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.

项目总结 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障碍 拒绝。突触功能障碍和丢失与阿尔茨海默病患者的认知损害密切相关。老龄化是领头羊 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 衰老和与年龄相关的神经退行性疾病。在11种依赖锌的HDACs中，HDAC9是最多的 大脑中丰富的异构体，仅在神经元中发现。我们提供的关键初步数据表明， 野生型小鼠海马区和前额叶皮质(PFC)中HDAC9的表达随着年龄的增长而减少 在AD的APP/PS1小鼠模型中，HDAC9表达的降低先于淀粉样蛋白沉积的开始。 与这些临床前研究结果一致，AD患者的背外侧HDAC9表达降低 一等兵。此外，HDAC9的全局或海马区CA1特异性缺失会导致认知障碍和 会损害突触的可塑性，而HDAC9的过度表达会产生认知增强的效果。我们假设 神经元HDAC9的减少介导了认知功能下降、突触功能障碍和其他 与脑老化和阿尔茨海默病相关的神经病理学。为了验证这一假设，我们提出了三个具体的假设 目标。在目标1中，我们将检验这样一个假设，即海马区和PFC区神经元中HDAC9的缺失与年龄- 以及与AD相关的神经病理和认知障碍。在目标2中，我们将验证组蛋白 甲基转移酶EZH2[多梳抑制复合体2(PRC2)的催化成分，它 在基因启动子上催化抑制性H3K27me3修饰]表观遗传沉默HDAC9的表达 衰老和AD时的海马体和前额叶皮质。在目标3中，我们将检验神经元五肽的假设 2(NP2)、神经生长因子诱导因子(VGF)和脑源性神经营养因子(BDNF)介导 HDAC9对海马区突触可塑性和认知的下游影响。我们预计，结果将是 洞察衰老和阿尔茨海默病相关基因表观遗传控制的分子机制 并为未来的治疗干预提供了潜在的靶点。