title: Role of S-nitrosoglutathione mediated mechanisms in tau hyper-phosphorylation.
abstract: 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.
authors: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA.
authors: Balasubramaniam
authors: B
authors: Annamalai
authors: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA.
authors: Je-Seong
authors: JS
authors: Won
authors: Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA.
authors: Seungho
authors: S
authors: Choi
authors: Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA.
authors: Inderjit
authors: I
authors: Singh
authors: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA; Department of Pathology and Laboratory Medicine Service, Ralph H. Johnson Veterans Administration Medical Center, Charleston, SC, USA. Electronic address: avtar.singh@va.gov.
authors: Avtar K
authors: AK
authors: Singh
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D002154:Calpain / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D018782:Maze Learning; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation; D017207:Rats, Sprague-Dawley; D026422:S-Nitrosoglutathione / Q000378:metabolism* / Q000494:pharmacology; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); C089495:neuronal Cdk5 activator (p25-p35); D016875:tau Proteins; D026422:S-Nitrosoglutathione; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D002154:Calpain
keywords: Calpain; Cdk5; GSK-3β; S-nitrosoglutathione; Tau; p25
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