Regulation and function of gamma-secretase

描述(申请人提供)：拟议研究的总体目标是阐明伽马分泌酶的特异性和调节机制，并为开发治疗阿尔茨海默病(AD)和其他人类疾病的特定抑制剂提供分子基础。γ-分泌酶分解淀粉样前体蛋白(APR)产生A-β多肽的C末端(A-β40和A-β42)，这是淀粉样蛋白产生的最后一步。A-β是AD中发现的淀粉样斑块的主要成分，被认为在AD的神经发病机制中起着关键作用。众所周知，A-β42比A-β40更容易聚集，因此促进A-β42产生增加的生物或环境因素可能会加速导致AD的病理级联反应。尽管对A-β多肽和γ-分泌酶进行了深入的研究，但控制A-β40和Abeta42产生的γ-分泌酶活性的专一性的分子机制仍未解决。提出的研究将提供更好的了解分子基础的伽玛分泌酶特异性，除了提供关键的洞察力阿尔茨海默病的发病机制。这项拟议研究的第一个目的是利用活性位点定向抑制剂识别除早老素以外的新蛋白质，这些蛋白质有助于伽马分泌酶的活性部位。第二个特定目的是研究自然发生的家族性AD突变体(APP和早老素)对伽马分泌酶活性的影响，以阐明AD的分子发病机制。第三个目的是分析对A-β40和A-β42产生不同活性的不同大小的伽马分泌酶复合体，以确定伽马分泌酶专一性的结构和分子基础。这些拟议的研究将导致对伽马分泌酶特异性的全面了解。此外，这些研究将有助于开发有效和特异的伽马分泌酶抑制剂，用于潜在的AD治疗。

DESCRIPTION (provided by applicant): The overall objective of the proposed study is to elucidate the mechanism of specificity and regulation of gamma-secretase and provide a molecular basis for developing specific inhibitors to treat Alzheimer's disease (AD) and other human disorders. Gamma-secretase cleaves amyloid precursor protein (APR) to generate the C-termini of A-beta peptides (A-beta40 and A-beta42), the final step of amyloid production. A-beta, the major constituent of amyloid plaques found in AD, is believed to play a critical role in the neuropathogenesis of AD. It is known that A-beta42 is more prone to aggregation than A-beta40, therefore biological or environmental factors that promote increased A-beta42 production may accelerate the pathological cascade leading to AD. Despite intensive studies on A-beta peptides and gamma-secretase, the molecular mechanism controlling the specificity of gamma-secretase activity for A-beta40 and Abeta42 production is unresolved. Proposed studies will offer a better understanding of the molecular basis for gamma-secretase specificity, in addition to providing critical insight into the pathogenesis of AD. The first aim of the proposed study is to identify novel proteins, in addition to presenilin, that contribute to the active site of gamma-secretase using active-site directed inhibitors. A second specific aim is to investigate the effect of naturally occurring familial AD mutants (APP and presenilin) on gamma-secretase activity to elucidate the molecular pathogenesis of AD. The third aim is to analyze different sizes of gamma-secretase complexes that possess varied activity for A-beta40 and A-beta42 production to define the structural and molecular basis of gamma-secretase specificity. These proposed studies will lead to a comprehensive understanding of gamma-secretase specificity. Moreover, these investigations will facilitate the development of potent and specific inhibitors of gamma-secretase for potential AD therapies.