title: Amyloid-β toxicity and tau hyperphosphorylation are linked via RCAN1 in Alzheimer's disease.
abstract: Amyloid-β peptide (Aβ) 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 Aβ upregulates expression of the Regulator of Calcineurin gene RCAN1, and this is mediated by Aβ-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-3β (GSK3β), a tau kinase. Thus, increased RCAN1 expression might be expected to decrease phospho-tau dephosphorylation (via calcineurin inhibition) and increase tau phosphorylation (via increased GSK3β activity). Indeed, we find that incubation of primary cortical neurons with Aβ results in increased phosphorylation of tau, unless RCAN1 gene expression is silenced, or antioxidants are added. Thus we propose a mechanism to link Aβ toxicity and tau hyperphosphorylation in AD: In our hypothesis, Aβ 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 GSK3β. Both mechanisms shift tau to a hyperphosphorylated state. We also find that lymphocytes from persons whose ApoE genotype is ε4/ε4 (with high risk of developing AD) show higher levels of RCAN1 and phospho-tau than those carrying the ApoE ε3/ε3 or ε3/ε4 genotypes. Thus upregulation of RCAN1 may be a valuable biomarker for AD risk.
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Valencia, INCLIVA, Valencia, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Lloret
authors.forename: Mari-Carmen
authors.initials: MC
authors.lastname: Badia
authors.forename: Esther
authors.initials: E
authors.lastname: Giraldo
authors.forename: Gennady
authors.initials: G
authors.lastname: Ermak
authors.forename: Maria-Dolores
authors.initials: MD
authors.lastname: Alonso
authors.forename: Federico V
authors.initials: FV
authors.lastname: Pallardó
authors.forename: Kelvin J A
authors.initials: KJ
authors.lastname: Davies
authors.forename: Jose
authors.initials: J
authors.lastname: Viña
mesh_terms: D000328:Adult; D000544:Alzheimer Disease / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004268:DNA-Binding Proteins; D004622:Embryo, Mammalian; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D014162:Transfection; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D010446:Peptide Fragments; C108612:RCAN1 protein, human; D034741:RNA, Small Interfering; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D019703:Calcineurin; D005978:Glutathione