Targeting Histone K4 Methylation for Treatment of Alzheimer's Disease and Related Dementia

摘要 神经退行性疾病包括阿尔茨海默病(AD)和额颞部痴呆 (FTD)正在困扰着大量的老年人。微管相关基因突变 导致微管解体和神经元变性的蛋白tau(MAPT)基因 与AD和FTD的发病机制有关，但对这些疾病的有效治疗 疾病仍然缺乏。新出现的证据表明，表观遗传失调，可以 诱导基因表达的病理改变，在衰老和衰老中起关键作用 神经退行性变。利用AD患者的死后组织和携带 突变的人Tau蛋白与FTD和AD相关，我们发现组蛋白3 与基因激活有关的赖氨酸4(H3K4me3)的三甲基化显著增加 在前额叶皮质(PFC)，AD和FTD受损的关键认知区。更重要的是， 我们发现，抑制H3K4特异性甲基转移酶可导致实质上的恢复 PFC锥体神经元的突触功能，以及记忆的显著改善- Tau AD模型中的相关行为。基于这些耐人寻味的结果，我们建议进一步 揭示H3K4me3在AD病理生理和治疗中的作用。结合分子， 将使用生化、电生理、行为和基因组方法来识别 AD人脑和Tau AD模型中H3K4异常甲基化(目标1)； 靶向H3K4特异性甲基转移酶对突触和认知功能障碍的挽救作用 在Tau AD模型(Aim 2)中，揭示其治疗作用的分子机制 在Tau AD模型中靶向H3K4特异性甲基转移酶。从这个项目中获得的成果 将有助于确定AD和相关神经退行性疾病的新治疗策略 与紧张症相关的。

Summary Neurodegenerative disorders including Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are afflicting a large number of aging people. Mutations in the microtubule-associated protein tau (MAPT) gene that lead to microtubule disassembly and neuronal degeneration have been implicated in the pathogenesis of AD and FTD, however effective treatment for these diseases is still lacking. Emerging evidence suggests that epigenetic dysregulation, which can induce pathological alteration of gene expression, plays a key role in aging and neurodegeneration. Using postmortem tissues from AD patients and transgenic mice carrying mutant human Tau protein associated with FTD and AD, we have found that histone 3 trimethylation at lysine 4 (H3K4me3), which is linked to gene activation, is significantly elevated in the prefrontal cortex (PFC), a key cognitive region impaired in AD and FTD. More importantly, we have found that inhibiting H3K4-specific methyltransferases leads to the substantial recovery of synaptic function in PFC pyramidal neurons, and the significant improvement of memory- related behaviors in Tau AD model. Based on these intriguing results, we propose to further reveal the role of H3K4me3 in AD pathophysiology and treatment. Combined molecular, biochemical, electrophysiological, behavioral, and genomic approaches will be used to identify aberrant H3K4 methylation in AD human brains and Tau AD model (Aim 1); to examine the rescue effects of targeting H3K4-specific methyltransferases on synaptic and cognitive deficits in Tau AD model (Aim 2); to reveal molecular mechanisms underlying the therapeutic effects of targeting H3K4-specific methyltransferases in Tau AD model. Results gained from this project will help to identify a novel therapeutic strategy for AD and related neurodegenerative disorders associated with tauopathies.