Bip Mediates Er Stress-induced Tau Hyperphosphorylation And The Protection Of Sil1

Senile dementia, also named Alzheimer's Disease (AD), the main clinical symptoms of which include cognitive impairment and the degraded learning and memory ability, is characterized by degeneration of neurons. More people may suffer from the risk of AD as the aged society coming, which bring financial burdens to society and families. Senile plaques (SP) and neurofibrillary tangles (NTFs) are the two main pathological changes of AD. NTFs which are compose of hyperphosphorylated tau, are closely positive correlated with the clinical dementia degree of AD patients.Endoplasmic reticulum (ER) is an important organelle which is involved in the balance of cellular Ca2+, synthesis and modify of proteins after proteins translation. Many pathological stimulation, such as ischemia, hypoxia and poison, induces ER stress, which is characterized as overexpression of ER molecular chaperone and unfolded protein response (UPR). Many researchs demonstrate that ER stress may be contribute to the progress of AD. ER molecular chaperone Immunoglobulin-binding protein (Bip) is important for ER, which increases during ER stress. So Bip is considered as a marker of ER stress. Upregulation of BiP in neurons of temporal cortex and hippocampus of AD patients is found. Our laboratory previously finds hyperphosphorylated tau increases with high-expression Bip in hippocampus of SD rats which suffer from constant illumination. However, the relationship between Bip and tau remains unclear.Glycogen synthase kinase-3β(GSK-3β) is an important protein phosphorylated kinase of tau. In AD, GSK-3βis activated. Our laboratory previously finds ER stress induces hyperphosphorylation of tau and activation of GSK-3β. And the activity of GSK-3βin knock-out Bip mice is inhibited. So we infer that Bip may be relevant to GSK-3β. In our research, we induced ER stress in vivo or vitro by inducer thapsigargin (TG). And we found hyperphosphorylation of tau at Ser396, Ser198/199/202 sites and activation of GSK-3β; While TG-induced phosphorylation of tau reduced after knocking down Bip; Overexpression of Bip induced hyperphosphorylation of tau via activating GSK-3βand increasing the association of GSK-3P with tau. Nucleotide exchange factor Sill is the most important nucleotide exchange factor of Bip, disorder of which affect on the energy exchange and fuction of Bip. We found Expression of Sill was reduced in ER stress, Bip-overexpression cells and the brain of Tg2576 mice. Overexpression of Sill reduced TG-induced and Bip-overexpression-induced hyperphophorylation of tau via inhibiting activation of GSK-3P and the binding of Bip with GSK-3βand tau; Knocking down Sill induced overexperssion of Bip and hyperphosphorylation of tau. Furthermore, overexpression of Bip or knocking down Sill remarkably inhibited neuronal axon growth in SD rat primary neurons.In our study, we demonstrate that Overexpression of Bip induces hyperphosphorylation of tau via activating GSK-3P and increasing the association of GSK-3P with tau; Sill protects from ER stress-induced and Bip-overexpression-induced hyperphosphorylation of tau. In conclusion, our research provides some proofs for the role of ER associative molecular chaperone in progress and prevention of AD.