Role of KDM6B in Alzheimer’s disease related dementia

项目总结 阿尔茨海默病(AD)是导致痴呆的主要原因之一，其特征是记忆和认知丧失干扰 与日常生活打交道。临床研究表明，早期异常的神经元活动从过度兴奋状态转变为 疾病的分期到晚期的低兴奋性是AD患者共有的一个关键特征。与此相适应， 主要兴奋性神经递质谷氨酸和囊泡谷氨酸转运体(vGluT1/2)的水平， 突触囊泡摄取谷氨酸的主要介质在AD患者晚期减少， 这导致了老年痴呆症。然而，导致谷氨酸失调的潜在病理， 阿尔茨海默病的异常神经元活动和突触功能障碍在很大程度上仍不清楚。我们最近的工作 组蛋白H3K27去甲基酶KDM6B是突触可塑性的特异性表观遗传调节因子 认知功能。条件性敲除兴奋性神经元中KDM6B基因减少突触前小泡 小鼠的数量、脊柱密度和谷氨酸释放/突触活性。此外，KDM6B KO小鼠表现出 行为学习和记忆缺陷。重要的是，KDM6B在老年脑中的表达减少，而 晚发性AD患者脑内组蛋白H3(H3K27me3)上的三甲基赖氨酸27(H3K27me3)表达增加。 与他们的认知缺陷高度相关。突触中KDM6B的募集和调节需要tau 可塑性和认知功能。Tau基因敲除干扰了突触基因的表达。正如我们所知， 病理性Tau常发生在AD中，扰乱其生理功能。这些发现引导我们 KDM6B-Tau基因异常引起的表观遗传学改变与神经元异常有关 活动转换、认知障碍与AD发病机制。这个R01项目的目标是1)破译 病理性Tau在KDM6B调节突触活性中的作用及2)KDM6B调节失调的影响 阿尔茨海默病小鼠模型的发病机制。为了确保拟议项目的成功，我们召集了 一支在AD相关神经退行性变、表观遗传调节和突触方面拥有专业知识的强大研究团队 活动。如果成功，该项目将揭示依赖Tau-KDM6B的表观遗传启动在AD中的重要性 突触高兴奋性和低兴奋性转换的发病机制和新的表观遗传学机制 和认知功能障碍，这可能提供一个创新的治疗目标和知识基础 制定合理的策略改善AD患者的认知功能。

Project summary Alzheimer's disease (AD) is a leading cause of dementia characterized by memory and cognitive loss interfering with daily life. Clinical studies showed that the aberrant neuronal activity switch from hyperexcitability at the early stage of disease to hypo-excitability at the late stage is a key feature shared in AD patients. In line with this, levels of the principal excitatory neurotransmitter glutamate and vesicular glutamate transporters (vGluT1/2), the primary mediators of glutamate uptake into synaptic vesicles, were decreased at the late stage of AD patients, which contributed to AD dementia. However, the underlying pathology that leads to glutamate misregulation, aberrant neuronal activity and synaptic dysfunction in AD dementia remains largely unknown. Our recent work identified histone H3K27 demethylase KDM6B as a specific epigenetic regulator of synaptic plasticity and cognitive functions. Conditional knockout of KDM6B in the excitatory neurons reduced presynaptic vesicle numbers, spine density and glutamate release/synaptic activity in mice. Moreover, KDM6B KO mice showed behavioral learning and memory deficits. Importantly, KDM6B expression was reduced in aged brain, while trimethyl lysine 27 on histone H3 (H3K27me3) was increased in brain from late-onset AD patients, which were highly correlated with their cognitive deficits. Tau was required for KDM6B recruitment and regulation in synaptic plasticity and cognitive functions. Tau knockdown interfered with synaptic gene expression. As we know, pathological Tau often occurred in AD and perturbed its physiological functions. These findings led us to hypothesize that epigenetic alteration caused by KDM6B-Tau dysregulation contributes to aberrant neuronal activity switch, cognitive impairment and AD pathogenesis. The goals of this R01 project are to 1) decipher the role of pathological Tau in KDM6B-regulated synaptic activity and 2) determine effects of KDM6B dysregulation on AD pathogenesis in AD mouse models. To ensure the success of the proposed project, we have assembled a strong research team with expertise in AD-related neurodegeneration, epigenetic regulation, and synaptic activity. If successful, this project will reveal the importance of Tau-KDM6B-dependent epigenetic priming in AD pathogenesis and define a new epigenetic mechanism underlying synaptic hyper- and hypo-excitability switch and cognitive impairment in AD, which may provide an innovative therapeutic target and a knowledge foundation on development of a rational strategy to improve cognitive functions in AD patients.