Decreased Abeta secretion by cells expressing familial Alzheimer's disease-linked mutant presenilin 1.

Presenilin (PS) is a catalytic subunit of the gamma-secretase complex that cleaves the intramembranous region of amyloid precursor protein (APP), producing amyloid beta (Abeta) peptide. Familial Alzheimer's disease (FAD) results from PS mutations, which may alter gamma-secretase activity to enhance the production of highly aggregable Abeta42. The precise pathogenic effects of mutant PS remain unclear. To exclude the effects of endogenous PS, we established cell lines from PS1/PS2-deficient (PS-/-) fibroblasts capable of stably expressing either wild-type (wt) PS1 or different mutant PS1s. Although both wt PS1 and mutant PS1 formed gamma-secretase complexes of the same size and containing the same components, the amount of Abeta secreted by FAD mutant PS1-expressing cells was significantly reduced. The ratio of Abeta42 to Abeta40 (Abeta42/Abeta40) secreted by these cells, however, was significantly higher than that secreted by cells expressing wt PS1, which corroborated findings from a previous report. The elevated Abeta42/Abeta40 ratio observed with mutant PS1-expressing cells may be due to reduced Abeta40 production not increased Abeta42 production.