HDAC9, Aging and Alzheimer's Disease

HDAC9、衰老和阿尔茨海默病

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos 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

项目摘要

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.

项目摘要阿尔茨海默氏病（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；但是，将衰老与AD发病机理联系起来的机制保持难以捉摸。老化出口对周围组织和大脑的深远影响。功能失调的串扰在衰老过程中，周围系统和大脑之间可能在AD的发病机理和进展中发挥作用。促进年龄会引起脂肪组织功能障碍，可驱动代谢下降和全身注射和导致神经保护脂肪因子和促炎细胞因子的失调，这可能加速大脑衰老和AD的发作或进展。我们发现衰老增加了组蛋白的表达脱乙酰基酶9（HDAC9），一种脂肪分化的内源性反射镜，在人和小鼠脂肪中组织，但会降低大脑中的HDAC9表达。我们的发现表明脂肪组织中的HDAC9和大脑在介导与衰老相关的作用中具有不同的作用。我们建议确定1）脂肪细胞的影响 HDAC9关于衰老和广告相关的代谢和炎症特征，神经病理学和认知障碍； 2）HDAC9在年龄和广告相关的海马和皮质神经元中的功能作用和认知表型； 3）HDAC9基因的年龄变化和相关变化的机制在脂肪组织和大脑中的表达。