Role of KDM6B in Alzheimer’s disease related dementia

KDM6B 在阿尔茨海默病相关痴呆中的作用

• 批准号: 10739281
• 负责人: Yingfei Wang
• 金额: $ 74.95万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739281
• 关键词: APP-PS1; Address; Age Months; Aging; Alzheimer associated neurodegeneration; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Animals; Behavioral; Brain; Cell Death; Clinical Research; Cognition; Cognitive deficits; Dementia; Development; Diamond; Disease; Disease Progression; Electrophysiology (science); Ensure; Epigenetic Process; Exhibits; Foundations; Functional disorder; Gene Expression; Genes; Glutamate Transporter; Glutamates; Goals; Heterozygote; Hippocampus; Histone H3; Histones; Human; Impaired cognition; In Vitro; Knockout Mice; Knowledge; Late Onset Alzheimer Disease; Learning; Life; Loss of Heterozygosity; Lysine; Mediator; Memory Loss; Memory impairment; Molecular; Mus; Nerve Degeneration; Neurons; Neurotransmitters; Nuclear Translocation; Pathogenesis; Pathologic; Pathologist; Pathology; Phosphorylation; Physiological; Protein Isoforms; Proteins; Regulation; Research; Role; Site; Synapses; Synaptic Vesicles; Synaptic plasticity; Vertebral column; Vesicle; Work; abeta accumulation; aging brain; cognitive function; conditional knockout; density; effective therapy; epigenetic regulation; excitatory neuron; experience; hyperphosphorylated tau; improved; in vivo; innovation; knock-down; mouse model; neglect; neuron loss; novel; presynaptic; prevent; promoter; recruit; success; tau Proteins; tau aggregation; tau dysfunction; tau interaction; tau-1; therapeutic target; uptake

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.

项目摘要 阿尔茨海默病（Alzheimer's disease，AD）是痴呆的主要原因，其特征在于记忆和认知丧失干扰 与日常生活。临床研究表明，异常神经元活动在早期从过度兴奋转换为异常神经元活动。 从疾病的早期阶段到晚期的低兴奋性是AD患者共有的关键特征。与此相一致， 水平的主要兴奋性神经递质谷氨酸和囊泡谷氨酸转运蛋白（vGluT 1/2）， 谷氨酸摄取进入突触囊泡的主要介质，在AD患者的晚期减少， 导致了AD痴呆然而，导致谷氨酸失调的潜在病理学， AD痴呆中的异常神经元活动和突触功能障碍在很大程度上仍是未知的。我们最近的工作 确定组蛋白H3 K27去甲基化酶KDM 6 B为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KDM 6 B减少突触前囊泡 数目、棘密度和谷氨酸释放/突触活性。此外，KDM 6 B KO小鼠显示， 行为学习和记忆缺陷。重要的是，KDM 6 B表达在老年脑中减少， 组蛋白H3上的三甲基赖氨酸27（H3 K27 me 3）在迟发性AD患者的脑中增加， 与他们的认知缺陷高度相关。Tau蛋白是突触后KDM 6 B募集和调节所必需的。 可塑性和认知功能。Tau基因敲低干扰突触基因表达。我们知道， 病理性Tau常发生在AD中，并干扰其生理功能。这些发现使我们 假设由KDM 6 B-Tau失调引起表观遗传改变有助于异常神经元 活动转换、认知功能障碍和AD发病机制。这个R 01项目的目标是：1）破译 病理性Tau在KDM 6 B调节的突触活性中的作用和2）确定KDM 6 B失调的作用 在AD小鼠模型中的AD发病机制。为了确保项目的成功，我们组织了 一个强大的研究团队，在AD相关的神经变性，表观遗传调控和突触 活动如果成功，该项目将揭示Tau-KDM 6 B依赖的表观遗传启动在AD中的重要性 发病机制和定义一个新的后生机制突触高和低兴奋性开关 和认知功能障碍，这可能会提供一个创新的治疗目标和知识基础 制定合理的策略来改善AD患者的认知功能。