Impaired mitochondrial biogenesis contributes to mitochondrial dysfunction in Alzheimer's disease

• Published in: Journal of neurochemistry Vol. 120; no. 3; pp. 419 - 429
• Main Authors: Sheng, Baiyang, Wang, Xinglong, Su, Bo, Lee, Hyoung-gon, Casadesus, Gemma, Perry, George, Zhu, Xiongwei
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.02.2012; Wiley-Blackwell
• Subjects: Adenosine Triphosphate - metabolism; Aged; Aged, 80 and over; Alzheimer Disease - pathology; Alzheimer Disease - physiopathology; Alzheimer's disease; Amyloid beta-Protein Precursor - metabolism; Biological and medical sciences; Cell Line, Tumor; Cellular biology; CREB-Binding Protein - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; DNA, Mitochondrial - metabolism; Dose-Response Relationship, Drug; Electron Transport Complex IV - metabolism; Enzyme Inhibitors - pharmacology; Errors of metabolism; Female; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Heat-Shock Proteins - metabolism; Hippocampus - ultrastructure; Humans; Male; Medical sciences; Metabolic diseases; Middle Aged; Miscellaneous hereditary metabolic disorders; Mitochondria; Mitochondria - metabolism; mitochondrial biogenesis; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; mitochondrial transcription factor A; Molecular biology; Neuroblastoma - pathology; Neuroblastoma - ultrastructure; Neurochemistry; Neurology; Neurons; nuclear respiratory factors; Nuclear Respiratory Factors - metabolism; Organelle Biogenesis; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; proliferator-activated receptor gamma coactivator 1α; RNA Interference - physiology; Trans-Activators - metabolism; Transcription Factors - metabolism; Transfection - methods; Alzheimer disease; Central nervous system; Alteration; Enzymopathy; mitochondrial biogenesis; Mitochondrial disorder; Encephalon; proliferator-activated receptor gamma coactivator 1α; Mitochondria; Degenerative disease; mitochondrial transcription factor A; Transcription factor; Alzheimer's disease; Biological receptor; Nervous system diseases; Metabolic diseases; Amyloid precursor protein; Genetic disease; Cerebral disorder; Neuron; Dysfunction; Central nervous system disease; Peroxisome; nuclear respiratory factors; ATP; Hippocampus
• ISSN: 0022-3042; 1471-4159; 1471-4159
• DOI: 10.1111/j.1471-4159.2011.07581.x

J. Neurochem. (2012) 120, 419–429. 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.