Abstract
Hypoxia and apoptosis are involved in the pathogenesis of Alzheimer's disease (AD). Hypoxia induces the formation of amyloid precursor protein in neurons, leading to the abnormal deposition of β-amyloid protein and hyperphosphorylation of Tau. Such changes increase the risk of AD. In the present study, a cellular model of hypoxia-induced AD was established by exposing HT-22 mouse hippocampal neurons to the chemical hypoxia-mimicking agent cobalt chloride (CoCl2). It was found that hypoxia increased neuronal apoptosis. Hypoxia caused an abnormal increase in the expression of the intracellular calcium channel protein Orai1 and cyclin-dependent kinase 5 (CDK5), resulting in hyperphosphorylation of Tau. Treatment with small-interfering RNA against Orai1 (siOrai1) or an Orai1-overexpression plasmid effectively intervened the CDK5-mediated hyperphosphorylation of Tau. In summary, following hypoxic injury of neuron, the Orai1-induced expression of CDK5 leads to Tau hyperphosphorylation. Tau hyperphosphorylation is an important pathophysiological manifestation in AD patients. These results indicated that hypoxia induces HT-22 cell death by Orai1/CDK5 pathway mediated Tau hyperphosporylation. This study simulated the pathological process associated with AD and proposed that hypoxia of intravascular cells with normal blood oxygen saturation might be one of a pathogenic mechanisms of AD. Therefore, this work may provide a new theoretical basis for AD prevention and treatment.