ER stress is involved in A beta-induced GSK-3 beta activation and tau phosphorylation

作者：Resende Rosa; Ferreiro Elisabete; Pereira Claudia^*; Oliveira Catarina Resende

来源：Journal of Neuroscience Research, 2008, 86(9): 2091-2099.

DOI：10.1002/jnr.21648

• Alzheimer's disease
• A beta oligomers
• tau phosphorylation
• glycogen synthase kinase (GSK-3 beta)
• endoplasmic reticulum

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-3 beta (GSK-3 beta). 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 (A beta) peptide accumulation. The aim of this work was to investigate whether soluble A beta 1-42, 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-3 beta. Several studies suggest that GSK-3 beta plays a central role in signaling the downstream effects of endoplasmic reticulum (ER) stress. Therefore, the involvement of ER Ca2(+) release in GSK-3 beta activation and tau phosphorylation induced by A beta 1-42 oligomers was evaluated using dantrolene, an inhibitor of Ca(2+) release through channels associated with ER ryanodine receptors. We observed that A beta 1-42 oligomers increase tau phosphorylation and compromises cell survival through a mechanism mediated by GSK-3 beta activation. We also demonstrated that oligomeric A beta 1-42 induces ER stress and that ER Ca(2+) release is involved in oligomer-induced GSK-3 beta activation and tau phosphorylation. This work suggests that GSK-3 beta can be a promising target for therapeutic intervention in AD.

• 出版日期2008-7