The aim of this research project is to elucidate the process of production, accumulation and clearance of amyloid β peptides, that are regarded as pathogenic proteins in Alzheimer's disease (AD), thereby creating a novel concept for the disease-modifying therapy for AD. Through the studies of γ-secretase, a membrane protease that produces Aβ peptide, we tried to clarify the mechanism of Aβ production and to block the most upstream cause of AD. Specifically we developed novel γ-secretase inhibitors harboring an enone-moiety and analyzed the mechanism of action of these compounds. Using Cys scan approach, we showed that the 6/7 transmembrane domains of presenilin 1, the latter being the catalytic subunit of γ-secretase, form a hydrophilic catalytic pore structure, We further analyzed the structure of γ-secretase and a related protease, SPP, using single particle analysis. We showed that CLAC, a novel amyloid plaque component protein, inhibits Aβ fibril formation in vitro, and is involved in the compaction of amyloid plaques in the brains of transgenic mice. We also showed that LRP1 is involved in the clearance of All peptides across the blood brain barrier, using an immortalized cell line of brain endothelial cells. We thus elucidated the key steps of Aβ deposition, i.e., γ-secretase, amyloid binding protein and Aβ clearance, using cutting edge technologies including proteomic analysis, RNAi and small molecule screen, providing clues to the development of novel therapeutic strategies for AD.