EVIDENCE THAT LEVELS OF PRESENILINS (PS1 AND PS2) ARE COORDINATELY REGULATED BY COMPETITION FOR LIMITING CELLULAR FACTORS

Mutations in two related genes, PS1 and PS2, account for the majority of early onset cases of familial Alzheimer's disease, PS1 and PS2 are homologous polytopic membrane proteins that are processed endoproteoly tically into two fragments in vivo. In the present report we examine t he fate of endogenous PS1 and PS2 after overexpression of human PS1 or PS2 in mouse N2a neuroblastoma cell lines and human PS1 in transgenic mice. Remarkably, in N2a cell lines and in brains of transgenic mice expressing human PS1, accumulation of human PSI derivatives is accompa nied by a compensatory, and highly selective, decrease in the steady-s tate levels of murine PSI and PS2 derivatives. Similarly, the levels o f murine PS1 derivatives are diminished in cultured cells overexpressi ng human PS2, To define the minimal sequence requirements for ''replac ement'' we expressed familial Alzheimer's disease-linked and experimen tal deletion variants of PSI, These studies revealed that compromised accumulation of murine PS1 and PS2 derivatives resulting from overexpr ession of human PS1 occurs in a manner independent of endoproteolytic cleavage, Our results are consistent with a model in which the abundan ce of PS1 and PS2 fragments is regulated coordinately by competition f or limiting cellular factor(s).