topics

a. Alzheimer's disease

We have analyzed the mechanisms by which familial Alzheimer's disease (AD)-associated mutations of presenilin 1 (PS1) and presenilin 2 (PS2) cause AD, using cultured cells and transgenic mice. We have shown that PS mutations affect the generation of amylid beta-protein (Abeta) from amylod precursor protein (APP) and enhance the production of highly amyloidogenic Abeta42 both intra- and extracellularly.

PS1 is essentially involved in the gamma-secretase cleavage of APP to generate Abeta. Recent studies have shown that PS1forms the gamma-secretase complex with other components such as nicastrin, APH-1 and PEN-2, and acts as its catalytic center. We have studied on the regulation of presenilin-gamma-secretase.

BACE is a membrane-bound protease that cleaves APP at the N-terminus of the Abeta domain. Inhibition of BACE is known to be an effective way to block the production of Abeta. Therefore, we are conducting research to elucidate the regulation mechanisms of BACE activity and to develop novel inhibitors of this protease.

b. Other degenerative dementias

Fronto-temporal dementia (FTD) is characterized by selective atrophy of the frontal and temporal cortex. FTD is pathologically heterogenous; the major forms of FTD are FTD with tau-positive inclusions (Pick's disease) and FTD with TDP-43-positive inclusions. Abnormal accumulation of these proteins is thought to be closely associated with the neurodegeneration in FTD. We are studying the molecular mechanisms of other neurodegenerative dementias including FTD.