Ischemia/reperfusion Induces Hyperphosphorylation Of Tau In Rats Hippocampus Via Er Stress

Alzhermer's Disease ( AD) is the most common neurodegenerative disease, which accounts for 60% of adult dementia. Cognitive impairment and the degraded learning and memory ability are the main clinical symptoms of AD patients. AD is mainly characterized by the formation of numerous intracellular neurofibrillary tangles (NFTs) and extracellular senile plaques (SPs) in the brain, which of neurofibrillary tangles (NFTs) is mainly formed by hyperphosphorylated tau protein. Tau protein is a microtubule-associated protein, and when hyperphosphorylated it loses its nomal characteristics and functions in tubulin assembling and axonal transport, and so on. The amount of NFTs formed by hyperphosphorylated tau is closely positivecorrelated with the clinical dementia degree of AD patients.Phosphorylation of tau is regulated by protein kinase and phosphatase, in which glycogen synthase kinase-3 (GSK-3β) and protein phosphatase 2A (PP2A) are the most important protein kinase and phosphatase involved in AD-like hyperphosphorylation of tau. Brain Ischemia/reperfusion is a frequent important pathophysiological process of brain injury. Some scholars have proposed "ischemia / reperfusion" hypothesis of AD and regard the reischemia/reperfusion as an important pathophysiological pathogenesis in the sporadic AD. However, the molecular mechanism of ischemia/reperfusion-induced AD remains unclear. Ischemia/reperfusion can cause cell stress response, such as endoplasmic reticulum stress (ER Stress). GRP78/Bip as an inherent molecular chaperone in the endoplasmic reticulum is the marker of ER stress. The increased ER stress and Bip expression were found in the AD brain. It is necessary to investigate that whether ischemia or ischemia/reperfusion can affect tau phosphorylation via the ER stress. ER stress can activate P38 and JNK, which are both important stress-induced kinase.In this study to investigate the relationship between ischemia/reperfusion and the AD-like tau hyperphosphorylation, the SD rats were used to make the animal models of cerebral ischemia 20min and ischemia/reperfusion (1d, 3d, 5d) by bilateral carotid artery occlusion. The phosphorylation levels of tau protein, the expressions and activities of GSK-3β, PP2A catalytic subunit (PP2Ac), P38 and JNK were observed. The results showed that reperfusion after ischemia 20min induced significantly increased tau phosphorylation in hippocampus at the Ser396, Ser404, Ser198/199/202 sites and increased Bip expression after ischemia 20min and reperfusion (1d, 3d, 5d). The expressions of P38, JNK, GSK-3β, PP2Ac had no significant change after ischemia and ischemia/reperfusion. The increased levels of phosphorylated P38 (activated form) after ischemia and reperfusion, increased phosphorylation levels of GSK-3βat Tyr216 after ischemia and reperfusion and decrased phosphorylation levels at Ser9 after reperfused 3d and 5d, and increased phosphorylation levels at Tyr307 of PP2Ac after reperfusion were observed. JNK phosphorylation levels have no obvious alteration after ischemia and reperfusion. To furtherly clarify the key role of ER stress in the hyperphosphorylation of tau after ischemia/reperfusion, we used the inhibitor of ER stress, PBA, to treat the ischemia/reperfusion rat models and found that PBA could significantly reduce the expression of Bip and the phosphorylation of tau at Ser396, Ser198/199/202 phosphorylation sites. These results confirmed that ischemia/reperfusion could cause ER stress, which induce hyperphosphorylation of tau via activating P38 and GSK-3βand inhibiting PP2A.