Studying Pathogenic Mechanism of Hereditary Cerebral Amyloid Angiopathy

遗传性脑淀粉样血管病发病机制研究

• 批准号: 10320430
• 负责人: Hyung Jin Ahn
• 金额: $ 39.75万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320430
• 关键词: Abeta synthesis; Affect; Affinity; Alzheimer' s Disease; Alzheimer' s disease patient; Amyloid beta-42; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Autopsy; Binding; Biological Markers; Blood - brain barrier anatomy; Blood Vessels; Blood capillaries; Blood coagulation; Brain; Cerebral Amyloid Angiopathy; Cerebrospinal Fluid; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular system; Cessation of life; Clinical; Coagulation Process; Dementia; Deposition; Diagnosis; Disease; Familial Cerebral Amyloid Angiopathy; Fibrin; Fibrin split products; Fibrinogen; Fibrinolysis; Functional disorder; Gene Proteins; Genes; Human; In Vitro; Incidence; Individual; Inflammation; Iowa; Late Onset Alzheimer Disease; Lead; Methods; Molecular; Mutation; N-terminal; Neurologic Dysfunctions; Pathogenicity; Pathologic; Pathology; Patients; Peptides; Play; Reporting; Research; Risk; Risk Factors; Role; Sampling; Scheme; Spectrum Analysis; Stroke; Structure; Therapeutic; Thrombosis; Vascular Diseases; abeta deposition; base; brain tissue; cerebrovascular; cerebrovascular pathology; early onset; experimental study; in vivo; in vivo imaging; inhibitor; mouse model; mutant; non-demented; novel; vascular contributions

Many Alzheimer's disease (AD) patients suffer from altered cerebral blood flow and a damaged cerebral vasculature. Moreover, the majority of patients with dementia present with both AD and vascular pathologies. Circulatory deficiencies could therefore play an important role in this disease. Cerebral amyloid angiopathy (CAA), where Aβ deposits around cerebral blood vessels, is a major contributor of vascular dysfunction in AD and is observed in more than 80% of AD patients. Post-mortem pathological examination of patients' brains with CAA shows perivascular microhemorrhage, microinfarcts, and capillary occlusion. However, the molecular mechanism underlying CAA formation and CAA-induced cerebrovascular pathology is unclear. In addition, a definitive diagnosis of CAA requires autopsy as there is no clear biomarker for CAA. There are rare familiar forms of CAA, called hereditary cerebral amyloid angiopathy (HCAA), in which patients display exaggerated CAA pathology and a severe clinical course of strokes as well as suffering from early onset neurological dysfunction, dementia, and ultimately death. The majority of HCAA occurrences coincide with mutations within the gene for the β-amyloid precursor protein (APP). While most APP mutations elevate total Aβ production or promote formation of the more toxic Aβ42, a subset of mutations related to HCAA causes an increase in vascular deposits of Aβ. Since patients afflicted by HCAA mutations have severe cerebrovascular deficits along with massive CAA, HCAA is an ideal disease to examine the pathogenic mechanisms of CAA. Increasing evidence suggests that fibrinogen, a major component of blood clots, contributes heavily to the cerebrovascular risk in AD. Fibrinogen binds to Aβ with high affinity, and this interaction increases the incidence of abnormal fibrin clots, CAA, inflammation, and cerebrovascular damage. Our preliminary results indicate that HCAA mutations highly increase Aβ’s binding affinity for fibrinogen and induce more severely altered fibrin clot structure than wild-type (WT) Aβ. Based on these findings, we hypothesize that HCAA mutations increase Aβ’s binding affinity for fibrinogen, which subsequently induces more severely altered fibrin clotting, increases vascular fibrin and Aβ deposition, and exacerbates inflammation and cerebrovascular damage. By investigating our hypothesis in a mouse model of HCAA, as well as antemortem CSF and postmortem brain tissue of HCAA patients, we aim to understand the molecular mechanism underlying increased CAA and cerebrovascular abnormalities in HCAA. If our proposed experiments are successful, the results will help us to better understand the pathogenic mechanism underlying the vascular contribution of CAA in both AD and HCAA patients. In addition, our research will provide a novel CSF biomarker for CAA. Furthermore, these findings may accelerate the discovery of tractable therapeutic methods for vascular pathology in AD.

许多阿尔茨海默氏病（AD）患者患有脑血流改变和脑部受损 脉管系统。此外，大多数痴呆症患者均患有AD和血管病理。 因此，循环缺陷可能在该疾病中起重要作用。脑淀粉样血管病 （CAA）Aβ沉积在脑血管周围是AD中血管功能障碍的主要因素 在超过80％的AD患者中观察到。尸体病后病理检查患者的大脑 CAA显示出血管周围的微毛发，微感染和毛细血管阻塞。但是，分子 CAA形成和CAA诱导的脑血管病理的机制尚不清楚。另外， CAA的确定诊断需要尸检，因为CAA没有明确的生物标志物。 有罕见的CAA形式，称为遗传性脑淀粉样血管病（HCAA），其中患者 表现出夸张的CAA病理学和严重的临床过程以及早期遭受的痛苦 发作神经功能障碍，痴呆症，最终死亡。大多数HCAA发生重合 β-淀粉样蛋白前体蛋白（APP）的基因内突变。而大多数应用程序突变都会提升 总Aβ产生或促进毒性Aβ42的形成，这是与HCAA相关的突变子集 导致Aβ的血管沉积物增加。由于患有HCAA突变的患者严重 脑血管与大量CAA一起定义，HCAA是一种检查致病性的理想疾病 CAA机制。 越来越多的证据表明，纤维蛋白原是血凝块的主要成分，对 AD中的脑血管风险。纤维蛋白原与具有高亲和力的Aβ结合，这种相互作用增加了 异常纤维蛋白血块，CAA，炎症和脑血管损伤的发生率。我们的初步结果 表明HCAA突变高度增加了Aβ对纤维蛋白原的结合亲和力，并更严重地诱导 纤维蛋白凝块结构的改变，而不是野生型（WT）Aβ。基于这些发现，我们假设HCAA 突变增加了Aβ对纤维蛋白原的结合亲和力，这随后影响纤维蛋白更严重改变 凝结，增加血管纤维蛋白和Aβ沉积，并加剧炎症和脑血管 损害。通过在HCAA的小鼠模型以及触角CSF和 HCAA患者的死后脑组织，我们旨在了解基本机制 HCAA中的CAA和脑血管异常增加。如果我们提出的实验成功， 结果将有助于我们更好地了解CAA血管贡献的基础病理机制 在AD和HCAA患者中。此外，我们的研究将为CAA提供新颖的CSF生物标志物。 此外，这些发现可能会加速可触及疗法的血管方法 广告中的病理学。