Pathological Influence of Vasculotropic Mutant Amyloid-Beta

描述（由申请人提供）：淀粉样蛋白（A¿）的脑血管积聚，一种被称为脑淀粉样血管病（CAA）的疾病，是阿尔茨海默病（AD）和几种相关家族性CAA疾病患者的常见病理特征。有大量证据表明，神经元来源的A¿肽通常会迁移到大脑微血管，在那里它们通过毛细血管血脑屏障进入循环，从中枢神经系统清除。家族型CAA涉及具有特定突变的A -肽的早期和严重脑血管积聚，如荷兰突变型E22Q和爱荷华突变型D23N。然而，在家族型CAA中，通常只有一个突变的A¿PP等位基因存在，这表明大脑中的A¿肽池是野生型和CAA突变形式的混合物。野生型和CAA突变型A¿肽如何在体内相互作用以影响清除并产生CAA病理尚不清楚。最近，我们建立了一种转基因小鼠模型，该模型在大脑中产生荷兰/爱荷华CAA突变a¿肽（Tg-SwDI），并产生脑微血管淀粉样蛋白，伴有相关的神经炎症和行为缺陷。Tg-SwDI小鼠为研究家族性微血管CAA的发生和后果提供了宝贵的模型。然而，Tg-SwDI小鼠的淀粉样蛋白病理仅是人类荷兰/爱荷华CAA突变A¿肽的结果。在该模型中，人类CAA突变型A¿肽对人类野生型A¿肽的积累和清除的影响尚不清楚。因此，我们假设人类CAA突变体A¿和人类野生型A¿肽在CNS中相互作用，影响转基因小鼠A¿的清除和脑血管积累。为了验证我们的假设，我们将采用实验方法，将碱基Tg-SwDI小鼠与两种不同的转基因模型杂交，这两种转基因模型分别产生：1)大脑中人类野生型A¿肽水平升高，并产生丰富的淀粉样蛋白病理；2)大脑中人类野生型A¿肽水平低，无淀粉样蛋白病理。然后，我们将评估对CAA的发展，CNS A -肽外排到循环中的影响，以及与CAA相关的下游神经炎症和行为缺陷。上述目标的完成将为野生型和CAA突变型A¿肽如何在大脑中相互作用提供新的重要信息。这些研究将为理解A¿在脑血管系统的清除和病理积累机制提供有用的见解，特别是在家族形式的CAA中，并可能为阻止CAA的启动和进展和/或促进A¿从中枢神经系统流出的方法提供新的途径。公共卫生相关性：一种被称为淀粉样蛋白(a)的蛋白质片段在大脑中的积累是阿尔茨海默病和相关疾病的一个关键病理特征。在A¿中发现了突变，导致它在大脑中的积累比正常A¿更严重。本提案的目的是研究突变的A¿如何与正常的A¿相互作用，以增加其在大脑中的积累。

DESCRIPTION (provided by applicant): Cerebrovascular accumulation of the amyloid ¿-protein (A¿), a condition known as cerebral amyloid angiopathy (CAA), is a common pathological feature of patients with Alzheimer's disease (AD) and several related familial CAA disorders. There is substantial evidence that neuronally-derived A¿ peptides normally migrate to the cerebral microvasculature where they are cleared from the CNS by transport across the capillary blood-brain barrier into the circulation. Familial forms of CAA involve the early and severe cerebrovascular accumulation of A¿ peptides with specific mutations such as the Dutch mutant E22Q and Iowa mutant D23N. However, in familial forms of CAA generally only one mutant A¿PP allele is present indicating that the pool A¿ peptides in brain is a mixture of wild-type and CAA mutant forms. How wild-type and CAA mutant A¿ peptides interact in vivo to affect clearance and produce CAA pathology is not understood. Recently, we generated a transgenic mouse model that produces Dutch/Iowa CAA mutant A¿ peptides in brain (Tg-SwDI) and develops cerebral microvascular amyloid with associated neuroinflammation and behavioral deficits. The Tg-SwDI mouse has provided an invaluable model to study the genesis and consequences of familial microvascular CAA. However, the amyloid pathology of Tg-SwDI mice is the result of only human Dutch/Iowa CAA mutant A¿ peptides. The impact of human CAA mutant A¿ peptides on the accumulation and clearance of human wild-type A¿ peptides in this model is unknown. Thus, we hypothesize in this proposal that human CAA mutant A¿ and human wild-type A¿ peptides interact in the CNS to influence clearance and cerebrovascular accumulation of A¿ in transgenic mice. To test our hypothesis we will take the experimental approach of crossing the base Tg-SwDI mice with two different transgenic models that produce either 1) elevated levels of human wild-type A¿ peptides in brain and develop abundant amyloid pathology or 2) low, physiological levels of human wild-type Ass peptides in brain with no amyloid pathology. Then we will evaluate the effects on development of CAA, CNS A¿ peptide efflux into the circulation, and the downstream neuroinflammation and behavioral deficits associated with CAA. Completion of the above goals will provide new and significant information regarding how wild- type and CAA mutant A¿ peptides interact in vivo in the brain. These studies will provide useful insight into understanding mechanisms involved in A¿ clearance and pathological accumulation at the cerebral vasculature, particularly in familial forms of CAA, and may lead to new avenues for approaches to impede the initiation and progression of CAA and/or facilitate A¿ efflux from the CNS. PUBLIC HEALTH RELEVANCE: Accumulation of a protein fragment, known as amyloid ¿ -protein (A¿), in the brain is a key pathological feature of Alzheimer's disease and related disorders. Mutations have been identified in A¿ that cause it to accumulate in brain more severely than normal A¿. The purpose of this proposal is to investigate how mutant A¿ interacts with normal A¿ to increase its accumulation in brain.