Hydrogen sulfide modulation of the K+ channel Kv2.1: A new signalling pathway to target in the treatment of Alzheimer’s disease

Numerous reports implicate hydrogen sulfide (H2S) as an important factor in Alzheimer’s disease (AD). Thus, for example, levels of the CBS activator, S-adenosylmethionine are reduced in AD patients, and plasma H2S levels are reported to be reduced in AD patients, whilst homocysteine levels (from which H2S is derived) are elevated. H2S has been shown to reduce BACE-1 expression (one of the enzymes required for amyloid peptide (Ab formation) and secretion of the neurotoxic Ab(1-42) in vitro. Furthermore, H2S has anti-inflammatory and anti-apoptotic activity in the CNS which can improve cognitive function in mild cognitive impairment, promotes induction of long-term potentiation and protects neurones against oxidative stress; thus it has great potential to protect against AD via multiple means, and new evidence is emerging that this is the case, both biochemically and in behavioural murine tests.

Oxidative damage of lipids and proteins is a hallmark feature of the early stages of AD. One key protein known to undergo oxidation is the K+ channel Kv2.1, resulting in increased vulnerability to apoptosis in a number of cell types, including hippocampal neurones. We have discovered that H2S, now accepted as a biological signalling molecule of widespread importance, directly modulates Kv2.1 activity and protects against apoptosis. In this study, we will establish the neuroprotective effects of H2S - acting via modulation of Kv2.1 – against the oxidative stress of AD. Our results will determine whether H2S has potential as a novel therapeutic approach in the treatment of AD, as it does for several other disorders.

Our new findings, taken together with the known vulnerability of Kv2.1 to deleterious oxidative modulation associated with AD, lead us to propose the hypothesis that regulation of neuronal Kv2.1 channels by H2S will provide protection against oxidative stress, and thereby provide a novel mechanism through which neurones can be protected in AD. To address this hypothesis, we will use a combination of patch-clamp electrophysiology, cell and molecular biology and in vivo behavioural tests to determine (i) the mechanism(s) underlying this action of H2S on Kv2.1 in neurones; (ii) the consequences of such regulation for neuronal survival following exposure to Ab (iii) whether H2S production is compromised in brain tissue from AD patients and in an in vivo model of AD; and (iv) determine whether endogenous or exogenous H2S can improve neuronal survival and memory performance in an in vivo model of AD. The project will also be supervised by Dr J Scragg. Given the current widespread interest in the development of H2S and H2S-donor compounds (as well as the discovery of H2S as a component of beneficial dietary factors) as a therapy for numerous diverse conditions, our study is particularly timely in establishing whether (and how) AD can also benefit from this emerging gasotransmitter.