Hydrogen sulfide is neuroprotective in Alzheimer's disease by sulfhydrating GSK3[beta] and inhibiting Tau hyperphosphorylation

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Publisher: National Academy of Sciences
Document Type: Report
Length: 6,849 words
Lexile Measure: 1380L

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Abstract :

Alzheimer's disease (AD), the most common cause of dementia and neurodegeneration in the elderly, is characterized by deterioration of memory and executive and motor functions. Neuropathologic hallmarks of AD include neurofibrillary tangles (NFTs), paired helical filaments, and amyloid plaques. Mutations in the microtubule-associated protein Tau, a major component of the NFTs, cause its hyperphosphorylation in AD. We have shown that signaling by the gaseous molecule hydrogen sulfide ([H.sub.2]S) is dysregulated during aging. [H.sub.2]S signals via a posttranslational modimodification termed sulfhydration/persulfidation, which participates in diverse cellular processes. Here we show that cystathionine [gamma]-lyase (CSE), the biosynthetic enzyme for [H.sub.2]S, binds wild type Tau, which enhances its catalytic activity. By contrast, CSE fails to bind Tau P301L, a mutant that is present in the 3xTg-AD mouse model of AD. We further show that CSE is depleted in 3xTg-AD mice as well as in human AD brains, and that [H.sub.2]S prevents hyperphosphorylation of Tau by sulfhydrating its kinase, glycogen synthase kinase 3[beta] (GSK3[beta]). Finally, we demonstrate that sulfhydration is diminished in AD, while administering the [H.sub.2]S donor sodium GYY4137 (NaGYY) to 3xTg-AD mice ameliorates motor and cognitive deficits in AD. Alzheimer's disease | Tau | sulfhydration | GSK3beta | hydrogen sulfide

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Gale Document Number: GALE|A649927424