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 阿尔茨海默氏病（AD）是痴呆症的主要原因，其特征是记忆和认知损失干扰 与日常生活。临床研究表明，异常的神经元活性从早期的过度兴奋性转变 在后期疾病到疾病的疾病阶段是AD患者共有的关键特征。因此， 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， 在AD患者的后期，谷氨酸摄取对突触囊泡的主要介体降低， 这导致了痴呆症。然而，导致谷氨酸不调节的潜在病理， AD痴呆症中异常的神经元活性和突触功能障碍在很大程度上未知。我们最近的工作 确定组蛋白H3K27脱甲基酶KDM6B是突触可塑性的特定表观遗传调节剂 认知功能。兴奋性神经元中KDM6B的有条件敲除减少了突触前囊泡 小鼠的数量，脊柱密度和谷氨酸释放/突触活性。此外，KDM6B KO小鼠显示 行为学习和记忆缺陷。重要的是，在老年大脑中降低了KDM6B的表达，而 组蛋白H3上的三甲基赖氨酸27（H3K27ME3）在较晚发作的AD患者中增加了大脑 与他们的认知缺陷高度相关。 tau是KDM6B招募和突触中的调节所必需的 可塑性和认知功能。 tau敲低干扰了突触基因表达。如我们所知， 病理tau通常发生在AD中，并扰动其生理功能。这些发现导致我们 假设由KDM6B-TAU失调引起的表观遗传改变会导致异常神经元 活性转换，认知障碍和AD发病机理。该R01项目的目标是1）解读 病理tau在KDM6B调节的突触活动中的作用和2）确定KDM6B失调的影响 关于AD小鼠模型中的AD发病机理。为了确保拟议项目的成功，我们已经组装了 一个具有广告相关神经变性，表观遗传调节和突触的专业知识的强大研究团队 活动。如果成功，该项目将揭示tau-kdm6b依赖性表观遗传启动的重要性 发病机理并定义了突触超高和低兴趣开关的新的表观遗传机制 AD中的认知障碍，这可能提供创新的治疗目标和知识基础 关于改善AD患者认知功能的合理策略的制定。