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The Journal of Neuroscience, December 1, 2000, 20(23):8717-8726
Presenilin-1 P264L Knock-In Mutation: Differential Effects on
A Production, Amyloid Deposition, and Neuronal Vulnerability
Robert
Siman1,
Andrew
G.
Reaume2,
Mary J.
Savage2,
Stephen
Trusko2,
Yin-Guo
Lin2,
Richard W.
Scott2, and
Dorothy G.
Flood2
1 Department of Pharmacology, University of
Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, and
2 Cephalon, West Chester, Pennsylvania 19380
The pathogenic mechanism linking presenilin-1 (PS-1) gene mutations
to familial Alzheimer's disease (FAD) is uncertain, but has been
proposed to include increased neuronal sensitivity to degeneration and
enhanced amyloidogenic processing of the  -amyloid precursor protein
(APP). We investigated this issue by using gene targeting with the
Cre-lox system to introduce an FAD-linked P264L mutation into the
endogenous mouse PS-1 gene, an approach that maintains
normal regulatory controls over expression. Primary cortical neurons
derived from PS-1 homozygous mutant knock-in mice exhibit basal
neurodegeneration similar to their PS-1 wild-type counterparts.
Staurosporine and A1-42 induce apoptosis, and neither the dose
dependence nor maximal extent of cell death is altered by the PS-1
knock-in mutation. Similarly, glutamate-induced neuronal necrosis is
unaffected by the PS-1P264L mutation. The lack of effect of the
PS-1P264L mutation is confirmed by measures of basal- and toxin-induced
caspase and calpain activation, biochemical indices of apoptotic and
necrotic signaling, respectively. To analyze the influence of the
PS-1P264L knock-in mutation on APP processing and the development of
AD-type neuropathology, we created mouse lines carrying mutations in
both PS-1 and APP. In contrast to the lack of effect on neuronal
vulnerability, cortical neurons cultured from PS-1P264L homozygous
mutant mice secrete A42 at an increased rate, whereas secretion of
A40 is reduced. Moreover, the PS-1 knock-in mutation selectively
increases A42 levels in the mouse brain and accelerates the onset of
amyloid deposition and its attendant reactive gliosis, even as a single
mutant allele. We conclude that expression of an FAD-linked mutant PS-1
at normal levels does not generally increase cortical neuronal
sensitivity to degeneration. Instead, enhanced amyloidogenic processing
of APP likely is critical to the pathogenesis of PS-1-linked FAD.
Key words:
presenilin; amyloid; plaque, neuronal necrosis; neuronal
apoptosis; plaque; amyloid precursor protein; A; familial
Alzheimer's Disease; gene targeting
Copyright © 2000 Society for Neuroscience 0270-6474/00/20238717-10$05.00/0
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