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PGC-1? overexpression exacerbates ?-amyloid and tau deposition in a transgenic mouse model of Alzheimer's disease.


ABSTRACT: The peroxisome proliferator-activated receptor ? coactivator 1-? (PGC-1?) interacts with various transcription factors involved in energy metabolism and in the regulation of mitochondrial biogenesis. PGC-1? mRNA levels are reduced in a number of neurodegenerative diseases and contribute to disease pathogenesis, since increased levels ameliorate behavioral defects and neuropathology of Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. PGC-1? and its downstream targets are reduced both in postmortem brain tissue of patients with Alzheimer's disease (AD) and in transgenic mouse models of AD. Therefore, we investigated whether increased expression of PGC-1? would exert beneficial effects in the Tg19959 transgenic mouse model of AD; Tg19959 mice express the human amyloid precursor gene (APP) with 2 familial AD mutations and develop increased ?-amyloid levels, plaque deposition, and memory deficits by 2-3 mo of age. Rather than an improvement, the cross of the Tg19959 mice with mice overexpressing human PGC-1? exacerbated amyloid and tau accumulation. This was accompanied by an impairment of proteasome activity. PGC-1? overexpression induced mitochondrial abnormalities, neuronal cell death, and an exacerbation of behavioral hyperactivity in the Tg19959 mice. These findings show that PGC-1? overexpression exacerbates the neuropathological and behavioral deficits that occur in transgenic mice with mutations in APP that are associated with human AD.

SUBMITTER: Dumont M 

PROVIDER: S-EPMC3963016 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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PGC-1α overexpression exacerbates β-amyloid and tau deposition in a transgenic mouse model of Alzheimer's disease.

Dumont Magali M   Stack Cliona C   Elipenahli Ceyhan C   Jainuddin Shari S   Launay Nathalie N   Gerges Meri M   Starkova Natalia N   Starkov Anatoly A AA   Calingasan Noel Y NY   Tampellini Davide D   Pujol Aurora A   Beal M Flint MF  

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20140107 4


The peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) interacts with various transcription factors involved in energy metabolism and in the regulation of mitochondrial biogenesis. PGC-1α mRNA levels are reduced in a number of neurodegenerative diseases and contribute to disease pathogenesis, since increased levels ameliorate behavioral defects and neuropathology of Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. PGC-1α and its downstream targets  ...[more]

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