TY - JOUR
T1 - PGC-1α expression decreases in the Alzheimer disease brain as a function of dementia
AU - Qin, Weiping
AU - Haroutunian, Vahram
AU - Katsel, Pavel
AU - Cardozo, Christopher P.
AU - Ho, Lap
AU - Buxbaum, Joseph D.
AU - Pasinetti, Giulio M.
PY - 2009/3
Y1 - 2009/3
N2 - 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-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-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.
AB - 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-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-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.
UR - http://www.scopus.com/inward/record.url?scp=62449166389&partnerID=8YFLogxK
U2 - 10.1001/archneurol.2008.588
DO - 10.1001/archneurol.2008.588
M3 - Article
C2 - 19273754
AN - SCOPUS:62449166389
SN - 0003-9942
VL - 66
SP - 352
EP - 361
JO - Archives of Neurology
JF - Archives of Neurology
IS - 3
ER -