Peptidyl boronic acids inhibit the degradation of presenilin-l in presenilin-l transfected cells

Early onset familial Alzheimer's disease (FAD) can be caused by mutations o r deletions in the presenilin-1 (PS-1) gene on chromosome 14. In cultured c ells and brain extracts PS-l,which is predicted to be an 8 transmembrane sp anning protein, is present mainly as N-and C-terminal fragments rather than as the holoprotein. In the studies reported here we have used newly develo ped and characterised peptidyl boronic acid inhibitors to elucidate the rol e of the proteasome in the cleavage of PS-1. In cells overexpressing PS-1, certain inhibitors of the peptidyl boronic acid type, which are potent and specific inhibitors of the proteasome, caused an accumulation of PS-1 holop rotein and N-terminal fragments in a concentration dependent manner. The in hibition of PS-1 breakdown in cells was correlated with inhibition of the c hymotrypsin-like activity of the proteasome in vitro. The accumulation of P S-1 was not observed in untransfected cells, or in cells transfected with t he empty vector, which had been treated with proteasome inhibitors, despite the proteasome being inhibited in these cells. This effect may be due to o ver-expressing large amounts of the PS-1 in the PS-1 transfected cells and illustrates that care must be taken in extrapolating data obtained in trans fected cells to untransfected cell systems.