Clarification of Molecular Mechanism For-AmyloidβGeneration in Alzheimer's Disease

点击翻译按钮获取中文摘要

Amyloidβ-peptides (Aβ) have been proposed to play a central role in the pathogenesis of Alzheimer disease (AD). The aim of our project is to test the validity of Aβ hypothesis and develop the novel therapeutic strategy for AD. Aβ are generated through the sequential proteolysis of Aβ precursor protein (APP)by β-and γ-secretase. We focus on the biology of γ-secretase, because the pathogenicity of Aβ is dependent on the cleavage site of γ-secretase. (a) Analyses of regulatory mechanism for Aβ generation: Previously we revealed that γ-secretase is a macromolecular complex containing presenilin (PS), and that a novel protein nicastrin (Nct) is an essential constituent of this complex. During this project, we have reported that the PS:Nct complex is indispensable for Notch cleavage as well as APP cleavage (Nat Cell Biol 2001), that the additional constituent PEN-2 is critical for activation of γ-secretase complex (J Neurochem, in press), and that Alcadein is a novel substrate for γ-secretase and involved in Fe65-mediated transcriptional regulation (J Biol Chem, in press). To examine the mechanism for enhancement of pathogenic Aβ (Aβ42/43) generation by clinical PS mutations, we performed a random mutagenesis screen to search for mutant PS 1 which affect the γ-secretase activity. We successfully identified the unique mutants that exclusively generated Aβ42/43 species (in preparation for publication). These mutants are useful to analyze the molecular basis for Aβ42/43 generation and to develop the new strategy for inhibiting Aβ42/43 generation. (b) Test for the validity of Aβ hypothesis: We have been tried to develop transgenic monkeys exhibiting symptom and pathology characteristic to AD. The transgenic monkeys should be useful not only for testing the validity of Aβ hypothesis but also for evaluating the potency and adverse effect of newly developed AD therapies.