Integrative translational discovery of vascular risk factors in aging and dementia

衰老和痴呆血管危险因素的综合转化发现

• 批准号: 9001610
• 负责人: GUOJUN BU
• 金额: $ 532.73万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9001610
• 关键词: Address; Affect; Age; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid deposition; Animal Model; Apolipoprotein E; Astrocytes; Atherosclerosis; Autopsy; Blood - brain barrier anatomy; Blood Vessels; Brain; Cells; Cerebral Amyloid Angiopathy; Cerebrovascular Circulation; Cerebrum; Clinic; Clinical; Cognitive; Collection; Data; Dementia; Deposition; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Disease; Disease model; Elderly; Environmental Risk Factor; Epidemiologic Studies; Epigenetic Process; Estrogen Replacement Therapy; Estrogens; Female; Functional disorder; Genes; Genetic; Genome; Genomics; Genotype; Goals; Gonadal Steroid Hormones; Human; Hypertension; Impaired cognition; Impairment; Incidence; Individual; Injury; Intracranial Atheroscleroses; Intracranial Hemorrhages; Kentucky; Knowledge; Lesion; Measures; Mediating; Metabolism; Methodology; Methylation; Modeling; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Outcome; Ovariectomy; Pathogenesis; Pathology; Pathway interactions; Patients; Perfusion; Phase; Phenotype; Play; Prevalence; Protein Isoforms; RNA Sequences; Risk; Risk Factors; Role; Senile Plaques; Severities; Severity of illness; Sex Characteristics; Signal Transduction; Staging; Stroke; System; Testing; Universities; Vascular Diseases; Vascular System; Work; abeta accumulation; age related; aged; amyloid pathology; apolipoprotein E-3; apolipoprotein E-4; base; cerebrovascular; cerebrovascular lesion; cognitive function; cohort; epidemiologic data; epigenome; epigenomics; exome sequencing; genetic association; genetic risk factor; high risk; induced pluripotent stem cell; insight; interdisciplinary approach; male; mild cognitive impairment; mouse model; neuroimaging; neuropathology; next generation; novel; public health relevance; sex; tau Proteins; therapeutic target; transcriptome sequencing

 DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the deposition of amyloid-β (Aβ) in the brain parenchyma as senile plaques and in the cerebrovasculature as cerebral amyloid angiopathy (CAA). CAA is also a major cause of intracranial hemorrhage in the elderly. Epidemiological studies indicate that disturbance of the vascular system contributes to the pathogenesis of both AD and CAA. In addition, the ε4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for both AD and CAA. ApoE4 exacerbates Aβ accumulation in the brain, causes blood-brain barrier breakdown and reduction of small vessels. While APOE4 carriers have a higher risk for AD in general, APOE4 effect is significantly stronger in females compared to males. Consistently, our preliminary results indicate that APOE4 has a stronger genetic association with CAA severity in females than males. Although females have a higher risk for AD, we found that males have more severe CAA than females in AD. These data suggest the presence of sex-specific, and both apoE-dependent and independent molecular pathways in the development of CAA and AD. In this proposal, we aim to define how sex and apoE isoforms differentially affect the risk for AD and CAA, and to identify novel genes and pathways that contribute to cerebrovascular pathology in aging and AD. We will use interdisciplinary, systems-based approaches by leveraging existing and generating new data in neuropathology, genome/epigenome, and neuroimaging fields in richly phenotyped, large autopsy brain collections and the longitudinally followed, elderly cohort, Mayo Clinic Study of Aging (MCSA). Our comprehensive hypothesis-driven and hypothesis-generating studies will provide novel insights into the molecular mechanisms underlying CAA and other cerebrovascular pathologies in AD. Our specific aims are as follows: Aim 1. Define the effects of sex and apoE isoforms on the pathological distribution and severity of CAA and parenchymal amyloid plaques; Aim 2. Identify novel pathways that contribute to the development of CAA and AD; Aim 3. Discover the impact of novel pathways on vascular risk in aging and dementia; Aim 4. Investigate the molecular mechanisms mediating the impact of apoE isoforms and estrogen on brain Aβ clearance and the formation of CAA and amyloid plaques. Collectively, these studies are expected to both uncover mechanisms underlying apoE and sex effects for AD/CAA and discover novel genes and pathways that will be candidate diagnostic and therapeutic targets.

 描述（由申请人提供）：阿尔茨海默病（AD）是一种进行性神经退行性疾病，其特征是淀粉样蛋白-β（Aβ）在脑实质中沉积为老年斑，在脑血管系统中沉积为脑淀粉样血管病（CAA）。 CAA也是老年人颅内出血的主要原因。流行病学研究表明，血管系统紊乱导致 AD 和 CAA 的发病。此外，载脂蛋白E (APOE) 基因的ε4 等位基因是AD 和CAA 最强的遗传风险因素。 ApoE4 加剧 Aβ 在大脑中的积累，导致血脑屏障破坏和小血管减少。虽然 APOE4 携带者患 AD 的风险总体较高，但与男性相比，APOE4 对女性的影响明显更强。我们的初步结果一致表明，与男性相比，APOE4 与女性 CAA 严重程度的遗传相关性更强。尽管女性患AD的风险较高，但我们发现男性患AD的CAA比女性更严重。这些数据表明在 CAA 和 AD 的发展中存在性别特异性、apoE 依赖性和独立分子途径。在本提案中，我们的目标是确定性别和 apoE 亚型如何对 AD 和 CAA 的风险产生不同的影响，并确定导致衰老和 AD 脑血管病理学的新基因和途径。我们将利用跨学科、基于系统的方法，利用神经病理学、基因组/表观基因组和神经影像学领域的现有数据和生成新的数据，这些数据来自表型丰富的大型尸检大脑集合和纵向跟踪的老年人队列梅奥诊所衰老研究（MCSA）。我们全面的假设驱动和假设生成研究将为 CAA 和 AD 中其他脑血管病理的分子机制提供新的见解。我们的具体目标如下： 目的 1. 明确性别和 apoE 亚型对 CAA 和实质淀粉样斑块的病理分布和严重程度的影响；目标 2. 确定有助于 CAA 和 AD 发展的新途径；目标 3. 发现新途径对衰老和痴呆血管风险的影响；目标 4. 研究 apoE 同工型和雌激素对大脑 Aβ 清除以及 CAA 和淀粉样斑块形成影响的分子机制。总的来说，这些研究预计将揭示 AD/CAA 的 apoE 和性别影响的潜在机制，并发现将成为候选诊断和治疗靶点的新基因和途径。