The aim of our research is to understand the mechanism of brain aging with specific emphasis on the study Alzheimer's disease (AD) through proteolysis. Proteolytic reactions often play critical roles in both physiological and pathological circumstances because of their irreversible nature, but their actual in vivo functions particularly in brain are not yet well understood. Among the various aspects of protease involvement in neuropathophysiology, our research focuses on two major themes. One is the metabolism of amyloid-βpeptide (Aβ), the cortical deposition of which triggers the pathological cascade leading to AD. Under physiological conditions, Aβ is constantly produced from its precursor and immediately catabolized, whereas dysmetabolism of Aβ seems to lead to pathological deposition upon aging. By elucidating the mechanism of Aβ metabolism, we intend to establish a new approach to prevent AD development by reducing Aβ burdens in aging brains. The other objective is to define the roles of intracellular proteases, calpains and caspases, and also of autophagy in the processes of neuronal dysfunction and degeneration in AD and other neurodegenerative diseases. Because these processes are relatively down-stream to Aβ deposition in the disease cascade, we expect the outcome to contribute to AD research in therapeutic rather than preventive terms. We also aim to identify the mechanisms (pathways), by which Aβ amyloidosis causes tauopathy and neurodegeneration. For this purpose, we generated 2nd generation mouse models of AD, which overproduce Aβ42 without overexpressing amyloid precursor protein. These models will also be useful for the search of biomarkers.