Modifiers of beta-amyloid metabolism and deposition

描述(申请人提供)：阿尔茨海默病(AD)，最常见的老年痴呆障碍，是老年人残疾和死亡的主要原因。AD的特点和诊断是以独特的神经病理改变为特征，包括细胞外淀粉样蛋白(A)肽的沉积。流行病学调查表明，阿尔茨海默病是一种复杂的、与年龄相关的疾病，有许多被认为是遗传和环境原因。人类遗传学研究表明，淀粉样前体蛋白基因的剂量改变和突变以及早老素1和早老素2基因的突变都会导致早发性AD，而APOE基因是晚发性AD的主要危险因素。大量证据表明，这些遗传因素会改变A代谢和/或A沉积。然而，到目前为止发现的AD基因在AD遗传风险中所占比例不到30%。由于迟发性神经退行性疾病的内在变异性和遗传异质性，对调节AD风险的其余遗传和环境因素的识别被证明是极其困难的。在过去的15年里，包括我们自己在内的几个小组一直专注于开发准确和明确的AD小鼠模型，在这种模型中，遗传背景和环境暴露都可以进行精确和可重复的修改，以努力深入了解影响APP处理、A？肽的产生和沉积、痴呆的发病以及AD中发生的神经病理异常的因素。在这项拨款申请的前一个资金阶段，我们产生了同源品系，其中人AD转基因被转移到不同的近交系小鼠品系中。随后，我们研究了不同的近交系遗传背景和特定的遗传改变对A？代谢和沉积以及其他AD表型的影响，并确定了调节代谢和沉积的独特的小鼠遗传位点。此外，在初步研究中，我们确定了环境因素，即高脂肪/高胆固醇饮食，对大脑A？水平的影响取决于小鼠的遗传背景。目前的研究试图利用C57BL/6J和A/J两个近交系小鼠的独特遗传资源，扩大和扩大这些研究的范围，重点放在调节A‘表型最不同的两个近交系小鼠的A’代谢和沉积的遗传和环境因素上。目前这项建议的具体目的是：1)用调节A代谢和沉积的基因(S)鉴定小鼠染色体。2)鉴定和鉴定调控Aβ沉积的遗传位点。3)确定饮食引起的代谢和沉积改变的遗传位点。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD), the most common dementing disorder of late life, is a major cause of disability and death in the elderly. AD is characterized and diagnosed by distinctive neuropathological alterations including extracellular deposits of the ¿-amyloid (A¿) peptide. Epidemiological investigations have demonstrated that AD is a complex, age-related disorder with numerous proposed genetic and environmental etiologies. Human genetic studies have shown that altered dosage and mutations in the amyloid precursor protein gene as well as mutations in presenilin 1 and presenilin 2 genes all cause early-onset AD, while the APOE gene is major risk factor in late-onset AD. Considerable evidence suggests that these genetic factors alter A¿ metabolism and/or A¿ deposition. However, the AD genes identified thus far account for less than 30% of genetic risk for AD. Due to the inherent variability and genetic heterogeneity in late-onset neurodegenerative disorders, the identification of the remainder of the genetic and environmental factors that modulate AD risk have proven extremely difficult. Over the past decade and a half, several groups, including our own, have focused on the development of accurate and defined mouse models of AD, in which both the genetic background and environmental exposure can be precisely and reproducibly modified in an effort to gain insight into factors that modify APP processing, the production and deposition of A¿ peptides, the onset of dementia and the neuropathological abnormalities that occur in AD. In the previous funding period of this grant application, we generated congenic strains, in which a human AD transgene was transferred into different inbred mouse strains. We subsequently characterized the effects of different inbred genetic backgrounds and specific genetic alterations on A¿ metabolism and deposition and other AD phenotypes and identified unique mouse genetic loci that regulate metabolism and deposition. In addition, in preliminary studies we determined that the effects of an environmental factor, namely high-fat/high-cholesterol diets, on brain A¿ levels are dependent upon the genetic background of the mice. The current studies seek to expand and extend these studies with a focus on genetic and environmental factors that regulate A¿ metabolism and deposition in two inbred mouse strains with the most divergent A¿ phenotypes, C57BL/6J and A/J, using the unique genetic resources available for these strains. The specific aims of the current proposal are to: 1) Identify mouse chromosomes with gene(s) that regulate A¿ metabolism and deposition. 2) Identify and characterize genetic loci that regulate A¿ deposition. 3) Characterize genetic loci responsible for diet-induced alterations in A¿ metabolism and deposition.