Pathological Influence of Vasculotropic Mutant Amyloid-Beta

描述(申请人提供)：淀粉样蛋白(A？)脑血管堆积，一种称为脑淀粉样血管病(CAA)的疾病，是阿尔茨海默病(AD)患者和几个相关家族性CAA疾病的共同病理特征。有大量证据表明，神经源性A型多肽通常迁移到脑微血管系统，在那里它们通过穿过毛细血管血脑屏障进入循环而从中枢神经系统清除。家族性CAA涉及早期和严重的脑血管积聚，具有特定突变，如荷兰突变E22Q和爱荷华州突变D23N。然而，在家族性CAA中，通常只存在一个突变的A？PP等位基因，这表明脑中的A？多肽是野生型和CAA突变形式的混合体。野生型和CAA突变型A？肽如何在体内相互作用影响清除和产生CAA病理尚不清楚。最近，我们建立了一个转基因小鼠模型，该模型在脑中产生荷兰/爱荷华州CAA突变A？肽(TG-Swdi)，并发展出与神经炎症和行为缺陷相关的脑微血管淀粉样蛋白。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小鼠的淀粉样病理只是人类荷兰/爱荷华州CAA突变多肽的结果。在该模型中，人CAA突变型A？多肽对人野生型A？多肽蓄积和清除的影响尚不清楚。因此，在这一建议中，我们假设人CAA突变体A？和人野生型A？多肽在中枢神经系统相互作用，影响转基因小鼠对A？的清除和脑血管积聚。为了验证我们的假设，我们将采取实验方法，将基础TG-Swdi小鼠与两种不同的转基因模型杂交，这两种模型要么产生1)脑中高水平的人野生型Aβ多肽并产生丰富的淀粉样病理；2)产生大脑中低水平的人野生型Ass多肽而没有淀粉样病理。然后我们将评估CAA对发育的影响，CNS A？肽外流进入循环，以及与CAA相关的下游神经炎症和行为障碍。上述目标的完成将为野生型和CAA突变型多肽如何在体内大脑中相互作用提供新的重要信息。这些研究将有助于了解A？清除和病理性积聚在脑血管中的机制，特别是在家族性CAA中，并可能导致新的途径来阻止CAA的发生和发展和/或促进A？从中枢神经系统流出。公共卫生相关性：大脑中一种称为淀粉样蛋白(A？)的蛋白质片段的积累是阿尔茨海默病和相关疾病的关键病理特征。已在A？基因中发现突变，使其在大脑中的积聚比正常A？基因更严重。这项建议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聚。

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.