PATHOBIOLOGICAL STUDIES OF VESSEL BACE1 IN CEREBROVASCULAR AMYLOID ANGIOPATHY

血管 BACE1 在脑血管淀粉样血管病中的病理学研究

• 批准号: 9174461
• 负责人: Rena Li
• 金额: $ 40万
• 依托单位: ROSKAMP INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9174461
• 关键词: Abeta synthesis; Adverse effects; Affect; Age; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloid deposition; Animal Model; Apoptosis; Area; Arteries; Back; Basement membrane; Blood Vessels; Brain; Brain hemorrhage; Brain region; Cell Death; Cells; Cerebral Amyloid Angiopathy; Cerebral cortex; Cerebrum; Cessation of life; Cleaved cell; Clinic; Data; Deposition; Down-Regulation; Event; Exhibits; Frequencies; Generations; Genetic; Goals; Hemorrhage; Human; Incidence; Inflammation; Inflammatory; Interferons; Interleukin-1; Knock-in Mouse; Knock-out; Knockout Mice; Leptomeninges; Letters; Medial; Modeling; Molecular; Mus; Nerve Degeneration; Neurons; Pathogenesis; Pathology; Pathway interactions; Patients; Peptides; Pericytes; Physiological; Production; Reporting; Role; Severities; Signal Pathway; Site; Smooth Muscle Myocytes; Stroke; TNF gene; Testing; Transgenic Mice; Vascular Endothelial Cell; Vascular Smooth Muscle; abeta deposition; abstracting; beta secretase; beta-site APP cleaving enzyme 1; brain endothelial cell; cell type; cerebrovascular; cerebrovascular amyloid; cytokine; in vivo; inhibitor/antagonist; mouse model; new therapeutic target; novel; prevent; promoter; receptor; secretase; tool

Abstract The incidence of Alzheimer disease (AD) with vascular degeneration is greatly increased following cerebral hemorrhagic stroke in which cerebral amyloid angiopathy (CAA) occurs in affected brain areas. The most common form of CAA is of the amyloid beta-peptide (Aβ) type. Aβ, which is derived from the beta-amyloid precursor protein (APP) by sequential proteolytic cleavages from β-secretase (BACE1) and -secretase, is widely believed to trigger a cascade of pathological events culminating in AD including accompanied by degeneration of vascular cells: vascular smooth muscle cells (VSMCs), vascular endothelial cells (VENCs) and pericytes. While extensive studies on pericytes in CAA have been performed, multiple studies demonstrated that an increasing accumulation of A in the vessel basement membrane is associated with the degeneration of adjacent VSMCs and VENCs. Importantly, our recent preliminary data showed that cerebral vascular cells from human CAA brains express high levels of β-secretase (BACE1). However, what causes vascular degeneration or death in CAA remains unclear. We recently reported that a cell death receptor, TNFRI, is required for Aβ- induced cell death and depletion of TNFRI reduced BACE1. In this application, we will study whether and how BACE1 can be up-regulated in vascular cells and what molecular mechanisms of BACE1 elevation causes cerebral vascular cell death in our new mouse models of AD related CAA. The ultimate goal of this proposal will not only advance our understanding the mechanisms of CAA- induced hemorrhage but, also to, in principle, identify novel therapeutic targets and offer novel alert for potential side effects of BACE1 inhibitors in patients with Alzheimer’s disease accompanying vascular degeneration. Key words: BACE1, TNF inflammation, animal models, neurodegeneration

摘要 阿尔茨海默病（AD）伴血管变性的发病率大大增加， 脑出血性中风，其中在受影响的脑中发生脑淀粉样血管病（CAA） 地区CAA最常见的形式是淀粉样β肽（A β）型。A β是由 从β-淀粉样前体蛋白（APP）通过连续的β-分泌酶蛋白水解裂解 （BACE1）和β-分泌酶，被广泛认为会引发一系列病理事件，最终导致 AD包括伴有血管细胞变性的血管平滑肌细胞（VSMCs）， 血管内皮细胞（VENC）和周细胞。虽然对CAA中周细胞的广泛研究 多项研究表明，血管中A β的积累增加， 基底膜与邻近的VSMCs和VENCs的变性有关。 重要的是，我们最近的初步数据显示，来自人类CAA大脑的脑血管细胞 表达高水平的β-分泌酶（BACE1）。然而，是什么导致血管变性或死亡呢 CAA的情况仍不清楚。我们最近报道了一种细胞死亡受体，TNFRI，是A β- 诱导的细胞死亡和TNFRI的消耗减少了BACE1。在本申请中，我们将研究 以及BACE1如何在血管细胞中上调，BACE1的分子机制是什么， 在我们新的AD相关CAA小鼠模型中，海拔升高导致脑血管细胞死亡。的 这一建议的最终目标不仅将促进我们对CAA机制的理解， 诱导出血，而且原则上也可以识别新的治疗靶点并提供新的警报 BACE1抑制剂在阿尔茨海默病患者中的潜在副作用， 血管变性 关键词：BACE1，TNF-α，炎症，动物模型，神经退行性变