Taisuke Tomita and Takeshi Iwatsubo Pages 661 - 670 ( 10 )
Alzheimers disease (AD) is the most common cause of dementia with aging, that is pathologically characterized by senile plaques that contain amyloid-b peptides (Aβ) and neurofibrillary tangles comprised of phosphorylated tau. Genetic and biological studies provide evidence that the production and deposition of Aβ contribute to the etiology of AD. g-Secretase is the pivotal enzyme in generating the C terminus of Aβ, that determines its aggregability and propensity for deposition. Drugs that regulate the production of Aβ by inhibiting g-secretase activity could provide an effective therapeutics for AD, although recent studies suggest that g-secretase plays important roles in novel signaling pathways that play essential roles in embryonic development. This review focuses on recent progresses in the g-secretase biology that shed substantial light on the proteolytic mechanism, regulation and composition of this unusual enzyme. Moreover, we review the recent development of inhibitors and provide a direction for the effective treatment of AD through inhibition of g-secretase activity.
Alzheimer's disease,amyloid,γ-secretase,presenilin,aspartic protease,intramembrane proteolysis,protease inhibitor
, Department of Neuropathologyand Neuroscience, Graduate School of Pharmaceutical Sciences, Universityof Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.