Amyloid-beta Toxicity and Tau Hyperphosphorylation are Linked Via RCAN1 in Alzheimer's Disease

作者：Lloret Ana; Badia Mari Carmen; Giraldo Esther; Ermak Gennady; Alonso Maria Dolores; Pallardo Federico V; Davies Kelvin J A; Vina Jose^*

来源：Journal of Alzheimer's Disease, 2011, 27(4): 701-709.

DOI：10.3233/JAD-2011-110890

• Alzheimer's disease
• amyloid-beta toxicity
• oxidative stress
• RCAN1

Amyloid-beta peptide (A beta) toxicity and tau hyperphosphorylation are hallmarks of Alzheimer's disease (AD). How their molecular relationships may affect the etiology, progression, and severity of the disease, however, has not been elucidated. We now report that incubation of fetal rat cortical neurons with A beta upregulates expression of the Regulator of Calcineurin gene RCAN1, and this is mediated by A beta-induced oxidative stress. Calcineurin (PPP3CA) is a serine-threonine phosphatase that dephosphorylates tau. RCAN1 proteins inhibit this phosphatase activity of calcineurin. Increased expression of RCAN1 also causes upregulation of glycogen synthase kinase-3 beta (GSK3 beta), a tau kinase. Thus, increased RCAN1 expression might be expected to decrease phospho-tau dephosphorylation (via calcineurin inhibition) and increase tau phosphorylation (via increased GSK3 beta activity). Indeed, we find that incubation of primary cortical neurons with A beta results in increased phosphorylation of tau, unless RCAN1 gene expression is silenced, or antioxidants are added. Thus we propose a mechanism to link A beta toxicity and tau hyperphosphorylation in AD: In our hypothesis, A beta causes mitochondrial oxidative stress and increases production of reactive oxygen species, which result in an upregulation of RCAN1 gene expression. RCAN1 proteins then both inhibit calcineurin and induce expression of GSK3 beta. Both mechanisms shift tau to a hyperphosphorylated state. We also find that lymphocytes from persons whose ApoE genotype is epsilon 4/epsilon 4 (with high risk of developing AD) show higher levels of RCAN1 and phospho-tau than those carrying the ApoE epsilon 3/epsilon 3 or epsilon 3/epsilon 4 genotypes. Thus upregulation of RCAN1 may be a valuable biomarker for AD risk.

• 出版日期2011