title: PGC-1α overexpression exacerbates β-amyloid and tau deposition in a transgenic mouse model of Alzheimer's disease.
abstract: 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 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-1α 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 β-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-1α exacerbated amyloid and tau accumulation. This was accompanied by an impairment of proteasome activity. PGC-1α overexpression induced mitochondrial abnormalities, neuronal cell death, and an exacerbation of behavioral hyperactivity in the Tg19959 mice. These findings show that PGC-1α overexpression exacerbates the neuropathological and behavioral deficits that occur in transgenic mice with mutations in APP that are associated with human AD.
authors.affiliation: 1Weill Cornell Medical College, Department of Neurology and Neuroscience, 525 East 68th St., Rm. A569A, New York, NY 10065, USA. mad2138@med.cornell.edu.
authors.forename: Magali
authors.initials: M
authors.lastname: Dumont
authors.forename: Cliona
authors.initials: C
authors.lastname: Stack
authors.forename: Ceyhan
authors.initials: C
authors.lastname: Elipenahli
authors.forename: Shari
authors.initials: S
authors.lastname: Jainuddin
authors.forename: Nathalie
authors.initials: N
authors.lastname: Launay
authors.forename: Meri
authors.initials: M
authors.lastname: Gerges
authors.forename: Natalia
authors.initials: N
authors.lastname: Starkova
authors.forename: Anatoly A
authors.initials: AA
authors.lastname: Starkov
authors.forename: Noel Y
authors.initials: NY
authors.lastname: Calingasan
authors.forename: Davide
authors.initials: D
authors.lastname: Tampellini
authors.forename: Aurora
authors.initials: A
authors.lastname: Pujol
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D016923:Cell Death / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D008569:Memory Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D001523:Mental Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009154:Mutation; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D058225:Plaque, Amyloid / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D016875:tau Proteins; D046988:Proteasome Endopeptidase Complex
keywords: Tg19959 mice; behavior; cell death; mitochondria