Hydromethylthionine rescues synaptic SNARE proteins in a mouse model of tauopathies: Interference by cholinesterase inhibitors

Karima Schwab; Dilyara Lauer; Mandy Magbagbeolu; Franz Theuring; Anna Gasiorowska; Maciej Zadrozny; Charles R Harrington; Claude M Wischik; Grażyna Niewiadomska; Gernot Riedel

doi:10.1016/j.brainresbull.2024.110955

Hydromethylthionine rescues synaptic SNARE proteins in a mouse model of tauopathies: Interference by cholinesterase inhibitors

Brain Res Bull. 2024 Apr 25:212:110955. doi: 10.1016/j.brainresbull.2024.110955. Online ahead of print.

Affiliations

¹ School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK; Institute of Pharmacology, Charité - Universitätsmedizin Berlin, Hessische Str. 3-4, Berlin 10115, Germany.
² Institute of Pharmacology, Charité - Universitätsmedizin Berlin, Hessische Str. 3-4, Berlin 10115, Germany.
³ Clinical and Research Department of Applied Physiology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw 02-106, Poland.
⁴ School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK; TauRx Therapeutics Ltd., 395 King Street, Aberdeen AB24 5RP, UK.
⁵ School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK. Electronic address: g.riedel@abdn.ac.uk.

PMID: 38677558
DOI: 10.1016/j.brainresbull.2024.110955

Abstract

In clinical trials for Alzheimer's disease (AD), hydromethylthionine mesylate (HMTM) showed reduced efficacy when administered as an add-on to symptomatic treatments, while it produced a significant improvement of cognitive function when taken as monotherapy. Interference of cholinesterase inhibition with HMTM was observed also in a tau transgenic mouse model, where rivastigmine reduced the pharmacological activity of HMTM at multiple brain levels including hippocampal acetylcholine release, synaptosomal glutamate release and mitochondrial activity. Here, we examined the effect of HMTM, given alone or in combination with the acetylcholinesterase inhibitor, rivastigmine, at the level of expression of selected pre-synaptic proteins (syntaxin-1; SNAP-25, VAMP-2, synaptophysin-1, synapsin-1, α-synuclein) in brain tissue harvested from tau-transgenic Line 1 (L1) and wild-type mice using immunohistochemistry. L1 mice overexpress the tau-core unit that induces tau aggregation and results in an AD-like phenotype. Synaptic proteins were lower in hippocampus and cortex but greater in basal forebrain regions in L1 compared to wild-type mice. HMTM partially normalised the expression pattern of several of these proteins in basal forebrain. This effect was diminished when HMTM was administered in combination with rivastigmine, where mean protein expression seemed supressed. This was further confirmed by group-based correlation network analyses where important levels of co-expression correlations in basal forebrain regions were lost in L1 mice and partially re-established when HMTM was given alone but not in combination with rivastigmine. These data indicate a reduction in pharmacological activity of HMTM when given as an add-on therapy, a result that is consistent with the responses observed in the clinic. Attenuation of the therapeutic effects of HMTM by cholinergic treatments may have important implications for other potential AD therapies.

Keywords: Alzheimer’s disease; Cholinesterase inhibitors; HMTM; Rivastigmine; Tau protein.