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J. Biol. Chem., Vol. 277, Issue 18, 15666-15670, May 3, 2002
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From the Université Catholique de Louvain, FARL/UCL 54 10, av Hippocrate 54, B-1200 Brussels, Belgium
Alzheimer disease (AD), the most frequent
cause of dementia, is characterized by an important neuronal loss. A
typical histological hallmark of AD is the extracellular deposition of
Intracellular Amyloid-
1-42, but Not Extracellular Soluble
Amyloid- Peptides, Induces Neuronal Apoptosis*
-amyloid peptide (A), which is produced by the cleavage of the
amyloid precursor protein (APP). Most of the gene mutations that
segregate with the inherited forms of AD result in increasing the ratio
of A42/A40 production. A42 also accumulates in neurons of AD
patients. Altogether, these data strongly suggest that the neuronal
production of A42 is a critical event in AD, but the intraneuronal
A42 toxicity has never been demonstrated. Here, we report that the
long term expression of human APP in rat cortical neurons induces
apoptosis. Although APP processing leads to production of extracellular
A1-40 and soluble APP, these extracellular derivatives do not
induce neuronal death. On the contrary, neurons undergo apoptosis as soon as they accumulate intracellular A1-42 following the
expression of full-length APP or a C-terminal deleted APP isoform. The
inhibition of intraneuronal A1-42 production by a functional
-secretase inhibitor increases neuronal survival. Therefore, the
accumulation of intraneuronal A1-42 is the key event in the
neurodegenerative process that we observed.
*
This work was supported by the Belgian Fonds de la Recherche
Scientifique Médicale, Pôles d'attraction
interuniversitaires/Services fédéraux des Affaires
scientifiques, techniques et culturelles, and the Queen Elisabeth
Medical Foundation.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 32-2-7649341;
Fax: 32-2-7645460; E-mail: octave@nchm.ucl.ac.be.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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