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

• 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
• 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' s Disease; Alzheimer' 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

 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.

 描述（由适用提供）：淀粉样β蛋白质（Aß）的脑血管积累，一种称为脑淀粉样血管病（CAA）的疾病，是血管认知障碍和痴呆症（VCID）的重要驱动因素，是Alzheimer's病（AD）患者的常见性疾病。 CAA可以通过多种机制促进VCID，包括慢性注射，灌注不足和缺血，容器壁完整性和出血的丧失。除了在AD中的患病率外，几种相关的农场CAA疾病是由位于Aß前体蛋白Aß肽序列中的特定突变引起的，包括荷兰型（E22Q）和爱荷华州型（D23N）突变。尽管荷兰突变体和爱荷华州突变体aßpepperides具有高纤维状的性质，但在这些农场疾病中，纤维aß却仅限于脑脉管系统。最近的证据表明，脑血管淀粉样蛋白不同于实质斑块淀粉样蛋白。然而，人们对为什么脑血管淀粉样蛋白形式及其独特的结构特征促进导致VCID的独特后果。这是该提议的重点是填补这一知识的关键空隙。根据该提议的每个假设，与实质原纤维淀粉样蛋白和独特的抗平行结构相比，纤维淀粉样蛋白I脑血管具有不同的结构特征，可通过CAA突变增强，驱动大脑中淀粉样蛋白的脑血管特异性沉积。为了解决这一假设，我们提出了三个具体目标。首先，我们将确定野生型的结构，组装和膜相互作用，以及Aß的荷兰和爱荷华州CAA突变体在溶液和模型膜系统中驱动其隔室沉积。其次，我们将确定Aß年代的家族性CAA变体如何在年代顺序上影响转基因小鼠大脑中野生型Aß的结构特征和组装。第三，我们将从AD病例的尸体后脑组织，零星的CAA病例和家族性CAA病例中分离出副斑块淀粉样蛋白和脑血管淀粉样蛋白，并研究其促进野生型和CAA突变突变体Aß肽的能力。这些重要的研究将揭示人类疾病中脑血管和副斑块淀粉样蛋白沉积物的独特结构特征。目前，没有专门针对CAA和VCID的可靠生物标志物或有效疗法。由于我们对脑血管淀粉样蛋白的独特结构属性及其早期寡聚前体的独特结构属性以及与副斑块淀粉样蛋白相比，它们的独特特征和过程使这些缺陷变得复杂。本提案将寻求在我们的知识中填补这一关键空隙，并将促进我们对CAA发病机理的理解，并为CAA和VCID的新型治疗干预措施和诊断标记提供未来发展的基础。