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(Received for publication, May 15, 1997, and in revised form, September 10, 1997)
§
,§¶
,§
and§
From the Departments of 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 endoproteolytically into two
fragments in vivo. In the present report we examine the
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 PS1 derivatives is
accompanied by a compensatory, and highly selective, decrease in the
steady-state levels of murine PS1 and PS2 derivatives. Similarly, the
levels of murine PS1 derivatives are diminished in cultured cells
overexpressing human PS2. To define the minimal sequence requirements
for "replacement" we expressed familial Alzheimer's disease-linked
and experimental deletion variants of PS1. These studies revealed that
compromised accumulation of murine PS1 and PS2 derivatives resulting
from overexpression of human PS1 occurs in a manner independent of endoproteolytic cleavage. Our results are consistent with a model in
which the abundance of PS1 and PS2 fragments is regulated coordinately by competition for limiting cellular factor(s).
Pathology, ¶ Neurology,
and 
Neuroscience and the § Division of
Neuropathology, The Johns Hopkins University School of Medicine,
Baltimore, Maryland 21205-2196
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