.

“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).”

• cites Lalonde et al., 2005 sourceNot checked — no full text of the source

Pioglitazone treatment reversed noncognitive behavioral deficits seen in APP/PS1 animals.

“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).”

• cites Lalonde et al., 2005 sourceNot checked — no full text of the source

Vehicle-treated APP/PS1 animals showed significant impairments in memory retention, evidenced by a low number of freezes in the cued environment.

“However, vehicle-treated APP/PS1 animals showed significant impairments in memory retention as evidenced by the low number of freezes in the cued environment (Fig. 8A).”

Genetic inactivation of PPARγ in astrocytes results in a dramatic reduction in expression of LXR target genes.

“The principal conceptual advance in this study was the recognition that in astrocytes and microglia the expression of apoe is robustly regulated through a coupled metabolic pathway regulated by PPARγ and LXRα, and genetic inactivation of PPARγ in astrocytes results in a dramatic reduction in the expression of these LXR target genes (Fig. 2).”

In astrocytes and microglia, expression of apoe is robustly regulated through a coupled metabolic pathway regulated by PPARγ and LXRα.

“The principal conceptual advance in this study was the recognition that in astrocytes and microglia the expression of apoe is robustly regulated through a coupled metabolic pathway regulated by PPARγ and LXRα, and genetic inactivation of PPARγ in astrocytes results in a dramatic reduction in the expression of these LXR target genes (Fig. 2).”

apoE-containing HDL particles facilitate the proteolytic degradation of soluble Aβ.

“Importantly, apoE-containing HDL particles facilitate the proteolytic degradation of soluble Aβ (sAβ) (Jiang et al., 2008).”

• cites Jiang et al., 2008 sourceNot checked — no full text of the source

PPARγ activation does not alter the expression or processing of APP.

“suggesting that PPARγ activation does not alter the expression or processing of APP (Fig. 4I,J,M,N).”

These data document a robust PPARγ-LXR linkage in the brain which has not previously been recognized.

“These data document a robust PPARγ-LXR linkage in the brain which has not previously been recognized.”

These data support the therapeutic utility of PPARγ agonists for the treatment of Alzheimer's disease.

“supports the therapeutic utility of PPARγ agonists for the treatment of Alzheimer's disease.”

Pioglitazone treatment facilitated the removal of both diffuse and dense-core Aβ deposits by microglia and astrocytes, presumably through engaging the phagocytic machinery of these cells.

“These data suggest that in addition to the clearance of soluble forms of Aβ, pioglitazone treatment facilitated the removal of both diffuse and dense-core Aβ deposits by microglia and astrocytes, presumably through engaging the phagocytic machinery of these cells.”

sAβ clearance results from stimulation of apoE-dependent proteolysis of Aβ.

“We argue that sAβ clearance results from stimulation of apoE-dependent proteolysis of Aβ, whereas deposited Aβ is removed phagocytically by microglia as a result of a PPARγ-dependent alternative M2 polarization of microglia.”

These data provide a mechanistic explanation for how PPARγ activation facilitates amyloid clearance.

“These data provide a mechanistic explanation for how PPARγ activation facilitates amyloid clearance and supports the therapeutic utility of PPARγ agonists”

PPARγ activation promotes the clearance of insoluble Aβ by astrocytes.

“These data support the view that PPARγ activation promotes the clearance of insoluble Aβ by astrocytes.”

The changes seen in amyloid deposition were a result of Aβ catabolism and not due to alterations in APP processing or changes in levels of Aβ-degrading enzymes.

“These data suggest that the changes seen in amyloid deposition were indeed a result of Aβ catabolism and not due to alterations in APP processing or changes in levels of Aβ-degrading enzymes.”

The reduction in levels of GFAP, CD45, and Iba1 in pioglitazone-treated animals may be attributed to the role of PPARγ in suppression of the inflammatory response.

“The reduction in levels of GFAP, CD45, and Iba1 in pioglitazone-treated animals may be attributed to the role of PPARγ in suppression of the inflammatory response.”

A brief 9 d pioglitazone treatment of APP/PS1 mice reversed pathological and behavioral phenotypes in treated mice.

“Strikingly, a brief 9 d pioglitazone treatment of APP/PS1 mice reversed pathological and behavioral phenotypes in treated mice.”

PPARγ activation has anti-inflammatory effects after amyloid deposition.

“verifying the anti-inflammatory effects of PPARγ activation after amyloid deposition (Fig. 7E,F).”

Deposited Aβ is removed phagocytically by microglia as a result of a PPARγ-dependent alternative M2 polarization of microglia.

“whereas deposited Aβ is removed phagocytically by microglia as a result of a PPARγ-dependent alternative M2 polarization of microglia.”

Activation of both PPAR and LXR pathways is necessary for the intracellular degradation of sAβ in microglia and astrocytes.

“suggesting that the activation of both PPAR and LXR pathways is necessary for the intracellular degradation of sAβ in these cell types (Fig. 2A,B).”

Small clinical trials found that pioglitazone treatment improved memory and cognition in patients with mild to moderate AD.

“Because of the efficacy of PPARγ 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).”

• cites Hanyu et al., 2009Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Sato et al., 2011Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Astrocytes are capable of taking up amyloid peptides.

“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).”

• cites Funato et al., 1998Not checked — no full text of the source
• cites Matsunaga et al., 2003 sourceNot checked — no full text of the source
• cites Nagele et al., 2003Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Astrocytes have a previously unappreciated role in the removal of amyloid from the brain.

“Moreover, we have identified a previously unappreciated role of astrocytes in the removal of amyloid from the brain.”

PPARγ activation results in rapid improvement of memory in an AD mouse model.

“These results demonstrate that PPARγ activation results in the rapid improvement of memory in an AD mouse model.”

A larger phase II clinical trial showed improvements in memory retention and attention with rosiglitazone treatment (6 months) in patients who did not possess an ApoE4 allele.

“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).”

• cites Risner et al., 2006Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

PPARγ activation enhances the phagocytic capabilities of peripheral M2 polarized macrophages.

“PPARγ activation has been shown to enhance the phagocytic capabilities of peripheral M2 polarized macrophages (Chinetti-Gbaguidi et al., 2011).”

• cites Chinetti-Gbaguidi et al., 2011 sourceNot checked — no full text of the source

It was difficult to assess Aβ uptake by microglia in 6-month-old animals because these animals are at the earlier stages of amyloid deposition.

“It was difficult to assess Aβ uptake by microglia in 6-month-old animals since these animals are at the earlier stages of amyloid deposition, and there are very few Iba1+ cells surrounding Aβ deposits in vehicle-treated animals and fewer still in pioglitazone-treated animals.”

PPARγ activation initiates amyloid clearance pathways in astrocytes.

“This study strongly supports the view that PPARγ activation initiates amyloid clearance pathways in astrocytes and suggests a reevaluation for the role of astrocytes in amyloid clearance in AD.”

• AssumptionRests on an assumption: Astrocytes greatly outnumber microglia in the CNS.

Clearance of soluble forms of Aβ occurs through PPARγ-induced expression of apoe, which promotes sAβ degradation.

“We report that the clearance of soluble forms of Aβ occurs through the ability of PPARγ to induce the expression of apoe through which it promotes sAβ degradation.”

apoE does not play a role in the M2 polarization of microglial cells that is seen in vivo.

“suggesting that apoE does not play a role in the M2 polarization of microglial cells that is seen in vivo.”

PPARγ activation has extraordinary efficacy in ameliorating the pathologic and behavioral deficits in an AD mouse model.

“We have documented the extraordinary efficacy of PPARγ activation in ameliorating the pathologic and behavioral deficits in an AD mouse model.”

PPARγ may act through distinct mechanisms to clear soluble and deposited, fibrillar forms of Aβ.

“A primary finding of this study is the demonstration that PPARγ may act through distinct mechanisms to clear soluble and deposited, fibrillar forms of Aβ.”

ApoE facilitates proteolysis of soluble Aβ peptides both in the interstitial fluid and intracellularly by microglia through the actions of IDE and neprilysin, respectively.

“We have previously documented that apoE acts to facilitate the proteolysis of soluble Aβ peptides both in the interstitial fluid and intracellularly by microglia through the actions of IDE and neprilysin, respectively (Jiang et al., 2008).”

• cites Jiang et al., 2008 sourceNot checked — no full text of the source

In these trials, rosiglitazone was administered at dosages much lower than those needed to see beneficial effects on AD pathophysiology in rodent models.

“It is important to note that in these trials rosiglitazone was administered at dosages that were much lower than those needed to see beneficial effects on AD pathophysiology in rodent models of the disease.”

PPARγ activation changes the inflammatory milieu of the brain by phenotypically polarizing microglia to an alternative, M2 phenotype, allowing them to phagocytically remove amyloid deposits.

“PPARγ activation changes the inflammatory milieu of the brain by phenotypically polarizing microglia to an alternative, M2 phenotype, allowing them to phagocytically remove amyloid deposits (Fig. 9).”

• AssumptionRests on an assumption: Microglia are the principal immune effector cells in the CNS and the only professional phagocytes in the CNS.
• AssumptionRests on an assumption: In AD, microglia are competent phagocytes but fail to effectively clear deposited Aβ from the brain.

This study provides an explanation for how PPARγ modulates AD-related pathology in a mouse model.

“Additionally, we have provided an explanation for how PPARγ modulates AD-related pathology in a mouse model.”