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- W2056643485 abstract "Amyloid-b peptide toxicity and tau hyperphosphorylation are two major hallmarks of Alzheimer's disease. However, their possible molecular relationship with regard to the pathophysiology of the disease has not been elucidated. Wistar rats were sacrificed at day 14 of gestation, and foetal neurons were isolated. After incubation with 5 micromolar beta-amyloid peptide, we mesured the expression of RCAN1, GSK3b and P-tau by western blotting. Silencing experiments were performed in PC12 cells. We also isolated lymphocytes from healthy persons carrying Apo E 3/4 or 4//4 alleles and measured RCAN1 and P-tau expression by western blotting. We report that incubation of foetal rat cortical neurons with Ab up-regulates RCAN1 (regulator of calcineurin, a gene whose expression isup-regulated by oxidative stress). RCAN1 is a calcineurin inhibitor. Calcineurin itself is a phosphatase of phospho-tau. Activation of RCAN1 also causes an up-regulation of GSK3b (a tau phosphorylase). Incubation of neurons with Ab results in an increased phosphorylation of tau. All these changes do not take place when RCAN1 is silenced. Thus we propose a mechanism to link Ab toxicity and tau hyperphosphorylation: Ab causes mitochondrial oxidative stress and increases ROS production which results in anup-regulation of RCAN1. RCAN1 inhibitscalcineurin and also activates GSK3b. Both mechanisms shift tau to a hyperphosphorylated state. These results have a human correlation: lymphocytes from persons whose ApoE genotype is ∊4/∊4 (with high risk of developing AD) show higher levels of RCAN1 and phospho-tau than those carrying the ApoE ∊3/∊3 or ∊3/∊4 genotypes. RCAN1 links beta-amyloid toxicity with tau hyperphosphorilation via oxidative stress. RCAN1 levels are higher in lymphopcytes from persons carrying Apo E 4 allele. Thus up-regulation ofRCAN1 may be a marker of risk to develop Alzheimer's disease." @default.
- W2056643485 created "2016-06-24" @default.
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- W2056643485 date "2011-07-01" @default.
- W2056643485 modified "2023-09-27" @default.
- W2056643485 title "P3-183: Role of RCAN1, a gene involved in the adaptation to oxidative stress, in Alzheimer's pathology" @default.
- W2056643485 doi "https://doi.org/10.1016/j.jalz.2011.05.1624" @default.
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