MOUSE GENETICS APPLIED TO ALZHEIMER'S DISEASE

三个不同基因中的任何一个基因的突变都会导致早发性阿尔茨海默病(AD)，这种疾病类似于在老年人中最常见的更为零星的形式。AD病理的一个不变特征是大脑中淀粉样斑块的积聚，主要由高度淀粉样变形成的病理是淀粉样前体蛋白(APP)的积聚组成。在APP、早老素1(PS1)或早老素2(PS2)的疾病相关突变的症状前携带者中观察到长型Abeta肽的升高，这表明APP的处理在疾病过程中处于中心地位。导致AD的基因和突变的识别使转基因小鼠模型的发展成为可能，这些模型概括了AD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，D基因涉及的生化途径在小鼠和人类身上似乎是相似的；例如，突变的，但不是野生型的。PS1转基因导致来自人类APP转基因或内源性小鼠APP基因的Abeta1-42升高。基因定义的小鼠种群和品系为探索AD提供了一条新的途径。在分离单个FAD突变的大家族中，发病年龄有很大的不同，这表明存在遗传修饰物，而且散发性AD几乎肯定有遗传成分。通过利用不同近交系小鼠之间的自然差异，对APP过度表达对生存、病理、行为和电生理影响的易感性进行遗传控制。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近交系转移到不同的自交系背景上，将有可能确定斑块负载与疾病表型的关系。初步的遗传分析表明，患有淀粉样斑块的小鼠行为异常的存在与否取决于遗传背景，而不是斑块的患病率。Tg2576转基因阵列在与重组近交系菌株面板的杂交中进行测试，将允许比较复杂的行为和电生理特征的遗传学，这些特征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是阿尔茨海默病患者认知能力下降和神经元丢失的关键因素。最后，测试包括载脂蛋白E和超氧化物歧化酶1在内的候选基因对APP过度表达产生的表型的影响，为剖析疾病途径和完善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.