MOUSE GENETICS APPLIED TO ALZHEIMER'S DISEASE

三种不同基因中的任何一种突变都可能导致早发性阿尔茨海默病（AD），这种疾病类似于老年人中最常见的散发形式。 AD病理学的不变特征是淀粉样斑块在脑中的积累，其主要由高度淀粉样蛋白形成病理学组成，即淀粉样前体蛋白（APP）的积累。 在APP、早老素1（PS1）或早老素2（PS2）中的疾病相关突变的症状前携带者中观察到长型A β肽的升高，表明APP加工是疾病过程的中心。 导致AD的基因和突变的鉴定使得开发概括AD的各个方面的转基因小鼠模型成为可能，包括淀粉样蛋白斑块和行为异常的发展。 更重要的是，D中涉及的生化途径似乎在小鼠和人类中相似;例如，突变体而不是野生型。 PS1转基因引起源自人APP转基因或内源性小鼠APP基因的A β 1 -42升高。 遗传定义的股票和小鼠品系为探索AD提供了新的途径。发病年龄已被证明有很大的差异，在大家庭中分离一个单一的FAD突变，这表明存在遗传修饰剂，散发性AD几乎肯定有遗传成分。 通过利用不同近交系小鼠品系之间的自然变异，遗传控制对APP过度表达对存活、病理、行为和电生理的影响的易感性。 最终目标是确定相关基因。 通过将Tg 2576转基因阵列从产生淀粉样蛋白斑块的远交系原种转移到不同的近交系背景上，将有可能确定斑块负荷与疾病表型的关系。 初步遗传分析表明，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。 在具有重组近交系品系的杂交体中测试Tg 2576转基因阵列将允许对复杂行为和电生理性状的遗传学进行比较，所述复杂行为和电生理性状需要对遗传上相同的动物进行重复测量。 这些和类似的实验将有助于确定是否细胞外淀粉样蛋白是必不可少的认知能力下降和神经元的损失在AD中看到。 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.