Mitochondrial dysfunction is a prominent feature of Alzheimer's disease (AD) brain. Our prior studies demonstrated reduced mitochondrial number in susceptible hippocampal neurons in the brain from AD patients and in M17 cells over-expressing familial AD-causing amyloid precursor protein (APP) mutant (APPswe). In the current study, we investigated whether alterations in mitochondrial biogenesis contribute to mitochondrial abnormalities in AD. Mitochondrial biogenesis is regulated by the peroxisome proliferator activator receptor gamma-coactivator 1α (PGC-1α)-nuclear respiratory factor (NRF)-mitochondrial transcription factor A pathway. Expression levels of PGC-1α, NRF 1, NRF 2, and mitochondrial transcription factor A were significantly decreased in both AD hippocampal tissues and APPswe M17 cells, suggesting a reduced mitochondrial biogenesis. Indeed, APPswe M17 cells demonstrated decreased mitochondrial DNA/nuclear DNA ratio, correlated with reduced ATP content, and decreased cytochrome C oxidase activity. Importantly, over-expression of PGC-1α could completely rescue while knockdown of PGC-1α could exacerbate impaired mitochondrial biogenesis and mitochondrial deficits in APPswe M17 cells, suggesting reduced mitochondrial biogenesis is likely involved in APPswe-induced mitochondrial deficits. We further demonstrated that reduced expression of p-CREB and PGC-1α in APPswe M17 cells could be rescued by cAMP in a dose-dependent manner, which could be inhibited by PKA inhibitor H89, suggesting that the PKA/CREB pathway plays a critical role in the regulation of PGC-1α expression in APPswe M17 cells. Overall, this study demonstrated that impaired mitochondrial biogenesis likely contributes to mitochondrial dysfunction in AD. Mitochondrial biogenesis is regulated by the PGC-1α-NRF-TFAM pathway. We found decreased expression of these molecules in both AD hippocampal tissues and APPswe M17 cells. PGC-1α over-expression could completely rescue while PGC-1α knockdown could exacerbate impaired mitochondrial biogenesis and mitochondrial deficits in APPswe cells. Furthermore, the PKA/CREB pathway plays a critical role in the regulation of PGC-1α expression in APPswe cells.
- Alzheimer's disease
- mitochondrial biogenesis
- mitochondrial transcription factor A
- nuclear respiratory factors
- proliferator-activated receptor gamma coactivator 1α
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience