期刊
ARCHIVES OF NEUROLOGY
卷 66, 期 3, 页码 352-361出版社
AMER MEDICAL ASSOC
DOI: 10.1001/archneurol.2008.588
关键词
-
资金
- Atkins Foundation
- National Institutes of Health [AG14766]
- Dana Foundation for Brain Research Initiative, Merit Review
- Department of Veterans Affairs Rehabilitation Research and Development Service [B4162C]
Objectives: To explore mechanisms through which altered peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) expression may influence Alzheimer disease (AD) amyloid neuropathology and to test the hypothesis that promotion of PGC-1 alpha 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 alpha 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 alpha in clinical dementia and found that PGC-1 alpha protein content was negatively associated with both AD-type neuritic plaque pathology and beta-amyloid (A beta)(X-42) contents. Moreover, we found that the predicted elevation of amyloidogenic A beta(1-42) and A beta(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 alpha expression. Most importantly, we found that the reconstitution of exogenous PGC-1 alpha 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. Conclusion: Therapeutic preservation of neuronal PGC-1 alpha expression promotes the nonamyloidogenic processing of amyloid precursor protein precluding the generation of amyloidogenic A beta peptides.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据