Hyperphosphorylation and polymerization of microtubule-associated protein tau into paired helical filaments (PHFs) is one of the hallmarks of Alzheimer's disease (AD). Here we report that neuronal tau hyperphosphorylation under AD conditions is regulated by S-nitrosoglutathione (GSNO), an endogenous nitric oxide carrier molecule. In cultured rat cortical primary neurons, we observed that GSNO treatment decreased the β-amyloid (Aβ₂₅₋₃₅)-induced pathological tau hyperphosphorylation (Ser396, Ser404, and Ser202/Thr205). The decreased tau hyperphosphorylation correlated with decreased activity of calpain and decreased p35 proteolysis into p25 and Cdk5 activation. GSNO treatment also attenuated the Aβ₂₅₋₃₅-induced activation of GSK-3β which is known to play critical role in tau hyperphosphorylation in addition to Cdk5. Consistent with above studies using cultured neurons, we also observed that systemic GSNO treatment of transgenic mouse model of AD (APPSw/PS1(dE9)) attenuated calpain-mediated p35 proteolysis and Cdk5/GSK-3β activities as well as tau hyperphosphorylation. In addition, GSNO treatment provided neuro- and cognitive protection in APPSw/PS1(dE9) mice. This study describing the GSNO-mediated regulation of tau hyperphosphorylation and cognitive function, for the first time, suggests for therapeutic potential of GSNO as neuro- and cognitive-protective agent for AD.
Keywords: Calpain; Cdk5; GSK-3β; S-nitrosoglutathione; Tau; p25.
Published by Elsevier Inc.