ER stress is involved in Aβ-induced GSK-3β activation and tau phosphorylation

✍ Scribed by Rosa Resende; Elisabete Ferreiro; Cláudia Pereira; Catarina Resende Oliveira

• Publisher: John Wiley and Sons
• Year: 2008
• Tongue: English
• Weight: 406 KB
• Volume: 86
• Category: Article
• ISSN: 0360-4012
• DOI: 10.1002/jnr.21648

✦ Synopsis

Abstract

Intracellular neurofibrillary tangles, one of the characteristic hallmarks of Alzheimer's disease (AD), are mainly composed of hyperphosphorylated tau. The abnormal tau phosphorylation seems to be related to altered activity of kinases such as glycogen synthase kinase‐3β (GSK‐3β). Tau pathology is thought to be a later event during the progression of the disease, and it seems to occur as a consequence of amyloid‐beta (Aβ) peptide accumulation. The aim of this work was to investigate whether soluble Aβ1–42, particularly oligomers that correspond to the neurotoxic species involved early in the development of AD, triggers tau phosphorylation by a mechanism involving activation of tau‐kinase GSK‐3β. Several studies suggest that GSK‐3β plays a central role in signaling the downstream effects of endoplasmic reticulum (ER) stress. Therefore, the involvement of ER Ca^2+^ release in GSK‐3β activation and tau phosphorylation induced by Aβ1–42 oligomers was evaluated using dantrolene, an inhibitor of Ca^2+^ release through channels associated with ER ryanodine receptors. We observed that Aβ1–42 oligomers increase tau phosphorylation and compromises cell survival through a mechanism mediated by GSK‐3β activation. We also demonstrated that oligomeric Aβ1–42 induces ER stress and that ER Ca^2+^ release is involved in oligomer‐induced GSK‐3β activation and tau phosphorylation. This work suggests that GSK‐3β can be a promising target for therapeutic intervention in AD. © 2008 Wiley‐Liss, Inc.