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

Overview

MeSH

  • Amyloid beta-Protein Precursor
  • Animals
  • Blotting, Western
  • Cell Death
  • Disease Models, Animal
  • Gene Expression
  • Humans
  • Memory Disorders
  • Mental Disorders
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Mice, Transgenic
  • Mutation
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Plaque, Amyloid
  • Proteasome Endopeptidase Complex
  • Reverse Transcriptase Polymerase Chain Reaction

MeSH Major

  • Alzheimer Disease
  • Amyloid beta-Peptides
  • Transcription Factors
  • tau Proteins

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.

publication date

  • April 2014

has subject area

  • Alzheimer Disease
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Animals
  • Blotting, Western
  • Cell Death
  • Disease Models, Animal
  • Gene Expression
  • Humans
  • Memory Disorders
  • Mental Disorders
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Mice, Transgenic
  • Mutation
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Plaque, Amyloid
  • Proteasome Endopeptidase Complex
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factors
  • tau Proteins

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3963016

Digital Object Identifier (DOI)

  • 10.1096/fj.13-236331

PubMed ID

  • 24398293

Additional Document Info

start page

  • 1745

end page

  • 1755

volume

  • 28

number

  • 4