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PGC-1 Expression Decreases in the Alzheimer Disease Brain as a Function of Dementia

Weiping Qin, MD, PhD; Vahram Haroutunian, PhD; Pavel Katsel, PhD; Christopher P. Cardozo, MD; Lap Ho, PhD; Joseph D. Buxbaum, PhD; Giulio M. Pasinetti, MD, PhD

Arch Neurol. 2009;66(3):352-361.

Objectives  To explore mechanisms through which altered peroxisome proliferator–activated receptor coactivator 1 (PGC-1) expression may influence Alzheimer disease (AD) amyloid neuropathology and to test the hypothesis that promotion of PGC-1 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-1 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-1 in clinical dementia and found that PGC-1 protein content was negatively associated with both AD-type neuritic plaque pathology and β-amyloid (Aβ)_X-42 contents. Moreover, we found that the predicted elevation of amyloidogenic Aβ_1-42 and Aβ_1-40 peptide 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-1 expression. Most importantly, we found that the reconstitution of exogenous PGC-1 expression in Tg2576 neurons attenuated the hyperglycemic-mediated β-amyloidogenesis through mechanisms involving the promotion of the "nonamyloidogenic" -secretase processing of amyloid precursor protein through the attenuation of the forkheadlike transcription factor 1 (FoxO3a) expression.

Conclusion  Therapeutic preservation of neuronal PGC-1 expression promotes the nonamyloidogenic processing of amyloid precursor protein precluding the generation of amyloidogenic Aβ peptides.

Author Affiliations: Departments of Psychiatry (Drs Qin, Haroutunian, Katsel, Ho, Buxbaum, and Pasinetti), Medicine (Dr Cardozo), and Neuroscience (Drs Ho, Buxbaum, and Pasinetti), Mount Sinai School of Medicine, New York, and Geriatric Research Education and Clinical Center (Drs Ho and Pasinetti), James J. Peters VA Medical Center (Drs Ho and Pasinetti), Bronx, New York.

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