Presenilin Knock-in Rat Model of Neurodegeneration

项目摘要/摘要 阿尔茨海默病(AD)是老年人中最常见的痴呆形式，目前没有 疾病修正疗法。家族性阿尔茨海默病(FAD)由淀粉样前体蛋白突变引起 (APP)，其处理可导致淀粉样β蛋白(Aβ)的形成，或通过早老素1/2的突变 (PSEN1/2)，部分由γ-分泌酶复合体组成，该复合体从APP片段中切割Aβ。我的龙- 学期的职业目标是研究阿尔茨海默病的神经退变机制。离得越近 正如这项建议所提出的那样，目标是在一种新的敲入鼠模型中表征神经退行性变。 Presenilin1功能障碍。PSEN1基因敲除(PSEN1-KO)小鼠和敲入(KI)小鼠具有纯合子Fad- 相关的L435F突变(Psen1LF/LF)是胚胎和围产期致死的，排除了更严格的 检测引起AD的PSEN1突变对神经退变的影响。考虑到更适合 以大鼠为模型生物，在手术干预和行为测试方面，我们产生了一种大鼠KI Psen1LF突变模型。我们发现，与Psen1LF/LF大鼠相比，Psen1LF/LF大鼠意外地存活了下来 尽管γ分泌酶活性丧失，但仍进入成年期。这些老鼠的存活为我们提供了机会 检查纯合子PSEN1 AD突变对神经退行性变的影响。

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.