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: 10392162
• 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/10392162
• 关键词: APP-PS1; 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 (Brain); Histone Deacetylase; Impaired cognition; Knockout Mice; Learning; Link; Mediating; Mediator of activation protein; Memory; Memory Loss; Memory impairment; Modification; Molecular; Mus; Nerve Degeneration; Nerve Growth Factors; Neurodegenerative Disorders; Neurons; Neuropeptides; Pathology; Peripheral; Pharmacology; 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; cognitive enhancement; cognitive function; epigenetic silencing; histone methyltransferase; improved; insight; mouse model; neuronal pentraxin; neuropathology; neurotransmission; overexpression; pathological aging; 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.

项目摘要 阿尔茨海默氏病（AD）是一种与年龄相关的神经退行性疾病，会导致记忆力丧失和认知 衰退。突触功能障碍和损失与AD中的认知障碍密切相关。衰老是领先 AD的危险因素和涉及组蛋白脱乙酰基酶（HDACS）的表观遗传机制在 衰老和与年龄有关的神经退行性疾病。在11个锌依赖性HDAC中，HDAC9是最多的 大脑中丰富的同工型，仅在神经元中发现。我们提供关键的初步数据，显示 HDAC9在海马和前额叶皮层（PFC）中的表达，野生型小鼠的衰老降低，并且 这降低了HDAC9表达在AD/PS1小鼠模型中淀粉样蛋白沉积的发作之前。 与这些临床前发现一致，AD患者暴露于背侧的HDAC9表达降低 PFC。此外，HDAC9的全球或海马CA1特异性缺失会引起认知障碍和 损害合成可塑性，而HDAC9过表达会产生认知增强作用。我们假设 降低了神经元HDAC9介导认知能力下降，突触功能障碍和其他 与大脑衰老和AD相关的神经病理学。为了检验这一假设，我们提出了三个特定的特定 目标。在AIM 1中，我们将检验以下假设：海马和PFC神经元中HDAC9的损失介导了年龄 以及与广告相关的神经病理学和认知障碍。在AIM 2中，我们将测试组蛋白的假设 甲基转移酶EZH2 [Polycomb反射复合物2（PRC2）的催化成分，其中 催化剂在基因启动子上的反射性H3K27ME3修饰]表观遗传在HDAC9表达中表达在 衰老和AD中的海马和PFC。在AIM 3中，我们将测试神经元五肽素的假设 2（NP2），神经生长因子诱导（VGF）和脑衍生的神经营养因子（BDNF）介导 HDAC9对海马突触可塑性和认知的下游影响。我们希望结果将 提供对与衰老和AD相关的基因表观遗传控制的基础的分子机制的见解 并为未来的治疗干预提供潜在的目标。