Novel Gene-Edited Rat Model for Development of CAA

脑淀粉样血管病（CAA）是一种常见的淀粉样脑小血管疾病， 其特征在于纤维状淀粉样蛋白b-蛋白（Ab）在脑血管中的积累。CAA是一个 阿尔茨海默病和相关疾病（ADRD）患者中常见的血管合并症，但也可以 偶尔发生，影响>50%>80岁的个体。此外，CAA的几种相关家族形式 由位于AbPP基因的Ab肽序列内的突变引起，包括荷兰型（E22 Q） 和Iowa型（D23 N）。Aβ在脑血管中的蓄积可导致血管周围神经炎症， 脑梗塞、微出血，严重时还会出现脑内出血（ICH）。因为这些 CAA是血管介导的认知障碍和痴呆（VCID）的重要原因。 研究CAA/VCID的发病机制，并开发和测试针对CAA/VCID的靶向治疗干预措施。 这种情况需要合适的实验动物模型。 迄今为止，CAA的研究主要集中在转基因啮齿动物的使用。然而，转基因 CAA和ADRD的模型有几个明显的缺点，包括依赖于人工过度， 转基因的表达，倾向于对宿主基因组的插入效应，并且容易丧失 转基因表达和遗传漂变。转基因的另一个主要缺点 线是病理发展通常是从表达的“唯一来源”，通常来自神经元，由于 到驱动转基因表达的启动子。然而，神经元Ab的“唯一来源”不太可能是神经元Ab的“唯一来源”。 CAA在人类中发展。由于CAA中Ab的细胞起源的复杂性没有在'sole'中捕获， 然而，这些转基因模型未能揭示这种疾病的真正发病机制。这个明显的缺点 促使人们寻求为CAA产生更好的实验动物模型，以更充分地捕捉 这种疾病的发病机制及其在VCID中的作用。 这项探索性提议的总体目标是广泛表征一种新的基因编辑大鼠模型， 小型船舶CAA。这将为CAA和ADRD领域提供一种最先进的动物模型， 了解这种病理状态如何准确地演变并导致脑血管病理，白色 物质损害和VCID。本建议的目的是描述一个上级模型的研究小 血管CAA，并提供给研究界一个更现实和生理相关的平台， 研究致病机制，并能够有效地询问新的潜在生物标志物， CAA的治疗干预。

Cerebral amyloid angiopathy (CAA) is a common amyloidal form of cerebral small vessel disease that is characterized by the accumulation of fibrillar amyloid b-protein (Ab) in blood vessels of the brain. CAA is a common vascular comorbidity in patients with Alzheimer’s disease and related disorders (ADRD) but also can occur sporadically affecting >50% of individuals >80 years. In addition, several related familial forms of CAA result from mutations that reside within the Ab peptide sequence of AbPP gene including Dutch-type (E22Q) and Iowa-type (D23N). Cerebral vascular accumulation of Aβ can result in perivascular neuroinflammation, cerebral infarction, microbleeds, and in severe cases, intracerebral hemorrhages (ICH). Because of these vascular impacts, CAA is a significant cause of vascular-mediated cognitive impairment and dementia (VCID). To investigate the pathogenesis of CAA/VCID and to develop and test targeted therapeutic interventions for this condition appropriate experimental animal models are needed. To date, studies on CAA have largely centered around the use of transgenic rodents. However, transgenic models of CAA and ADRDs come with several significant shortcomings including reliance on artificial over- expression of the transgene, prone to insertional effects on the host genome and susceptible to loss of transgene expression and genetic drift in subsequent generations. Another major shortcoming of transgenic lines is that pathology that develops typically is from a ‘sole source’ of expression, typically from neurons, due to the promoters that drive transgene expression. However, a ‘sole source’ of neuronal Ab is unlikely how the CAA develops in humans. Since the complexity of the cellular origins of Ab in CAA are not captured in ‘sole source’ transgenic models they fail to reveal the true pathogenesis of this disorder. This glaring shortcoming has prompted the quest to generate yet a better experimental animal model for CAA to more fully capture the pathogenesis of this condition and its role in VCID. The overall goal of this exploratory proposal is to extensively characterize a novel gene-edited rat model for small vessel CAA. This will provide a state-of-the-art animal model to the field of CAA and ADRD to more fully understand how this pathological condition accurately evolves and leads to cerebral vascular pathology, white matter damage, and VCID. The aim of this proposal is to describe a superior model for the study of small vessel CAA and provide to the research community a more realistic and physiologically relevant platform to investigate pathogenic mechanisms and to be able to effectively interrogate new potential biomarkers and therapeutic interventions for CAA.