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

总结 神经退行性疾病，包括阿尔茨海默病（AD）和额颞叶痴呆 (FTD)正在折磨着大量的老年人微管相关基因突变 导致微管分解和神经元变性的tau蛋白（MAPT）基因， 与AD和FTD的发病机制有关，然而， 疾病仍然缺乏。新出现的证据表明，表观遗传失调， 诱导基因表达病理改变，在衰老中起关键作用， 神经变性使用AD患者和携带AD基因的转基因小鼠的死后组织 与FTD和AD相关的突变型人Tau蛋白，我们发现组蛋白3 与基因激活相关的赖氨酸4（H3 K4 me 3）的三甲基化显著升高 在前额叶皮层（PFC），一个关键的认知区域受损的AD和FTD。更重要的是， 我们已经发现，抑制H3 K4特异性甲基转移酶导致了 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。基于这些有趣的结果，我们建议进一步 揭示H3 K4 me 3在AD病理生理学和治疗中的作用。结合分子， 生物化学、电生理学、行为学和基因组学方法将用于识别 AD人脑和Tau AD模型中的异常H3 K4甲基化（目的1）; 靶向H3 K4特异性甲基转移酶对突触和认知缺陷的拯救作用 在Tau AD模型中（目的2）;揭示作为Tau AD治疗作用基础的分子机制。 靶向Tau AD模型中的H3 K4特异性甲基转移酶。本项目取得的成果 将有助于确定AD和相关神经退行性疾病的新治疗策略 与tau蛋白病有关

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.