权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Understanding the Origins of Amyloid Deposition in Cerebral Amyloid Angiopathy

了解脑淀粉样血管病中淀粉样蛋白沉积的起源

基本信息

批准号：
9919003
负责人：
STEVEN Owen SMITH
金额：
$ 38.38万
依托单位：
UNIVERSITY OF RHODE ISLAND
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-10-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9919003
关键词：
Address Adopted Alleles Alzheimer&apos s Disease Alzheimer&apos s disease patient Amyloid Amyloid Fibrils Amyloid beta-42 Amyloid beta-Protein Amyloid deposition Binding Biological Markers Blood Vessels Brain Cerebral Amyloid Angiopathy Cerebrovascular system Chronic Chronology Dementia Deposition Development Disease Environment Familial Cerebral Amyloid Angiopathy Familial disease Future Gangliosides Goals Hemorrhage Human In Vitro Inflammation Investigation Iowa Ischemia Knowledge Laboratories Membrane Mutation NMR Spectroscopy Nature Pathogenesis Pathologic Patients Peptides Prevalence Process Production Protein Precursors Proteins Research Sampling Seeds Senile Plaques Spectroscopy, Fourier Transform Infrared Sporadic Cerebral Amyloid Angiopathy Structure System Transgenic Mice Variant Vascular Cognitive Impairment abeta accumulation amyloid formation amyloid pathology amyloid structure brain parenchyma brain tissue cerebrovascular comorbidity diagnostic biomarker early onset effective therapy human disease hypoperfusion membrane model monomer mouse model mutant novel therapeutic intervention preference protein aminoacid sequence public health relevance vascular cognitive impairment and dementia

项目摘要

DESCRIPTION (provided by applicant): Cerebrovascular accumulation of the amyloid ß-protein (Aß), a condition known as cerebral amyloid angiopathy (CAA), is an important driver of vascular cognitive impairment and dementia (VCID) and is a common comorbidity of patients with Alzheimer's disease (AD). CAA can promote VCID through a number of mechanisms including chronic inflammation, hypoperfusion and ischemia, loss of vessel wall integrity and hemorrhage. In addition to its prevalence in AD, several related familial CAA disorders result from specific mutations that reside within the Aß peptide sequence of the Aß precursor protein including the Dutch-type (E22Q) and Iowa-type (D23N) mutations. Despite the highly fibrillogenic nature of Dutch mutant and Iowa mutant Aß peptides, fibrillar Aß is restricted to te cerebral vasculature in these familial disorders. Recent evidence suggests the cerebral vascular amyloid is distinct from parenchymal plaque amyloid. However, there is a poor understanding as to why cerebral vascular amyloid forms and its unique structural features that promotes distinct pathological consequences leading to VCID. Thus, the focus of this proposal is to fill this critica void in knowledge. Accordingly, the overall hypothesis of this proposal is that fibrillar amyloid i cerebral blood vessels possesses distinct structural features compared to parenchymal fibrillar amyloid and unique anti-parallel structures, enhanced by CAA mutations, drives the cerebral vascular specific deposition of amyloid in brain. To address this hypothesis we propose three specific aims. First, we will determine the structure, assembly and membrane interactions of wild-type and the Dutch and Iowa CAA mutants of Aß in solution and model membrane systems that drive their compartmental deposition. Second, we will determine how familial CAA variants of Aß chronologically influence the structural features and assembly of wild-type Aß in the brains of transgenic mice. Third, we will isolate parenchymal plaque amyloid and cerebral vascular amyloid from post mortem brain tissue of AD cases, sporadic CAA cases and familial CAA cases and investigate their ability to promote assembly of wild-type and CAA mutant Aß peptides. These important studies will reveal the distinct structural signatures of cerebral vascular and parenchymal plaque amyloid deposits in human disease. Presently, there are no reliable biomarkers or effective therapies specifically for CAA and VCID. These deficiencies are complicated by our lack of understanding of the unique structural attributes of cerebral vascular amyloid and its early-stage oligomeric precursors, and their distinctive features and processes compared to parenchymal plaque amyloid. The present proposal will seek to fill this critical void in our knowledge and will advance our understanding of the pathogenesis of CAA and provide the basis for the future development of novel therapeutic interventions and diagnostic markers for CAA and VCID.