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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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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.