Hypoxia induces HT-22 neuronal cell death via Orai1/CDK5 pathway-mediated Tau hyperphosphorylation.

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 (CoCl). 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.