Processing of wild-type and mutant familial Alzheimer's disease-associatedpresenilin-1 in cultured neurons

Mutations of presenilin (PS)-1, an endoplasmic reticulum/Golgi transmembran e protein, have been associated with early-onset familial Alzheimer's disea se (FAD). In mammalian brain, PS1 exists primarily as its processed fragmen ts; however, the role of this cleavage event in PS1 function remains unclea r. Although some investigators have shown that mutant PS1 processing is una ltered (with the exception of PSI-Delta E9, which lacks the cleavage site) in stably transfected cells and PS1-FAD transgenic mice, other investigator s have reported altered FAD mutant PS1 and PS2 protein processing in transi ently transfected cells and human FAD patients. The present study uses reco mbinant replication-defective adenoviral vectors to transiently express wil d-type (WT) or mutant PS1 in various cells, including primary cultured hipp ocampal neurons. We show that in contrast to PS1-WT, overexpression of muta nt PS1 results in an increased ratio of mutant holoprotein to endoproteolyt ic products that is dependent on cell type and differentiation state. In ad dition, mutant PS1 overexpression leads to an increase in caspase-type prot ease derived fragments above that seen with PS1-WT overexpression, Furtherm ore, overexpression of at least one mutant significantly alters the process ing of coexpressed PS1-WT, suggesting that mutant PS1 may affect PS1-WT fun ction. These findings suggest that a defect in PS1 holoprotein stability ma y be a general defect seen in cells expressing mutant PS1, especially neuro nal cells, and may play a critical role in the pathogenesis of FAD.