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The Journal of Neuroscience, September 1, 2000, 20(17):6452-6458
Aging Increased Amyloid Peptide and Caused Amyloid Plaques in
Brain of Old APP/V717I Transgenic Mice by a Different Mechanism than
Mutant Presenilin1
Ilse
Dewachter1,
Jo
Van Dorpe1,
Liesbet
Smeijers1,
Martine
Gilis1,
Cuno
Kuipéri1,
Isabelle
Laenen1,
Nathalie
Caluwaerts1,
Dieder
Moechars4,
Frédéric
Checler2,
Hugo
Vanderstichele3, and
Fred
Van
Leuven1
1 Experimental Genetics Group, Center for Human
Genetics, Flemish Institute for Biotechnology, Katholieke Universiteit
Leuven, B-3000 Leuven, Belgium, 2 Institut de Pharmacologie
Moléculaire et Cellulaire/Centre National de la Recherche
Scientifique, Unité Propre de Recherche 411, Valbonne 06560, France, 3 Innogenetics NV, Industriepark Zwijnaarde, 9052 Gent, Belgium, and 4 Janssen Research Foundation, 2340 Beerse, Belgium
Aging of transgenic mice that overexpress the London mutant of
amyloid precursor protein (APP/V717I) (Moechars et al., 1999a) was now
demonstrated not to affect the normalized levels of  - or  -cleaved
secreted APP nor of the -C-terminal stubs. This indicated that aging
did not markedly disturb either - or -secretase cleavage of APP
and failed to explain the origin of the massive amounts of amyloid
peptides A40 and A42, soluble and precipitated as amyloid plaques
in the brain of old APP/V717I transgenic mice. We tested the hypothesis
that aging acted on presenilin1 (PS1) to affect  -secretase-mediated
production of amyloid peptides by comparing aged APP/V717I transgenic
mice to double transgenic mice coexpressing human PS1 and APP/V717I. In
double transgenic mice with mutant (A246E) but not wild-type human PS1,
brain amyloid peptide levels increased and resulted in amyloid plaques
when the mice were only 6-9 months old, much earlier than in APP/V717I transgenic mice (12-15 months old). Mutant PS1 increased mainly brain
A42 levels, whereas in aged APP/V717I transgenic mice, both A42
and A40 increased. This resulted in a dramatic difference in the
A42/A40 ratio of precipitated or plaque-associated amyloid peptides, i.e., 3.11 ± 0.22 in double APP/V717I × PS1/A246E
transgenic mice compared with 0.43 ± 0.07 in aged APP/V717I
transgenic mice, and demonstrated a clear difference between the effect
of aging and the effect of the insertion of a mutant PS1 transgene. In conclusion, we demonstrate that aging did not favor amyloidogenic over
nonamyloidogenic processing of APP, nor did it exert a mutant PS1-like
effect on -secretase. Therefore, the data are interpreted to suggest
that parenchymal and vascular accumulation of amyloid in aging brain
resulted from failure to clear the amyloid peptides rather than from
increased production.
Key words:
amyloid precursor protein; APP processing; aging; presenilin; transgenic mice; amyloid plaques; amyloid peptide
Copyright © 2000 Society for Neuroscience 0270-6474/00/20176452-07$05.00/0
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