a. Studies on Alzheimer's disease

Cerebral accumulation of -amyloid protein (A) is thought to play a primary role in the pathomechanism of Alzheimer's disease (AD). Major species of A are A40 and A42, the latter of which is highly amyloidogenic and is deposited from the early stage. Recent studies indicate that soluble A oligomers rather than insoluble A fibrils are more neurotoxic and induce neuronal dysfunction.
A is produced by two-step cleavages of its precursor, amyloid precursor protein (APP): APP is cleaved first by -secretase at an extracellular site (-cleavage) and then by -secretase within a membrane (-cleavage). -secretase and -secretase have been identified as a membrane-bound protease BACE and a multimeric complex consisting of presenilin as an active center and other membrane proteins (nicastrin, APH-1, and PEN-2), respectively.

2)@Our previous studies
We have analyzed the mechanisms by which familial AD-associated mutations of presenilin 1 and presenilin 2 cause AD, using cultured cells and transgenic mice. We have shown that presenilin mutations affect the generation of A and enhance the production of A42 both intra- and extracellularly. We have also done several studies on the regulation of presenilin--secretase.

Inhibition of -secretase BACE is known to be an effective way to block the production of Aand is a feasible therapeutic strategy against AD. We have been conducting research to elucidate the regulation mechanisms of BACE activity. For example, we have demonstrated that the membrane proteins called reticulons interact with BACE and inhibit its A-producing activity, using cultured cells and transgenic mice.

3) Our current studies
A oligomers are considered to play a primary role in the pathogenesis of Alzheimer's disease. We are investigating the neurotocix mechanisms triggered by A oligomers. We also attempt to develop neuroprotective agents against A oligomer toxicity.

Our current projects are as follows:
@A study on the dysregulation of BACE expression in AD pathology
@A study on the mechanisms of A oligomers-associated neurotoxicity
@A study to develop novel therapeutic agents for AD

b. Other studies

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 have studied the molecular mechanisms of other neurodegenerative dementias including FTD.

In addition, we are making a study to develop novel biomarkers useful for early diagnosis of dementia disorders in collaboration with NCNP Hospital and Medical Genome Center.