Roles of DNA methylation on memory and serotonin neurotransmission in Alzheimer's disease

Abstract

Alzheimer’s disease (AD) is becoming increasingly prevalent as the global population ages. AD is characterized by amyloid-β plaque accumulation and irreversible neuron loss in the brain, which lead to cognitive impairments and affective dysregulations. Despite decades of research, the complex pathogenic mechanisms of AD remain largely elusive. The brain serotonin (5-HT) system has established roles in memory regulation. It has been demonstrated that the brain 5-HT system undergoes structural and functional changes in AD. Transcriptional changes of 5-HT neurotransmission regulating genes in neuropsychiatric diseases were recently shown by several lines of evidence to be regulated by promoter and gene body DNA methylation. These findings agreed with emerging research evidence suggesting that aberrant changes in brain DNA methylation processes are critically involved in gene transcription dysregulations that underly memory impairments in AD. In this thesis, alterations in brain 5-HT neurotransmission in the 5xFAD mouse model of AD were examined. Degeneration of hippocampal 5-HT projection fibers was observed in 5xFAD mice. Notably, hippocampal 5-HT innervation was restored, and DNA methylation status and transcription of 5-HT receptor/transporter genes were modulated by long-term L-methionine (MET) supplementation, a treatment previously proved to be effective in improving memory by reversing hippocampal DNA hypomethylation in 5xFAD mice. The roles of hippocampal DNA methyltransferase 3a (DNMT3a) in mediating the pro-cognitive molecular changes of MET were then examined in 5xFAD mice by hippocampal specific knockdown of DNMT3a. It was shown that DNMT3a is necessary for MET-induced spatial memory enhancement, amyloid-β reduction, microgliosis reduction, and 5-HT fiber preservation in the hippocampus. Whether DNMT3a can modulate these processes independently from MET was further examined by hippocampal specific overexpression or knockdown of DNMT3a. Surprisingly, both manipulations were found to impair spatial memory, and such effects were seen in both wildtype and 5xFAD mice, suggesting that the physiological homeostasis of DNA methylation/demethylation processes is pivotal in normal memory functions. Moreover, overexpression and knockdown of DNMT3a were found to differentially affect amyloid-β deposition, microgliosis, and 5-HT neurotransmission in the hippocampus. Overall, findings in this thesis accentuated the important roles of DNA methylation in memory regulation in AD and established the brain 5-HT system as a viable target of DNA methylation modulating therapeutics for AD.