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: 9251922
• 负责人: STEVEN Owen SMITH
• 金额: $ 6.95万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2017-06-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9251922
• 关键词: Address; Adopted; Alleles; Alzheimer' s Disease; Amyloid; Amyloid Fibrils; Amyloid beta-Protein; Amyloid deposition; Binding; Biological Markers; Blood Vessels; Brain; Cerebral Amyloid Angiopathy; Cerebrovascular system; Chronic; Chronology; Comorbidity; Dementia; Deposition; Development; Disease; Environment; Familial Cerebral Amyloid Angiopathy; Familial disease; Fourier Transform; 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; 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; 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(申请人提供)：脑血管淀粉样蛋白积聚(A？)，一种被称为脑淀粉样血管病(CAA)的疾病，是血管认知障碍和痴呆(VCID)的重要驱动因素，也是阿尔茨海默病(AD)患者的常见共病。CAA可通过慢性炎症、低灌流和缺血、血管壁完整性丧失和出血等多种机制促进VCID的发生。除了在AD中的流行外，一些相关的家族性CAA疾病是由位于Aü前体蛋白的A？肽序列中的特定突变引起的，包括荷兰型(E22Q)和爱荷华型(D23N)突变。尽管荷兰突变型和爱荷华州突变型多肽具有高度的纤维原性，但在这些家族性疾病中，纤维蛋白Aü仅限于脑血管系统。最近的证据表明，脑血管淀粉样蛋白与实质斑块淀粉样蛋白不同。然而，对于脑血管淀粉样蛋白形成的原因以及其独特的结构特征导致VCID的不同病理后果，人们了解得很少。因此，这项建议的重点是填补这一知识上的批评空白。因此，这一建议的总体假设是，与实质纤维淀粉样蛋白相比，纤维淀粉样蛋白I脑血管具有明显的结构特征，独特的反平行结构，由CAA突变增强，驱动脑内淀粉样蛋白在脑血管中的特异性沉积。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Aü的野生型、荷兰和爱荷华州CAA突变体在溶液和模型膜系统中的结构、组装和膜相互作用，这些膜系统驱动它们的隔室沉积。其次，我们将确定家族性A？CAA变异如何按时间顺序影响转基因小鼠大脑中野生型A？的结构特征和组装。第三，我们将从AD患者、散发性CAA患者和家族性CAA患者的尸检脑组织中分离出实质斑块淀粉样蛋白和脑血管淀粉样蛋白，并研究它们促进野生型和CAA突变型多肽组装的能力。这些重要的研究将揭示人类疾病中脑血管和实质斑块淀粉样沉积的明显结构特征。目前，还没有针对CAA和VCID的可靠的生物标志物或有效的治疗方法。由于我们缺乏对脑血管淀粉样蛋白及其早期寡聚前体的独特结构属性的了解，以及它们与实质斑块淀粉样蛋白相比的独特特征和过程，这些缺陷变得更加复杂。本研究将试图填补我们认识上的这一重要空白，并将促进我们对CAA发病机制的理解，并为未来CAA和VCID的新的治疗干预措施和诊断标记物的发展提供基础。