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

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 (H2S) is dysregulated during aging. H2S 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 H2S, 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 H2S 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 H2S donor sodium GYY4137 (NaGYY) to 3xTg-AD mice ameliorates motor and cognitive deficits in AD.

Hydrogen Sulfide Metabolite, Sodium Thiosulfate: Clinical Applications and Underlying Molecular Mechanisms

“…Many of the biochemical characteristics of H 2 S signaling that provide cytoprotective effects, such as persulfidation of signaling proteins, can be accomplished with thiosulfate instead. For example, a study by Giovinazzo et al [ 99 ] showed that H 2 S donor molecule GYY4137 inhibits Tau hyperphosphorylation by persulfidation of kinase GSK3β, ultimately ameliorating cognitive and motor deficits in Alzheimer’s disease. STS, as we previously mentioned, has been shown to trigger persulfidation reactions in the sulfur oxidation pathway [ 37 ] and in the Nrf2 signaling pathway [ 95 ].…”

The Role of Protein Persulfidation in Brain Aging and Neurodegeneration

“…A common characteristic reported in the literature, found in even unrelated ND, is the loss/decrease of CSE which has been observed in human samples of Parkinson's, Huntington's, Alzheimer, and spinocerebellar ataxia 3 diseases, as well as in corresponding animal disease models (Vandiver et al, 2013 ; Paul et al, 2014 ; Snijder et al, 2015 ; Giovinazzo et al, 2021 ). A global decrease of protein persulfidation has also been observed for the latter three diseases (Snijder et al, 2015 ; Zivanovic et al, 2019 ; Giovinazzo et al, 2021 ).…”

“…A common characteristic reported in the literature, found in even unrelated ND, is the loss/decrease of CSE which has been observed in human samples of Parkinson's, Huntington's, Alzheimer, and spinocerebellar ataxia 3 diseases, as well as in corresponding animal disease models (Vandiver et al, 2013 ; Paul et al, 2014 ; Snijder et al, 2015 ; Giovinazzo et al, 2021 ). A global decrease of protein persulfidation has also been observed for the latter three diseases (Snijder et al, 2015 ; Zivanovic et al, 2019 ; Giovinazzo et al, 2021 ). Besides a general protection, persulfidation could also represent a redox switch mechanism by which protein structure and/or function might be affected, and the search of these particular targets may pave the way to more targeted drug design toward ND therapeutics.…”

“…at C218, resulting in the loss of the enzyme's activity and diminishing tau phosphorylation (Giovinazzo et al, 2021). A decrease of CSE levels in aging brain and consequently the decrease of GSK3β persulfidation will result in an accumulation of phosphorylated tau and tau aggregation (Figure 5B).…”

“…The use of water-soluble sodium salt of GYY4137 improved motor and cognitive deficits in AD mouse model (Giovinazzo et al, 2021), while administration of NaHS once a day for 3 months ameliorated memory deficits in another study (Liu et al, 2016). However, most of the studies done to date use inorganic sulfide salts as a source of H 2 S and although they are good for proof-of-concept observation there is a need for a development of real H 2 S-releasing therapeutics.…”