| First Author | Dumont M | Year | 2014 |
| Journal | FASEB J | Volume | 28 |
| Issue | 4 | Pages | 1745-55 |
| PubMed ID | 24398293 | Mgi Jnum | J:312211 |
| Mgi Id | MGI:6783000 | Doi | 10.1096/fj.13-236331 |
| Citation | Dumont M, et al. (2014) PGC-1alpha overexpression exacerbates beta-amyloid and tau deposition in a transgenic mouse model of Alzheimer's disease. FASEB J 28(4):1745-55 |
| abstractText | The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha) interacts with various transcription factors involved in energy metabolism and in the regulation of mitochondrial biogenesis. PGC-1alpha 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-1alpha 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-1alpha 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 beta-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-1alpha exacerbated amyloid and tau accumulation. This was accompanied by an impairment of proteasome activity. PGC-1alpha overexpression induced mitochondrial abnormalities, neuronal cell death, and an exacerbation of behavioral hyperactivity in the Tg19959 mice. These findings show that PGC-1alpha overexpression exacerbates the neuropathological and behavioral deficits that occur in transgenic mice with mutations in APP that are associated with human AD. |
