Hypoxia increases Abeta generation by altering beta- and gamma-cleavage of APP.
Environmental factors are significant contributors for the development of Alzheimer's disease (AD). The greatly increased incidence of AD following stroke and cerebral ischemia suggests that hypoxia is a risk factor which may accelerate AD pathogenesis by altering amyloid precursor protein (APP) processing. However, the molecular mechanisms underlying the hypoxia mediated AD pathogenesis have not been fully elucidated. In the present study we demonstrated that repeated hypoxia increased beta-amyloid (Abeta) generation and neuritic plaques formation by elevating beta-cleavage of APP in APP(swe)+PS1(A246E) transgenic mice. We also found that hypoxia enhanced the expression of APH-1a, a component of gamma-secretase complex, which in turn may lead to increase in gamma-cleavage activity. Furthermore, we demonstrated that repeated hypoxia treatment can activate macroautophagy, which may contribute to the increases in Abeta production since pretreatment with macroautophagy inhibitor 3-methyladenine significantly blocked chemical hypoxic condition-induced increase in Abeta production in SH-SY5Y cells. Taken together, our results suggest an important role of hypoxia in modulating the APP processing by facilitating both beta- and gamma-cleavage which may result in a significant increase of Abeta generation.
Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
Liang
L
Li
Xiaojie
X
Zhang
Dehua
D
Yang
Guangrui
G
Luo
Shen
S
Chen
Weidong
W
Le
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000235:genetics; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D010450:Endopeptidases; D006801:Humans; D002534:Hypoxia, Brain / Q000150:complications* / Q000378:metabolism* / Q000503:physiopathology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010447:Peptide Hydrolases / Q000378:metabolism; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D053764:Presenilin-1; C025946:3-methyladenine; C475154:APH1A protein, human; D010450:Endopeptidases; D010447:Peptide Hydrolases; D000225:Adenine