Transgenic Rat Model of Cerebral Amyloid Angiopathy

 描述（由申请方提供）：淀粉样β-蛋白（A β）的脑血管蓄积，一种称为脑淀粉样血管病（CAA）的疾病，是血管性认知障碍（VCI）的重要原因，也是阿尔茨海默病（AD）患者的常见病理特征。此外，几种相关的家族性CAA病症由位于A β PP基因的A β肽序列内的突变引起，包括荷兰型（E22 Q）和爱荷华州型（D23 N）。越来越多的证据表明，脑微血管淀粉样蛋白可促进AD和相关CAA疾病患者的小血管病变、神经炎症和认知缺陷。先前，我们产生了独特的转基因小鼠，其在脑中产生荷兰/爱荷华州CAA突变体人ARAD 1，命名为Tg-SwDI，其发展早发性和显著的皮质下纤维状脑微血管ARAD 1沉积。尽管Tg-SwDI小鼠在皮质下小血管CAA、相关病理和认知障碍的研究中提供了价值和独特的见解，但使用该模型仍存在显著的缺点。例如，与人类和高等动物相比，小鼠具有小的脑，几乎没有白色物质，因此限制了神经成像能力和对这些区域中重要的血管介导的变化的研究。此外，与高等物种相比，小鼠认知能力的研究受到更多限制。因此，有一个重要的需要更好的模型，以进一步了解小血管CAA对脑病理和功能的影响。 鉴于目前小鼠模型的局限性，转基因大鼠生产的进展为开发更合适和可重复的物种来模拟小血管CAA提供了机会。因此，该探索性R21提案的总体假设和目的是，新型转基因大鼠的产生和表征将提供一种上级模型来研究皮质下小血管CAA对脑病理学和认知功能的影响。为了实现这一目标，我们提出产生在脑中表达Dutch/爱荷华州CAA突变体的新型转基因大鼠，随后1）进行时间生物化学和病理学表征; 2）确定小血管CAA对认知功能的后果;和3）进行神经成像研究以使用microMRI确定小血管CAA对脑病理学的影响。 在这里，我们采取了非正统的方法，提交了一个多PI探索性的建议，将汇集三个合作的研究人员与不同的，但高度互补，专业知识，以产生和表征新的转基因大鼠CAA。研究人员的专业知识范围从生产大量的转基因小鼠模型和生化和病理表征（货车Nostrand博士），先进的啮齿动物行为和认知表征（罗宾逊博士）和啮齿动物模型的高分辨率神经成像形态测量分析（Benveniste博士）。我们小组的目的是为小血管CAA的研究建立一个上级模型，并为研究界提供一个急需的、更先进的和有价值的这种疾病的动物模型，以研究致病机制，并评估潜在的诊断和治疗干预与相关的认知和神经病理学终点。

 DESCRIPTION (provided by applicant): Cerebrovascular accumulation of the amyloid ß-protein (Aß), a condition known as cerebral amyloid angiopathy (CAA), is an important cause of vascular cognitive impairment (VCI) and a common pathological feature of patients with Alzheimer's disease (AD). In addition, several related familial CAA disorders result from mutations that reside within the Aß peptide sequence of AßPP gene including Dutch-type (E22Q) and Iowa- type (D23N). Evidence continues to accumulate indicating that cerebral microvascular amyloid can promote small vessel pathology, neuroinflammation and cognitive deficits in patients with AD and related CAA disorders. Previously, we generated unique transgenic mice that produce Dutch/Iowa CAA mutant human Aß in brain, designated Tg-SwDI, that develop early-onset and prominent subcortical fibrillar cerebral microvascular Aß deposition. Despite the value and unique insight that Tg-SwDI mice have provided in the study of subcortical small vessel CAA, associated pathologies and cognitive impairment there remains significant shortcomings with the use of this model. For example, in contrast to humans and higher animals, mice possess small brains with little white matter thus limiting neuroimaging capabilities and the study of important vascular mediated changes in these regions. In addition, the study of cognitive abilities in mice are much more restricted compared to higher species. Thus, there is an important need for better models to further our understanding of the impact of small vessel CAA on brain pathology and function. In light of the limitations of current mouse models, advances in the production of transgenic rats provide the opportunity to develop a more appropriate and reproducible species to model small vessel CAA. Thus, the overall hypothesis and aim of this exploratory R21 proposal is that the generation and characterization of novel transgenic rats will provide a superior model to study the impact of subcortical small vessel CAA on brain pathology and cognitive function. To accomplish this goal we propose to generate novel transgenic rats expressing Dutch/Iowa CAA mutant Aß in brain and subsequently 1) conduct temporal biochemical and pathological characterization; 2) determine the consequences of small vessel CAA on cognitive functions; and 3) perform neuroimaging studies to determine the impact of small vessel CAA on brain pathology using microMRI. Here, we take the unorthodox approach of submitting a multi-PI exploratory proposal that will bring together three collaborative investigators with distinct, but highly complimentary, expertise to generate and characterize novel transgenic rats for CAA. The investigators range in expertise from production of numerous transgenic mouse models and biochemical and pathological characterization (Dr. Van Nostrand), advanced behavioral and cognitive characterization of rodents (Dr. Robinson) and high-resolution neuroimaging morphometric analysis of rodent models (Dr. Benveniste). The aim of our group is to generate a superior model for the study of small vessel CAA and provide a much needed, more advanced and invaluable animal model of this condition to the research community for investigating pathogenic mechanisms and to evaluate potential diagnostic and therapeutic interventions with relevant cognitive and neuropathological endpoints.