Mechanisms of brain phenotypes caused by FAD-linked Presenilin-1 Mutations

项目总结/摘要 编码早老素-1（PS1）和早老素-2（PS2）的PSEN 1和PSEN 2基因中的突变是最常见的。 家族性阿尔茨海默病（FAD）的常见原因，强调了早老素功能在 疾病的发病机制，但潜在的机制仍然没有解决。γ-的异常APP加工 PS1的分泌酶和γ-分泌酶非依赖性活性与FAD的发病机制有关。我们 最近的研究令人惊讶地表明，PS1中的致病突变可以使其作为催化剂的功能丧失， γ-分泌酶复合物的亚基，并通过功能丧失产生FAD相关表型 机制为了评估FAD突变在体内的影响，特别是在致病性突变的大脑中， 过程发生时，我们产生了两个独立的Psen 1基因敲入（KI）小鼠系， 在FAD患者中鉴定的染色体PSEN 1突变。我们的分析揭示了结果中的表型 纯合子KI小鼠与Psen 1无效突变引起的小鼠无法区分，伴有 脑中γ-分泌酶活性基本上完全丧失。Psen 1 L435 F KI突变的杂合性 在海马短期和长期突触可塑性和海马学习中产生缺陷， 记忆使人联想到那些由成人大脑中的早老素的条件失活引起的记忆。有趣的是， 杂合子KI小鼠也显示皮质Aβ42/Aβ40比值升高和皮质Aβ42/Aβ40比值升高。 在突变APP转基因背景上沉积。此外，Psen 1 L435 F KI突变不能 支持老化大脑中的神经元存活，引发广泛的大脑皮质神经变性。在这 竞争性续期申请，我们建议调查是否和什么重要的问题 FAD突变引起的这些突触、行为和神经退行性表型在某种程度上是 这可归因于APP加工异常和γ-分泌酶活性受损，或者APP非依赖性 和/或PS1的γ-分泌酶非依赖性功能。我们建议进行多学科的分子，突触， 行为和组织学分析，使用新的小鼠模型，以了解APP的贡献 加工和γ-分泌酶非依赖性活性对成人早老素功能和FAD相关功能障碍的影响 个脑袋我们的研究结果将对FAD发病机制的理解产生重大影响， 制定有效的治疗策略。

Project Summary/Abstract Mutations in the PSEN1 and PSEN2 genes encoding Presenilin-1 (PS1) and Presenilin-2 (PS2) are the most common cause of familial Alzheimer's disease (FAD), highlighting the importance of Presenilin function in disease pathogenesis, but the underlying mechanisms remain unresolved. Aberrant APP processing by γ- secretase and γ-secretase-independent activities of PS1 have been implicated in FAD pathogenesis. Our recent work has shown surprisingly that pathogenic mutations in PS1 can inactivate its function as the catalytic subunit of the γ-secretase complex and produce FAD-related phenotypes through a loss-of-function mechanism. To assess the effects of FAD mutations in vivo, particularly in the brain where the pathogenic process occurs, we generated two independent lines of Psen1 knock-in (KI) mice that precisely reproduce chromosomal PSEN1 mutations identified in FAD patients. Our analysis revealed phenotypes in the resulting homozygous KI mice indistinguishable from those caused by a Psen1 null mutation, accompanied by essentially complete loss of γ-secretase activity in the brain. Heterozygosity for the Psen1 L435F KI mutation produced deficits in hippocampal short- and long-term synaptic plasticity and hippocampal learning and memory reminiscent of those caused by conditional inactivation of Presenilins in the adult brain. Intriguingly, heterozygous KI mice also displayed elevation of the cortical Aβ42/Aβ40 ratio and exacerbation of cortical Aβ deposition on a mutant APP transgenic background. Moreover, the Psen1 L435F KI mutation was unable to support neuronal survival in the aging brain, triggering widespread cerebral cortical neurodegeneration. In this competing renewal application, we propose to investigate the important questions of whether and to what extent these synaptic, behavioral, and neurodegenerative phenotypes caused by the FAD mutation are attributable to aberrant APP processing and impaired γ-secretase activity, or alternatively to APP-independent and/or γ-secretase-independent functions of PS1. We propose to perform multidisciplinary molecular, synaptic, behavioral, and histological analysis using novel mouse models to understand the contributions of APP processing and γ-secretase-independent activity to Presenilin function and FAD-related dysfunction in the adult brain. The results of our studies will have significant impact on understanding of FAD pathogenesis and strategies to devise effective therapies.