HDAC9, Aging and Alzheimer's Disease

项目总结 阿尔茨海默病(AD)是一种进行性神经退行性疾病，占痴呆的60%-80% 案子。衰老是AD的主要危险因素；然而，将衰老与AD发病联系起来的机制 仍然难以捉摸。衰老对周围组织和大脑有深远的影响。功能失调的串音 衰老过程中外周系统与脑之间的相互作用可能在AD的发生发展中起一定作用。 增龄导致脂肪组织功能障碍，导致代谢下降和全身性炎症 导致神经保护性脂肪因子和促炎细胞因子的异常产生，这可能 加速大脑老化和阿尔茨海默病的发生或发展。我们发现，衰老会增加组蛋白的表达 脱乙酰酶9(HDAC9)是人和小鼠脂肪中的内源性成脂分化抑制因子 组织，但减少HDAC9在大脑中的表达。我们的发现表明脂肪组织中的HDAC9和 大脑在调节衰老相关效应方面扮演着不同的角色。我们建议确定1)脂肪细胞的影响 HDAC9关于衰老和AD相关的代谢和炎症情况、神经病理学和认知障碍； 2)HDAC9在老年性和阿尔茨海默病相关神经病理中的作用 和认知表型；以及3)HDAC9基因与年龄和AD相关变化的机制 在脂肪组织和脑中的表达。

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.