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（由适用提供）：阿尔茨海默氏病（AD）是一种进行性神经退行性疾病，其特征在于脑实质中淀粉样蛋白-β（Aβ）的沉积为老年斑块，并在脑脑屏体中以脑淀粉样蛋白（CAA）为特征。 CAA也是古老的颅内出血的主要原因。流行病学研究表明，血管系统的灾难有助于AD和CAA的发病机理。此外，载脂蛋白E（APOE）基因的ε4等位基因是AD和CAA的强遗传危险因素。 APOE4加剧了Aβ在大脑中的积累，会导致血脑屏障分解并减少小vissels。尽管APOE4载体总体上具有更高的AD风险，但与男性相比，女性的APOE4效应明显更强。一致地，我们的初步结果表明，尽管女性的AD风险较高，但APOE4具有更强的速度，但我们发现男性比AD中的女性更严重。这些数据表明在CAA和AD的发展中存在性别特异性以及APOE依赖性和独立的分子途径。在此提案中，我们旨在定义性别和APOE同工型如何不同地影响AD和CAA的风险，并确定有助于衰老和AD中脑血管病理学的新型基因和途径。我们将通过利用现有的并生成神经病理学，基因组/表观基因组和神经影像领域的新数据来使用跨学科的方法，并在丰富的表型，大型尸检大脑收集和纵向的纵向术中，遵循的纵向大脑，较早的同龄人，Mayo临床研究（MCSA）（MCSA）。我们全面的假设驱动和假设生成的研究将提供有关AD中CAA和其他脑血管病理的分子机制的新见解。我们的具体目的如下：目标1。定义性别和APOE同工型对CAA和副淀粉样蛋白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发展的新型途径；目标3。发现新途径对衰老和痴呆症血管风险的影响；目标4。研究介导APOE同工型和雌激素对脑Aβ清除率的影响以及CAA和淀粉样蛋白斑的形成的分子机制。总的来说，这些研究有望发现APOE的基础机制和AD/CAA的性别影响，并发现新型基因和途径，这些基因和途径将是候选诊断和治疗靶标。