The neuroprotective role of Hydrogen Sulfide in Alzheimer’s disease

Alzheimer’s disease (AD), a neurodegenerative disease, is a leading cause of dementia. AD is characterised by microtubule-associated protein Tau hyperphosphorylation and β-amyloid peptides aggregates, which ultimately leads to the development of neurofibrillary tangles (NFTs) and amyloid (Aβ) plaques respectively (1). Approximately 26.6 million people globally suffered from AD in 2006, and this number is projected to quadruple by 2050! AD is usually found in people over the age of 65 years ; however, familial/genetic AD can have an earlier onset but is less prevalent (2). In the United States, 1 in every 9 people over the age of 65 is suffering from AD , among which ⅔ are women. Further, it has been estimated that 1 in 3 over the age of 65 will die due to AD and at present AD is incurable (3) . Therefore, research  focused on identifying pharmacological solutions for AD treatment is extremely important. 

Hydrogen sulfide (H2S) is one of the three endogenous signaling gasotransmitter molecules and has been under investigation as having potential therapeutic effects for AD. H2S is synthesized by cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST) during the metabolism of dietary amino acid methionine and cysteine (4). H2S plays a critical role in hippocampal memory formation, inflammation, vasorelaxation, and angiogenesis (5). Several studies show that H2S slows down the progression of AD by targeting multiple pathophysiological mechanisms. 

Pretreatment with Sodium hydrosulfide (NaHS), an H2S donor, improved learning and memory deficits in β-amyloid induced Alzheimer rat model, hinting at its potential to improve memory in AD patients. Further, NaHS reduced apoptosis, IL-1β and TNF-α levels, astrogliosis, and microgliosis in the hippocampus of AD rats in this study, in part by inhibiting the activity of p38 MAPK and p65 NF-κB (6). Another study using H2S donors and Tabiano’s spa-waters rich in H2S projected a multi-factorial beneficial role of H2S in slowing down AD progression (2). Treatment with H2S donors/spa water decreased Aβ plaques, inflammation, apoptosis, excitotoxicity-triggered oxidative and nitrosative stress, expression of the amyloid precursor protein, presenilin-1, and tau phosphorylation (at Thr181, Ser396, and Ser202) in the hippocampus of triple transgenic (3xTg-AD) mice (2). Furthermore, researchers observed a reduction in the activity of N-terminal kinases, extracellular signal-regulated kinases, and p38, which are involved in tau phosphorylation and apoptosis (2). Giovinazzo et al. showed that H2S induces sulfhydration of glycogen synthase kinase 3β, kinase for tau protein, and prevents hyperphosphorylation of Tau. Both CSE expressions, the biosynthetic enzyme for H2S, and sulfhydration are diminished in 3xTg-AD mice (1). In addition,  sodium GYY413 (NaGYY), a slow releasing H2S donor, improved motor and cognitive deficits in AD mice (1). H2S also downregulates  BACE1 and gamma-secretase (presenilin-1), protease required to produce β-amyloid peptides from amyloid precursor protein (APP) (7). In addition, H2S defies the microglial polarization to the M1 phenotype, which is proinflammatory and plays a vital role in the pathogenesis of AD (7). The physiological concentration of H2S promotes long-term potentiation of the hippocampus by enhancing NMDA receptor-mediated response, thereby improving learning and memory function (5). Since learning and memory function decline with AD, the above evidence reveals that H2S could potentially treat these symptoms of AD.

There is a consensus that H2S is dysregulated in AD and related dementia and, therefore, can be a potential biomarker for the diagnosis and intervention. Total plasma sulfide has been shown to be the strongest indicator of Alzheimer’s disease and related dementia (ADRD) (8). However, there are conflicting results whether H2S levels are upregulated and downregulated, but increasing or decreasing H2S levels is pathological (8). Previous studies report a decrease in H2S levels in the AD brain (2,5) and a negative correlation between plasma levels of HS and severity of AD (2,9). However, Disbrow et al. observed an increase in total H2S and specific metabolites levels in the plasma of ADRD patients (8). The discrepancies in findings can result from variation in the population used for study and methods employed to measure H2S. 

The strategies that can boost either the synthesis or levels of H2S in the brain hold therapeutic potential in AD. CSB, one of the main enzymes in the synthesis of H2S, uses cysteine as its rate-limiting substrate and gets allosterically activated by S-adenosylmethionine (SAM) (7). Supplemental taurine, an amino sulfonic acid, increased the expression of both CSB and CSE in vascular tissues and augmented the plasma levels of H2S (7). The global decrease in DNA methylation on the frontal cortex and hippocampus and decreased promoter methylation of the APP, BACE-1, and presenilin-1 genes are classic characteristics of AD. Therefore, in addition to the administration of cysteine and taurine, which directly increase the production of H2S, other agents including SAM, folate, vitamin B12, and betaine can boost the presence of methyl groups in the brain and can aid in AD prevention(7). 

Based on the evidence at hand, it is convincing that several agents linked to H2S production exhibit neuroprotective utility; however, further rodent studies are required to confirm the benefits of these dietary supplements in AD. 

1. Giovinazzo D, Bursac B, Sbodio JI, et al. Hydrogen sulfide is neuroprotective in Alzheimer’s disease by sulfhydrating GSK3β and inhibiting Tau hyperphosphorylation. Proc Natl Acad Sci U S A. Jan 2021;118(4)doi:10.1073/pnas.2017225118
2. Giuliani D, Ottani A, Zaffe D, et al. Hydrogen sulfide slows down progression of experimental Alzheimer’s disease by targeting multiple pathophysiological mechanisms. Neurobiol Learn Mem. Sep 2013;104:82-91. doi:10.1016/j.nlm.2013.05.006
3. Accessed May 12, 2021. https://www.alzheimersresearchfoundation.com
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5. Kamat PK, Kyles P, Kalani A, Tyagi N. Hydrogen Sulfide Ameliorates Homocysteine-Induced Alzheimer’s Disease-Like Pathology, Blood-Brain Barrier Disruption, and Synaptic Disorder. Mol Neurobiol. May 2016;53(4):2451-2467. doi:10.1007/s12035-015-9212-4
6. Xuan A, Long D, Li J, et al. Hydrogen sulfide attenuates spatial memory impairment and hippocampal neuroinflammation in β-amyloid rat model of Alzheimer’s disease. J Neuroinflammation. Aug 2012;9:202. doi:10.1186/1742-2094-9-202
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8. Disbrow E, Stokes KY, Ledbetter C, et al. Plasma hydrogen sulfide: A biomarker of Alzheimer’s disease and related dementias. Alzheimers Dement. Mar 2021;doi:10.1002/alz.12305
9. Liu XQ, Jiang P, Huang H, Yan Y. [Plasma levels of endogenous hydrogen sulfide and homocysteine in patients with Alzheimer’s disease and vascular dementia and the significance thereof]. Zhonghua Yi Xue Za Zhi. Aug 2008;88(32):2246-9.