MOUSE GENETICS APPLIED TO ALZHEIMER'S DISEASE

三种不同基因中的任何一种发生突变都可能导致早发性阿尔茨海默病（AD），这与最常发生在老年人身上的散发性阿尔茨海默病相似。阿尔茨海默病的一个不变的病理特征是淀粉样斑块在大脑中的积累，主要由高度淀粉样变性病理组成的是淀粉样前体蛋白（APP）的积累。在APP、早老素1 （PS1）或早老素2 （PS2）疾病相关突变的症状前携带者中观察到长形β肽的升高，这表明APP加工是疾病过程的核心。对阿尔茨海默病的基因和突变的鉴定使得开发转基因小鼠模型成为可能，这些模型概括了阿尔茨海默病的各个方面，包括淀粉样斑块的发展和行为异常。更重要的是，与D有关的生化途径在小鼠和人类中似乎是相似的；例如，突变型但不是野生型，PS1转基因可引起源自人类APP转基因或内源性小鼠APP基因的Abeta1-42的升高。遗传定义的小鼠种群和品系为阿尔茨海默病的研究提供了新的途径。在分离单一FAD突变的大家族中，发病年龄差异很大，这表明存在遗传修饰因子，而散发性AD几乎肯定具有遗传成分。通过利用不同近交系小鼠的自然变异，研究APP过表达对小鼠生存、病理、行为和电生理的易感性遗传调控。最终目标是确定相关基因。通过将Tg2576转基因阵列从产生淀粉样斑块的远交系转移到不同的近交系背景，将有可能确定斑块负荷与疾病表型的关系。初步的遗传分析表明，淀粉样斑块小鼠行为异常的存在与否取决于遗传背景，而不是斑块的流行程度。Tg2576转基因阵列在杂交种和重组自交系板上的测试将允许比较复杂的行为和电生理性状的遗传学，这些性状需要在基因相同的动物上进行重复测量。这些和类似的实验将有助于确定细胞外淀粉样蛋白是否对阿尔茨海默氏症的认知能力下降和神经元丧失至关重要。最后，测试候选基因（包括载脂蛋白E和超氧化物歧化酶1）对APP过表达产生的表型的影响，为解剖疾病途径和完善AD小鼠模型提供了一种手段。

Mutations in any one of three distinct genes can cause early-onset Alzheimer disease (AD) that is similar to the much more sporadic form that occurs most frequently in older individuals. An invariant feature of AD pathology is the accumulation of amyloid plaques in the brain, composed primarily of the highly amyloidogenic pathology is the accumulation of amyloid precursor protein (APP). Elevation of long-form Abeta peptide is observed in presymptomatic carriers of disease-linked mutation in APP, presenilin 1 (PS1) or presenilin 2 (PS2) suggesting that APP processing is central to the disease process. The identification of genes and mutations causing AD have made possible the development of transgenic mouse models that recapitulate aspects of AD, including development of amyloid plaques and behavioral abnormalities. More importantly, the biochemical pathways involved in D seem to be similar in mice and humans; for example, mutant but not wild-type,. PS1 transgenes cause elevation of Abeta1-42 derived from a human APP transgene or from the endogenous mouse APP gene. Genetically defined stocks and strains of mice offer a new avenue for exploration of AD. Age of onset has been shown to vary considerably in large families segregating a single FAD mutation suggesting the existence of genetic modifiers, and sporadic AD almost certainly has a genetic component. By exploiting natural variation among different inbred mouse strains, genetic control of susceptibility to effects of APP over-expression on survival, pathology, behavior and electrophysiology. The ultimate goal is to identify the genes involved. By transferring the Tg2576 transgene-array from the outbred stock that develops amyloid plaques onto different inbred backgrounds, it will be possible to determine the relationship of plaque load to disease phenotypes. Preliminary genetic analysis indicates the presence or absence of behavioral abnormalities in mice with amyloid plaques depends on genetic background rather than plaque prevalence. Testing the Tg2576 transgene array in hybrids with recombinant inbred strain panels will allow comparison of the genetics of complex behavioral and electrophysiological traits that require replicates measurements on genetically identical animals. These and similar experiments will help determine whether extracellular amyloid is essential for the cognitive decline and neuronal loss seen in AD. Finally, testing the effects of candidate genes, including apolipoprotein E and superoxide dismutase 1, on the phenotypes produced by APP over-expression provides a means to dissect disease pathways and refine mouse models for AD.