Abstract

Objectives To explore mechanisms through which altered peroxisome proliferator–activated receptor γ coactivator 1α (PGC-1α) expression may influence Alzheimer disease (AD) amyloid neuropathology and to test the hypothesis that promotion of PGC-1α expression in neurons might be developed as a novel therapeutic strategy in AD. Design Case-control. Patients Human postmortem brain (hippocampal formation) samples from AD cases and age-matched non-AD cases. Results Using genome-wide complementary DNA microarray analysis, we found that PGC-1α messenger RNA expression was significantly decreased as a function of progression of clinical dementia in the AD brain. Following confirmatory real-time polymerase chain reaction assay, we continued to explore the role of PGC-1α in clinical dementia and found that PGC-1α protein content was negatively associated with both AD-type neuritic plaque pathology and β-amyloid (Aβ)X-42contents. Moreover, we found that the predicted elevation of amyloidogenic Aβ1-42and Aβ1-40peptide accumulation in embryonic cortico-hippocampal neurons derived from Tg2576 AD mice under hyperglycemic conditions (glucose level, 182-273 mg/dL) coincided with a dose-dependent attenuation in PGC-1α expression. Most importantly, we found that the reconstitution of exogenous PGC-1α expression in Tg2576 neurons attenuated the hyperglycemic-mediated β-amyloidogenesis through mechanisms involving the promotion of the “nonamyloidogenic” α-secretase processing of amyloid precursor protein through the attenuation of the forkheadlike transcription factor 1 (FoxO3a) expression. Conclusion Therapeutic preservation of neuronal PGC-1α expression promotes the nonamyloidogenic processing of amyloid precursor protein precluding the generation of amyloidogenic Aβ peptides.