Prenatal hypoxia may aggravate the cognitive impairment and Alzheimer's disease neuropathology in APPSwe/PS1A246E transgenic mice

Xin Zhang, Lixi Li, Xiaojie Zhang, Wenjie Xie, Liang Li, Dehua Yang, Xin Heng, Yunlan Du, Rachelle S. Doody, Weidong Le

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

Most cases of Alzheimer's disease (AD) arise through interactions between genetic and environmental factors. It is believed that hypoxia is an important environmental factor influencing the development of AD. Our group has previously demonstrated that hypoxia increased β-amyloid (Aβ) generation in aged AD mice. Here, we further investigate the pathological role of prenatal hypoxia in AD. We exposed the pregnant APPSwe/PS1A246E transgenic mice to high-altitude hypoxia in a hypobaric chamber during days 7-20 of gestation. We found that prenatal hypoxic mice exhibited a remarkable deficit in spatial learning and memory and a significant decrease in synapses. We also documented a significantly higher level of amyloid precursor protein, lower level of the Aβ-degrading enzyme neprilysin, and increased Aβ accumulation in the brain of prenatal hypoxic mice. Finally, we demonstrated striking neuropathologic changes in prenatal hypoxic AD mice, showing increased phosphorylation of tau, decreased hypoxia-induced factor, and enhanced activation of astrocytes and microglia. These data suggest that although the characteristic features of AD appear later in life, hypoxemia in the prenatal stage may contribute to the pathogenesis of the disease, supporting the notion that environmental factors can trigger or aggravate AD.

Original languageEnglish (US)
Pages (from-to)663-678
Number of pages16
JournalNeurobiology of Aging
Volume34
Issue number3
DOIs
StatePublished - Mar 2013

Keywords

  • Alzheimer's disease; Prenatal hypoxia; Learning and memory; Synapses; β-amyloid; Tau protein; Neprilysin; Hypoxia-inducible factor

ASJC Scopus subject areas

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

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