HDAC9, Aging and Alzheimer's Disease

HDAC9、衰老和阿尔茨海默病

• 批准号: 10017152
• 负责人: Xin-Yun Lu
• 金额: $ 76.28万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017152
• 关键词: APP-PS1; Ablation; Accounting; Adipocytes; Adipose tissue; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Anti-Inflammatory Agents; Binding; Blood - brain barrier anatomy; Brain; Brain region; Cognitive; Cognitive deficits; Dementia; Development; EZH2 gene; Elderly; Endocrine Glands; Enhancers; Epigenetic Process; Exhibits; Family member; Functional disorder; Future; Gene Expression; Genetic Transcription; HDAC9 gene; Hippocampus (Brain); Histone Deacetylase; Homologous Gene; Human; Impaired cognition; Impairment; Inflammation; Inflammatory; Knock-out; Knockout Mice; Learning; Link; Maintenance; Mediating; Memory; Metabolic; Modification; Molecular; Mus; Muscle Cells; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurons; Pathogenesis; Peripheral; Peroxisome Proliferator-Activated Receptors; Phenotype; Play; Prefrontal Cortex; Process; Production; Proteins; Role; Synapses; System; Testing; Therapeutic Intervention; Tissues; Transgenic Organisms; Up-Regulation; adipokines; adiponectin; age effect; aged; aging brain; base; cytokine; improved; insight; metabolic profile; mouse model; neuropathology; novel; overexpression; prevent; promoter; transcription factor

PROJECT SUMMARY Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, accounting for 60–80 % of dementia cases. Aging is the leading risk factor for AD; however, the mechanisms linking aging to the pathogenesis of AD remain elusive. Aging exerts profound impacts on peripheral tissues and brain. The dysfunctional crosstalk between peripheral systems and brain during aging may play a role in the pathogenesis and progression of AD. Advancing age induces adipose tissue dysfunction that drives metabolic decline and systemic inflammation and causes dysregulated production of neuroprotective adipokines and proinflammatory cytokines, which may accelerate brain aging and the onset or progression of AD. We found that aging increases expression of histone deacetylase 9 (HDAC9), an endogenous repressor of adipogenic differentiation, in human and mouse adipose tissue, but decreases HDAC9 expression in the brain. Our findings suggest that HDAC9 in adipose tissue and brain has distinct roles in mediating aging-related effects. We propose to determine 1) the impact of adipocyte HDAC9 on aging- and AD-related metabolic and inflammatory profiles, neuropathology and cognitive impairment; 2) the functional role of HDAC9 in hippocampal and cortical neurons in age- and AD-related neuropathological and cognitive phenotypes; and 3) the mechanisms underlying age- and AD-associated changes in HDAC9 gene expression in adipose tissue and brain.

项目概要 阿尔茨海默病 (AD) 是一种进行性神经退行性疾病，占痴呆症的 60-80% 案例。衰老是 AD 的主要危险因素；然而，衰老与 AD 发病机制之间的联系机制 仍然难以捉摸。衰老对周围组织和大脑产生深远的影响。功能失调的串扰 衰老过程中外周系统和大脑之间的相互作用可能在 AD 的发病机制和进展中发挥作用。 年龄增长会引起脂肪组织功能障碍，从而导致代谢下降和全身炎症， 导致神经保护性脂肪因子和促炎细胞因子的产生失调，这可能 加速大脑老化和 AD 的发生或进展。我们发现衰老会增加组蛋白的表达 脱乙酰酶 9 (HDAC9)，人类和小鼠脂肪中脂肪形成分化的内源性抑制因子 组织中，但会降低大脑中 HDAC9 的表达。我们的研究结果表明脂肪组织中的 HDAC9 大脑在调节衰老相关效应方面发挥着独特的作用。我们建议确定 1) 脂肪细胞的影响 HDAC9 对衰老和 AD 相关代谢和炎症特征、神经病理学和认知障碍的影响； 2）HDAC9在海马和皮质神经元中在年龄和AD相关神经病理学中的功能作用 和认知表型； 3) HDAC9 基因中与年龄和 AD 相关的变化的机制 在脂肪组织和脑中表达。