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.

项目概要 阿尔茨海默病 (AD) 是导致痴呆症的主要原因，其特征是记忆力和认知能力丧失 与日常生活。临床研究表明，异常的神经元活动在早期就从过度兴奋转变为 疾病阶段到晚期兴奋性低下是 AD 患者共有的一个关键特征。与此相符， 主要兴奋性神经递质谷氨酸和囊泡谷氨酸转运蛋白 (vGluT1/2) 的水平， 突触小泡摄取谷氨酸的主要介质在 AD 患者晚期减少， 这导致了 AD 痴呆症。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仍然很大程度上未知。我们最近的工作 确定组蛋白 H3K27 去甲基化酶 KDM6B 是突触可塑性的特定表观遗传调节因子， 认知功能。兴奋性神经元中 KDM6B 的条件性敲除减少了突触前小泡 小鼠的数量、脊柱密度和谷氨酸释放/突触活动。此外，KDM6B KO 小鼠显示 行为学习和记忆缺陷。重要的是，KDM6B 表达在老年大脑中减少，而 晚发性 AD 患者大脑中组蛋白 H3 (H3K27me3) 上的三甲基赖氨酸 27 增加， 与他们的认知缺陷高度相关。 Tau 是突触中 KDM6B 招募和调节所必需的 可塑性和认知功能。 Tau 蛋白敲低会干扰突触基因表达。据我们所知， 病理性Tau蛋白常出现在AD中并扰乱其生理功能。这些发现使我们发现 假设 KDM6B-Tau 失调引起的表观遗传改变导致神经元异常 活动转换、认知障碍和 AD 发病机制。该 R01 项目的目标是 1) 破译 病理性 Tau 在 KDM6B 调节的突触活动中的作用以及 2) 确定 KDM6B 失调的影响 AD 小鼠模型中 AD 发病机制的研究。为了确保拟议项目的成功，我们聚集了 强大的研究团队，在 AD 相关神经变性、表观遗传调控和突触方面拥有专业知识 活动。如果成功，该项目将揭示 Tau-KDM6B 依赖性表观遗传启动在 AD 中的重要性 发病机制并定义突触高兴奋性和低兴奋性转换背后的新表观遗传机制 AD 中的认知障碍和认知障碍，可能提供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。