PGC-1alpha expression decreases in the Alzheimer disease brain as a function of dementia.
OBJECTIVE
To explore mechanisms through which altered peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) expression may influence Alzheimer disease (AD) amyloid neuropathology and to test the hypothesis that promotion of PGC-1alpha expression in neurons might be developed as a novel therapeutic strategy in AD.


METHODS
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-1alpha 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-1alpha in clinical dementia and found that PGC-1alpha protein content was negatively associated with both AD-type neuritic plaque pathology and beta-amyloid (Abeta)(X-42) contents. Moreover, we found that the predicted elevation of amyloidogenic Abeta(1-42) and Abeta(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-1alpha expression. Most importantly, we found that the reconstitution of exogenous PGC-1alpha expression in Tg2576 neurons attenuated the hyperglycemic-mediated beta-amyloidogenesis through mechanisms involving the promotion of the "nonamyloidogenic" alpha-secretase processing of amyloid precursor protein through the attenuation of the forkheadlike transcription factor 1 (FoxO3a) expression.


CONCLUSIONS
Therapeutic preservation of neuronal PGC-1alpha expression promotes the nonamyloidogenic processing of amyloid precursor protein precluding the generation of amyloidogenic Abeta peptides.
Qin
Weiping
W
Department of Psychiatry, Mount Sinai School of Medicine, Bronx, NY, USA. weiping.qin@mssm.edu.
Haroutunian
Vahram
V
Katsel
Pavel
P
Cardozo
Christopher P
CP
Ho
Lap
L
Buxbaum
Joseph D
JD
Pasinetti
Giulio M
GM
D000544:Alzheimer Disease / Q000209:etiology / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D016022:Case-Control Studies; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000737:chemistry; D003704:Dementia / Q000150:complications / Q000473:pathology*; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D004622:Embryo, Mammalian; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D005947:Glucose / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010446:Peptide Fragments / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D017077:Culture Media, Conditioned; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D010446:Peptide Fragments; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger; D014157:Transcription Factors; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D049452:Green Fluorescent Proteins; D053829:Amyloid Precursor Protein Secretases; D005947:Glucose