Dataset Information

Metabolic stress modulates Alzheimer's ?-secretase gene transcription via SIRT1-PPAR?-PGC-1 in neurons.

ABSTRACT: Classic cardio-metabolic risk factors such as hypertension, stroke, diabetes, and hypercholesterolemia all increase the risk of Alzheimer's disease. We found increased transcription of ?-secretase/BACE1, the rate-limiting enzyme for A? generation, in eNOS-deficient mouse brains and after feeding mice a high-fat, high-cholesterol diet. Up- or downregulation of PGC-1? reciprocally regulated BACE1 in vitro and in vivo. Modest fasting in mice reduced BACE1 transcription in the brains, which was accompanied by elevated PGC-1 expression and activity. Moreover, the suppressive effect of PGC-1 was dependent on activated PPAR?, likely via SIRT1-mediated deacetylation in a ligand-independent manner. The BACE1 promoter contains multiple PPAR-RXR sites, and direct interactions among SIRT1-PPAR?-PGC-1 at these sites were enhanced with fasting. The interference on the BACE1 gene identified here represents a unique noncanonical mechanism of PPAR?-PGC-1 in transcriptional repression in neurons in response to metabolic signals that may involve recruitment of corepressor NCoR.

SUBMITTER: Wang R

PROVIDER: S-EPMC5396538 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Metabolic stress modulates Alzheimer's β-secretase gene transcription via SIRT1-PPARγ-PGC-1 in neurons.

Wang Ruishan R Li Jing Jing JJ Diao Shiyong S Kwak Young-Don YD Liu Li L Zhi Lianteng L Büeler Hansruedi H Bhat Narayan R NR Williams Robert W RW Park Edwards A EA Liao Francesca-Fang FF

Cell metabolism 20130501 5

Classic cardio-metabolic risk factors such as hypertension, stroke, diabetes, and hypercholesterolemia all increase the risk of Alzheimer's disease. We found increased transcription of β-secretase/BACE1, the rate-limiting enzyme for Aβ generation, in eNOS-deficient mouse brains and after feeding mice a high-fat, high-cholesterol diet. Up- or downregulation of PGC-1α reciprocally regulated BACE1 in vitro and in vivo. Modest fasting in mice reduced BACE1 transcription in the brains, which was acco ...[more]

PMID: 23663737

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Project description:Alzheimer's disease (AD) is a prevalent neurodegenerative disease account for 60-80% of the total number of people with dementia, but its treatment and prevention strategies are still in a long process of exploration. It has been reported that a healthy lifestyle may be an effective non-pharmacological intervention for the prevention and treatment of AD, including increased physical activity and the consumption of polyphenol-rich foods. This study, therefore, investigated the effects of 8 weeks of moderate-intensity aerobic exercise (EX), administration of chlorogenic acid administration (GCA), and a combination of both (EX+GCA) on β-amyloid (Aβ) deposition, inflammatory factors, oxidative stress markers, neuronal damage, and cognitive performance in the brains of AD model mice (APP/PS1) and which signaling pathways may be responsible for these effects. The study used Western blot to detect the expression of signaling pathway-related proteins, enzyme-linked immunosorbent assay to detect the expression of inflammatory factors, hematoxylin-eosin staining to detect hippocampal neuronal morphology, immunohistochemistry to detect changes in Aβ deposition in the hippocampus, an oxidative stress marker kit to detect oxidative stress status and the Morris water maze to detect changes in cognitive performance. This study showed that an 8-week intervention (EX/GCA/EX+GCA) activating the SIRT1/PGC-1α signaling pathway improved oxidative stress, neuroinflammation, Aβ deposition, and cognitive performance in mice. However, there was no obvious difference between the EX and GCA groups. In contrast, the combined EX+GCA intervention was significantly better than phase EX or GCA. Our study suggests that although relief of Aβ deposition, neuroinflammation, oxidative stress, neuronal damage, and cognitive decline could also be achieved with EX or GCA, the combined EX+GCA intervention showed better results. These relief effects on AD-related conditions may be obtained by mediating the activation of the SIRT1/PGC-1α signaling pathway. This study is the first to explore the improvement of AD-related conditions with a combined lifestyle of EX+GCA. This healthy lifestyle could be a candidate option for the treatment of AD.

Dataset Information

Metabolic stress modulates Alzheimer's ?-secretase gene transcription via SIRT1-PPAR?-PGC-1 in neurons.

Publications

Metabolic stress modulates Alzheimer's β-secretase gene transcription via SIRT1-PPARγ-PGC-1 in neurons.

Similar Datasets

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