Modifiers of beta-amyloid metabolism and deposition

描述（由申请人提供）：阿尔茨海默病（AD）是老年人最常见的痴呆症，是老年人残疾和死亡的主要原因。AD的特征和诊断是独特的神经病理学改变，包括细胞外沉积的淀粉样蛋白（A）肽。流行病学调查表明，AD是一种复杂的、与年龄相关的疾病，有许多已提出的遗传和环境病因。人类遗传学研究表明，改变剂量和淀粉样前体蛋白基因突变以及早老素1和早老素2基因突变均导致早发性AD，而APOE基因是晚发性AD的主要危险因素。相当多的证据表明，这些遗传因素改变A？代谢和/或A？沉积。然而，迄今为止发现的AD基因占AD遗传风险的不到30%。由于迟发性神经退行性疾病的固有变异性和遗传异质性，已证明难以识别调节AD风险的其余遗传和环境因素。在过去的15年里，包括我们自己在内的几个研究小组一直致力于开发精确和明确的AD小鼠模型，在这些模型中，遗传背景和环境暴露都可以被精确和可重复地修改，以深入了解改变APP加工、A β产生和沉积的因素。肽，痴呆症的发作和AD中发生的神经病理学异常。在本资助申请的前一个资助期内，我们产生了同源品系，其中人类AD转基因被转移到不同的近交系小鼠品系中。随后，我们表征了不同近交遗传背景和特定遗传改变对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。目前的研究试图扩大和扩展这些研究，重点是调节A？代谢和沉积的遗传和环境因素，在两个近交系小鼠品系中具有最不同的A？表型，C57 BL/6 J和A/J，使用这些品系的独特遗传资源。目前建议的具体目标是：1）确定小鼠染色体与基因调节A？代谢和沉积。2)识别和表征调节A？沉积的遗传位点。3)表征负责饮食诱导的A？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.