Hypoxia increases Aβ generation by altering β- and γ-cleavage of APP

Liang Li, Xiaojie Zhang, Dehua Yang, Guangrui Luo, Shen Chen, Weidong Le

Research output: Contribution to journalArticlepeer-review

157 Scopus citations

Abstract

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 β-amyloid (Aβ) generation and neuritic plaques formation by elevating β-cleavage of APP in APPswe + PS1A246E transgenic mice. We also found that hypoxia enhanced the expression of APH-1a, a component of γ-secretase complex, which in turn may lead to increase in γ-cleavage activity. Furthermore, we demonstrated that repeated hypoxia treatment can activate macroautophagy, which may contribute to the increases in Aβ production since pretreatment with macroautophagy inhibitor 3-methyladenine significantly blocked chemical hypoxic condition-induced increase in Aβ production in SH-SY5Y cells. Taken together, our results suggest an important role of hypoxia in modulating the APP processing by facilitating both β- and γ-cleavage which may result in a significant increase of Aβ generation.

Original languageEnglish (US)
Pages (from-to)1091-1098
Number of pages8
JournalNeurobiology of Aging
Volume30
Issue number7
DOIs
StatePublished - Jul 2009

Keywords

  • β- and γ-cleavage
  • APP processing
  • Hypoxia
  • Macroautophagy

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)
  • Aging
  • Developmental Biology
  • Geriatrics and Gerontology

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