Supporting data for 'Neuroplasticity and DNA methylation-related mechanism of L-methionine in cognition '

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.

近期研究揭示了DNA甲基化动态特性在记忆形成与维持中的重要性。蛋氨酸作为一碳代谢的必需成分，在基因与环境相互作用中发挥着关键作用。一碳代谢的破坏与多种神经退行性疾病的病理生理学相关，例如与年龄相关的痴呆症和阿尔茨海默病（AD），其中记忆丧失是其核心症状。在本论文中，我系统地回顾了文献中报道的AD病理生理学中的神经表观遗传学改变，旨在描绘出导致认知障碍的潜在分子缺陷。随后，我考察了AD中改变的DNA甲基化对参与记忆形成的神经化学途径组成部分的影响。我进一步展示了延长L-蛋氨酸（MET）治疗能够通过恢复5xFAD转基因小鼠中的MeCP2-CREB-BDNF和CaN-Akt-GSK3β级联反应来挽救记忆缺陷并减轻淀粉样蛋白负荷。在发现MET能够有效正常化AD动物模型中某些DNA甲基化机制之后，我研究了神经调节技术对依赖于神经元活动的某些DNA甲基化机制的影响，并提出了这些机制作为可能的记忆调节靶点。接着，我将前一章中确定的MET对AD的影响扩展到老年动物，作为一种与颞前皮层深部脑刺激（PrL DBS）相结合的治疗范式。我表明，尽管MET单独对老年动物没有行为效应，但它增强了PrL DBS的记忆增强效果。MET能够挽救老年动物中观察到的全局DNA低甲基化，并协同PrL DBS诱导表达与可塑性相关的基因和蛋白。随后，我展示了特异性抑制海马DNMT能够消除PrL DBS的记忆增强效果，确立了DNMT在介导PrL DBS对认知影响中的重要作用。最后，我提出了Bdnf基因的表观遗传调控作为记忆消除的关键，以及BDNF调控作为缓解抑郁和与恐惧相关的焦虑障碍的潜在靶点。总体而言，我的论文提供了证据，证明了DNA甲基化在记忆障碍中的重要作用，以及MET作为AD和痴呆症的有效治疗手段。