Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
Date (from‐to) : 2008 -2010
Author : KINOSHITA Ayae; KUBOTA Masakazu
We investigated the pathological mechanisms caused by mutations of Presenilin 1, a responsible protein for familial Alzheimer's disease(AD). We focused on insulin signaling as an influential factor of PS1 and revealed its effect on the localization and conformation of PS1. Our result showed that insulin inhibited GSK3 beta activation, thus leading to inhibition of PS1 phosphorylation and that insulin signaling is involved in the translocation of PS1 to the cell surface and its cleavage functions. Furthermore, we found that insulin receptor, IR, is cleaved by PS1, then its intracellular domain translocates to the nucleus, which activates transcription of Akt. Taken together, we conclude that insulin signaling is modulated by PS1. Next, we created a novel AD model mouse with diabetic condition by giving high fat diet to APP Tg mouse. This mouse showed a marked impairment of short-term memory, suggesting that diabetes is an aggravating factor for AD.