Ischemia/reperfusion induces hippocampal tau hyperphosphorylation in rats via ER stress

Abstract

The main clinical symptoms of Alzhermer's Disease (AD) patients are cognitive impairment and the degraded learning and memory ability. The amount of intracellular neurofibrillary (NFTs) formed by hyperphosphorylated tau is closely positivecorrelated with the clinical dementia degree of AD patients. Phosphorylation of tau is mainly regulated by protein kinase glycogen synthase kinase-3 (GSK-3β) and phosphatase protein phosphatase 2A (PP2A). 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. 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 expression of Bip were found in the AD brain. To investigate that whether ischemia or ischemia/reperfusion can affect tau phosphorylation via the ER stress. 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 and the inhibitor of ER stress, 4-phenyl butyric acid (PBA) was used. The phosphorylation levels of tau protein, the expressions and activities of GSK-3β, PP2A catalytic subunit (PP2Ac) 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 GSK-3β and PP2Ac had no significant change after ischemia and ischemia/reperfusion. The increased phosphorylation levels of GSK-3β at Tyr216 after ischemia and reperfusion and decreased phosphorylation levels at Ser9 after reperfused 3d and 5d, and increased phosphorylation levels at Tyr307 of PP2Ac after reperfusion were observed. We used 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 GSK-3β and inhibiting PP2A.