Affiliations: [a] Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China | [b] Center for Translational Research on Neurological Diseases, the 1st Affiliated Hospital, Dalian Medical University, Dalian, China | [c] Collaborative Innovation Center for Brain Science, the 1st Affiliated Hospital, Dalian Medical University, Dalian, China
Correspondence:
[*]
Correspondence to: Weidong Le, Institute of Neurology,Ruijin Hospital, Shanghai Jiao Tong University,
School of Medicine, 200025 Shanghai, China. Tel.: +86 21 64370045/Ext. 611201; Fax: +86 21 54669084;
wdle@sibs.ac.cn
Abstract: Alzheimer’s disease (AD) is the most common form of dementia with the accumulation of senile plaques and neurofibrillary tangles in the brain. Autophagy is the key machinery for mammalian cells to degrade damaged organelles and abnormal proteins. Enormous evidence suggests that the autophagy pathway is impaired in AD. Our previous study revealed that hypoxia induced autophagic activation leading to more amyloid-β production in vitro. In this study, we investigated whether autophagic dysfunction is involved in the hypoxia mediated-pathogenesis of AD. We used APPSwe/PS1dE9 transgenic (Tg) mice and wildtype (Wt) littermates. We documented that chronic hypoxia caused more and larger senile plaques in the brains of Tg mice. In addition, chronic hypoxia induced activation of autophagy in the brains of both Wt and Tg mice, and compared to the normal autophagic flux in Wt mice, the autophagic flux was impaired in the brains of H-Tg mice with a large amount of autophagic vacuole accumulation and significant high level of P62. In an in vitro study, we showed that hypoxia-induced autophagy significantly elevated the level of hAβ42. Furthermore, we found that chronic hypoxia activated AMPK and further inhibited the mTOR signaling pathway, while inhibition of AMPK attenuated autophagy induction through the enhancement of mTOR phosphorylation. In short, our study provides new insight into the mechanism underlying chronic hypoxia-mediated AD pathogenesis.
