Introduction: Methylamines (MAs) are important brain metabolites that are known to exhibit neuroprotective effects. However, their role in the cholinergic system has not been well explored. In the present study, we investigated the effect of 4 MAs (sarcosine; dimethylglycine, DMG; betaine; and trimethylamine N-oxide, TMAO) on the structure and function integrity of acetylcholinesterase (AChE), an important enzyme in the cholinergic system responsible for the hydrolysis of the neurotransmitter acetylcholine (ACh) to choline and acetate.

Methods: The findings were generated from the systematic functional activity assay of AChE in the presence of MAs and further characterization using in silico, biophysical, and cellular approaches.

Results: We discovered that betaine and DMG are competitive inhibitors of AChE and could also reverse the cytotoxic effect of Aβ in cells, which is a key characteristic of AChE inhibitors. We also observed that betaine and DMG enhance the efficacy of donepezil, rivastigmine, and galantamine which are currently used drugs for the treatment of dementia.

Conclusions: As Betaine and DMG are FDA-approved supplements, the results implicate that they could be employed independently for the treatment of dementia. The use of AChE inhibitors is not sufficient to control different symptoms of dementia as the pathophysiology of dementia is multifactorial. Therefore, the use of a combinatorial therapy of AChE inhibitors and Betaine/DMG mixtures represents a newer approach.