期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 27, 页码 8445-8450出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1504890112
关键词
PPARalpha; ADAM10; APP; Alzheimer's disease
资金
- National Institutes on Aging Predoctoral training Grant [5T32 AG000269]
- National Institutes of Health [AT6681, NS083054]
- Veteran Affairs [I01BX003033-01]
Amyloid precursor protein (APP) derivative beta-amyloid (A beta) plays an important role in the pathogenesis of Alzheimer's disease (AD). Sequential proteolysis of APP by beta-secretase and.-secretase generates A beta. Conversely, the alpha-secretase a disintegrin and metalloproteinase 10 (ADAM10) cleaves APP within the eventual A beta sequence and precludes A beta generation. Therefore, up-regulation of ADAM10 represents a plausible therapeutic strategy to combat overproduction of neurotoxic A beta. Peroxisome proliferator-activated receptor alpha (PPAR alpha) is a transcription factor that regulates genes involved in fatty acid metabolism. Here, we determined that the Adam10 promoter harbors PPAR response elements; that knockdown of PPAR alpha, but not PPAR beta or PPAR gamma, decreases the expression of Adam10; and that lentiviral overexpression of PPAR alpha restored ADAM10 expression in Ppara(-/-) neurons. Gemfibrozil, an agonist of PPAR alpha, induced the recruitment of PPAR alpha:retinoid x receptor alpha, but not PPAR gamma coactivator 1 alpha (PGC1 alpha), to the Adam10 promoter in wild-type mouse hippocampal neurons and shifted APP processing toward the alpha-secretase, as determined by augmented soluble APP alpha and decreased A beta production. Accordingly, Ppara(-/-) mice displayed elevated SDS-stable, endogenous A beta and A beta(1-42) relative to wild-type littermates, whereas 5XFAD mice null for PPAR alpha (5X/alpha(-/-)) exhibited greater cerebral A beta load relative to 5XFAD littermates. These results identify PPAR alpha as an important factor regulating neuronal ADAM10 expression and, thus, alpha-secretase proteolysis of APP.
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