Neuronal HDAC9, Synaptic Plasticity and Alzheimer's Disease

神经元 HDAC9、突触可塑性和阿尔茨海默病

• 批准号: 10554326
• 负责人: Xin-Yun Lu
• 金额: $ 56.76万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10554326
• 关键词: APP-PS1; Acceleration; Accounting; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-Protein; Amyloid deposition; Automobile Driving; Binding; Brain; Brain region; Brain-Derived Neurotrophic Factor; Cells; Cerebral cortex; Cognition; Cognitive; Cognitive deficits; Complex; Data; Dementia; Development; Disease Progression; Down-Regulation; EZH2 gene; Epigenetic Process; Exhibits; Functional disorder; Future; Genes; Glutamates; HDAC9 gene; Hippocampus; Histone Deacetylase; Impaired cognition; Impairment; Knockout Mice; Learning; Link; Mediating; Mediator; Memory; Memory Loss; Memory impairment; Modification; Molecular; Mus; Nerve Degeneration; Nerve Growth Factors; Neurodegenerative Disorders; Neurons; Neuropeptides; Neurotrophin 3; Pathology; Peripheral; Play; Polycomb; Prefrontal Cortex; Process; Protein Isoforms; Reporting; Role; Synapses; Synaptic plasticity; Testing; Therapeutic Intervention; Tissues; Wild Type Mouse; Zinc; age effect; age related neurodegeneration; aging brain; base; candidate identification; cognitive enhancement; cognitive function; histone methyltransferase; improved; insight; mouse model; myocyte-specific enhancer-binding-factor 2C; neuronal pentraxin; neuropathology; neurotransmission; overexpression; pathological aging; pharmacologic; pre-clinical; promoter; recruit; tau Proteins; transcription factor; transcriptome sequencing

PROJECT SUMMARY Alzheimer’s disease (AD) is an age-related neurodegenerative disorder that causes memory loss and cognitive decline. Synaptic dysfunction and loss correlates strongly with cognitive impairment in AD. Aging is the leading risk factor for AD, and epigenetic mechanisms involving histone deacetylases (HDACs) play an important role in aging and age-related neurodegenerative disorders. Among the 11 zinc-dependent HDACs, HDAC9 is the most abundant isoform in the brain, found exclusively in neurons. We provide key preliminary data showing that HDAC9 expression in the hippocampus and prefrontal cortex (PFC) diminishes with aging in wild-type mice, and that reduced HDAC9 expression precedes the onset of amyloid deposition in the APP/PS1 mouse model of AD. Consistent with these preclinical findings, AD patients exhibited decreased HDAC9 expression in the dorsolateral PFC. Moreover, global or hippocampal CA1-specific deletion of HDAC9 induces cognitive impairment and impairs synaptic plasticity, while HDAC9 overexpression produces cognitive-enhancing effects. We hypothesize that reduced neuronal HDAC9 mediates cognitive decline, synaptic dysfunction and other neuropathologies associated with brain aging and AD. To test this hypothesis, we propose three specific aims. In Aim 1, we will test the hypothesis that loss of HDAC9 in hippocampal and PFC neurons mediates age- and AD-related neuropathology and cognitive impairment. In Aim 2, we will test the hypothesis that the histone methyltransferase EZH2 [the catalytic component of the polycomb repressive complex 2 (PRC2), which catalyzes repressive H3K27me3 modifications at gene promoters] epigenetically silences HDAC9 expression in the hippocampus and PFC during aging and in AD. In Aim 3, we will test the hypothesis that neuronal pentraxin 2 (NP2), nerve growth factor inducible (VGF), and brain-derived neurotrophic factor (BDNF) mediate the downstream effects of HDAC9 on hippocampal synaptic plasticity and cognition. We expect that the results will provide insight into molecular mechanisms underlying the epigenetic control of genes related to aging and AD and offer potential targets for future therapeutic interventions.

项目概要 阿尔茨海默病 (AD) 是一种与年龄相关的神经退行性疾病，会导致记忆丧失和认知能力下降 衰退。突触功能障碍和丧失与 AD 认知障碍密切相关。老龄化是主导 AD 的危险因素和涉及组蛋白脱乙酰酶 (HDAC) 的表观遗传机制在 AD 的危险因素中发挥着重要作用 衰老和与年龄相关的神经退行性疾病。在11种锌依赖性HDAC中，HDAC9是最依赖锌的。 大脑中存在丰富的同工型，仅在神经元中存在。我们提供的关键初步数据表明 在野生型小鼠中，海马和前额皮质 (PFC) 中的 HDAC9 表达随着年龄的增长而减少，并且 在 AD 的 APP/PS1 小鼠模型中，HDAC9 表达的减少先于淀粉样蛋白沉积的发生。 与这些临床前发现一致，AD 患者的背外侧 HDAC9 表达降低 全氟碳化物。此外，HDAC9 的整体或海马 CA1 特异性缺失会导致认知障碍和 损害突触可塑性，而 HDAC9 过度表达会产生认知增强作用。我们假设 神经元 HDAC9 减少会介导认知能力下降、突触功能障碍等 与大脑衰老和 AD 相关的神经病理学。为了检验这个假设，我们提出了三个具体的 目标。在目标 1 中，我们将检验以下假设：海马和 PFC 神经元中 HDAC9 的缺失会介导年龄增长。 AD 相关的神经病理学和认知障碍。在目标 2 中，我们将检验组蛋白的假设 甲基转移酶 EZH2 [多梳抑制复合物 2 (PRC2) 的催化成分， 催化基因启动子处的抑制性 H3K27me3 修饰]表观遗传学沉默 HDAC9 表达 衰老过程中和 AD 中的海马体和 PFC。在目标 3 中，我们将检验神经元五聚蛋白的假设 2 (NP2)、诱导型神经生长因子 (VGF) 和脑源性神经营养因子 (BDNF) 介导 HDAC9 对海马突触可塑性和认知的下游影响。我们预计结果将 深入了解与衰老和 AD 相关的基因表观遗传控制的分子机制 并为未来的治疗干预提供潜在目标。