Neuroplasticity and DNA methylation-related mechanism of L-methionine in cognition

Abstract

Recent studies have shed light on the importance of the dynamic property of DNA methylation in memory formation and maintenance. Methionine is an essential component in one-carbon metabolism, which plays a pivotal role in gene-environment interaction. The disruption of the one-carbon metabolism is implicated in the pathophysiology of various neurodegenerative disorders, for instance age-related dementia and Alzheimer’s disease (AD), in which memory loss is manifested as the core symptom.

In this thesis, I systematically reviewed the neuroepigenetic alterations involved in the pathophysiology of AD seen in literature as an attempt to delineate potential molecular deficits contributing to cognitive impairment. The influence of altered DNA methylation in AD on components involved in neurochemical pathways on memory formation was then examined. I then showed that protracted L-methionine (MET) treatment rescued memory deficits and attenuated amyloid burden through restoring MeCP2-CREB-BDNF and CaN-Akt-GSK3β cascades in 5xFAD transgenic mice. Following the findings that MET effectively normalized certain DNA methylation machinery in AD animal model, I investigated the effect of neuromodulation techniques on certain DNA methylation mechanisms that depend on neuronal activity, and made the case for the said mechanisms as possible memory modulation targets. I then extended the effects of MET on AD identified in the previous chapter to aged animals as a combined treatment paradigm with prelimbic cortical deep brain stimulation (PrL DBS). I showed that while MET alone had no behavioral effect on aged animals, it potentiated the memory-enhancing effect of PrL DBS. MET was able to rescue the global DNA hypomethylation observed in aged animals, and induce expression of plasticity-related genes and proteins in a synergistic manner with PrL DBS. I then showed that inhibition of DNMT in the hippocampus specifically abolished the memory-enhancing effect of PrL DBS, established the integral role of DNMT in mediating the effect of PrL DBS on cognition. Lastly, I proposed the epigenetic regulations of Bdnf gene as the key to memory extinction and BDNF modulation as a potential target for alleviating depression and fear-related anxiety disorders. Overall, my thesis presents evidence demonstrating the important role of DNA methylation in memory disorders and MET as a viable therapeutic in AD and dementia.