Hydrogen sulfide is neuroprotective in Alzheimer's disease by sulfhydrating GSK3β and inhibiting Tau hyperphosphorylation.

Giovinazzo D
Bursac B
Sbodio JI
Nalluru S
Vignane T
Snowman AM
Albacarys LM
Sedlak TW
Torregrossa R
Whiteman M
Filipovic MR
Snyder SH
Paul BD
Scientific 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 (HS) is dysregulated during aging. HS signals via a posttranslational modification termed sulfhydration/persulfidation, which participates in diverse cellular processes. Here we show that cystathionine γ-lyase (CSE), the biosynthetic enzyme for HS, 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 HS prevents hyperphosphorylation of Tau by sulfhydrating its kinase, glycogen synthase kinase 3β (GSK3β). Finally, we demonstrate that sulfhydration is diminished in AD, while administering the HS donor sodium GYY4137 (NaGYY) to 3xTg-AD mice ameliorates motor and cognitive deficits in AD.


2021. Proc Natl Acad Sci U S A, 118(4).

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