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P1‐340: Methylglyoxal facilitates tau hyperphosphorylation and memory impairment in rat
Author(s) -
Zhou Xin-Wen,
Li Xiao-Hong,
Lv Bin-Ling,
Xie Jia-Zhao
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.893
Subject(s) - hyperphosphorylation , glycation , pathogenesis , oxidative stress , hippocampus , medicine , axon , morris water navigation task , endocrinology , western blot , tau protein , chemistry , phosphorylation , population , alzheimer's disease , neuroscience , biology , biochemistry , disease , receptor , environmental health , gene
of lewy bodies and the major contributor of PD. Recent genetic studies have demonstrated that microtubule-associated protein tau (MAPT) is a risk factor for PD. Methods: In this study, we show that when human neuroblastoma M17 cells are treated with PD-inducing toxin MPTP, the level of intracellular alpha synuclein protein increases in a dose-dependent manner. Results: Increased alpha synuclein level promotes tau phosphorylation at Ser-214 and Ser-262 by cAMP-protein kinase (PKA) and destabilizes microtubules. In vitro, alpha synucelin binds to Ser-214 phosphorylated tau and promotes PKA-catalyzed tau phosphorylation at Ser-262. PD-associated alpha synuclein mutation: A30P, A53T and E46K all promote the association of alpha synuclein with tau and increase tau phosphorylation at Ser262. Conclusions: Our data indicate that alpha synuclein binds to phosphorylated Ser-214 of tau and causes a conformational change allowing PKA to phosphorylate Ser-262. Phosphorylation at Ser-262 then inhibits tau binding to microtubules and destabilizes microtubule cytoskeleton leading to neuronal degeneration.