| Autor: |
Weiping Qin, Haroutunian, Vahram, Katsel, Pavel, Cardozo, Christopher P., Lap Ho, Buxbaum, Joseph D., Pasinetti, Giulio M. |
| Zdroj: |
Archives of Neurology; Mar2009, Vol. 66 Issue 3, p352-361, 10p |
| Abstrakt: |
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 Aβ1-42 and Aβ1-40 peptide accumulation in embryonic cortico-hippocampal neurons derived from Tg2576 AD mice under hyperglycemic conditions (glucose level, 182-273 mg/dL) coincided with a dosedependent 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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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