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

• Published in: Neurobiology of aging Vol. 34; no. 3; pp. 663 - 678
• Main Authors: Zhang, Xin, Li, Lixi, Zhang, Xiaojie, Xie, Wenjie, Li, Liang, Yang, Dehua, Heng, Xin, Du, Yunlan, Doody, Rachelle S, Le, Weidong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-03-2013
• Subjects: Alzheimer Disease - etiology; Alzheimer Disease - genetics; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Animals; Astrocytes - metabolism; Brain - metabolism; Brain - pathology; Brain - physiopathology; Disease Models, Animal; Female; Fetal Hypoxia - complications; Gene-Environment Interaction; Genetic Predisposition to Disease; Hypoxia-inducible factor; Internal Medicine; Learning and memory; Learning Disorders - etiology; Learning Disorders - genetics; Memory Disorders - etiology; Memory Disorders - genetics; Mice; Mice, Transgenic; Microglia - metabolism; Neprilysin; Neurology; Phosphorylation; Plaque, Amyloid - pathology; Pregnancy; Prenatal hypoxia; Synapses; Synapses - pathology; Tau protein; tau Proteins - metabolism; β-amyloid; Learning and memory; Tau protein; Prenatal hypoxia; Hypoxia-inducible factor; Neprilysin; Alzheimer's disease; Synapses; β-amyloid
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2012.06.012

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.