Presenilin Knock-in Rat Model of Neurodegeneration

项目概要/摘要 阿尔茨海默氏病（AD）是老年人中最常见的痴呆形式，并且目前不存在任何 疾病修饰疗法家族性AD（FAD）是由淀粉样前体蛋白突变引起的 (APP)，其加工可导致淀粉样蛋白β（Aβ）的形成，或通过早老素1/2的突变 （PSEN 1/2），其部分地包含从APP的片段切割Aβ的γ-分泌酶复合物。 长期职业目标是研究阿尔茨海默病神经退行性变的机制。越接近 正如本提案所提出的，目标是在一种新的大鼠基因敲入模型中描述神经变性的特征。 早老素1功能障碍。Psen 1-敲除（Psen 1-KO）小鼠和具有纯合FAD-1基因的敲入（KI）小鼠 相关的L435 F突变（Psen 1 LF/LF）是胚胎和围产期致死的，排除了更严格的 检查导致AD的Psen 1突变对神经变性的影响。由于更适合 大鼠作为模型生物，关于手术干预和行为测试，我们产生了大鼠KI Psen 1 LF突变模型。我们发现，出乎意料的是，与Psen 1 LF/LF相反，Psen 1 LF/LF大鼠存活 尽管γ-分泌酶活性丧失。这些老鼠的生存提供了机会， 检查纯合Psen 1 AD突变对神经变性的影响。

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is the most common form of dementia in the elderly, and currently there exists no disease modifying therapy. Familial forms of AD (FAD) are caused by mutations in Amyloid Precursor Protein (APP), whose processing can result in the formation of amyloid beta (Aβ), or by mutations in Presenilin 1/2 (PSEN1/2), which comprise in part the γ-secretase complex that cleaves Aβ from fragments of APP. My long- term career goal is to study the mechanism of neurodegeneration in Alzheimer disease. The more proximate goal, as put forward in this proposal, is to characterize the neurodegeneration in a new rat knock-in model of Presenilin1 dysfunction. Psen1-knockout (Psen1-KO) mice and knock-in (KI) mice with homozygous FAD- associated L435F mutations (Psen1LF/LF) are embryonic and perinatally lethal, precluding a more rigorous examination of the effect of AD-causing Psen1 mutations on neurodegeneration. Given the better suitability of rats as a model organism, with regards to surgical interventions and behavior testing, we generated a rat KI model of the Psen1LF mutation. We find that, unexpectedly and in contrast to Psen1LF/LF, Psen1LF/LF rats survive into adulthood despite a loss of γ-secretase activity. The survival of these rats affords the opportunity to examine the effect of homozygous Psen1 AD mutations on neurodegeneration.