Visit our Expo - Redox and Inflammation signaling 2012

Session XII : Cell death and neurodegenerative diseases Poster XII, 15
Involvement of cathepsin S in amyloid precursor protein-mediated neuronal cell death
Carole HONIGMANN, Corinne MBEBI, Luc DUPUIS, Jean-Philippe LOEFFLER and
Yves LARMET.
INSERM U-692, Laboratoire de Signalisations Moléculaires et Neurodégénérescence,
Université Louis Pasteur, Faculté de Médecine, Strasbourg, France
E-mails : honigmann@neurochem.u-strasbg.fr, mbebi@neurochem.u-strasbg.fr,
larmet@neurochem.u-strasbg.fr, loeffler@neurochem.u-strasbg.fr,
The Amyloid Precursor Protein (APP), the precursor of beta-amyloid, plays a central role in
Alzheimer's disease (AD) since mutations in the APP gene are associated with early onset
AD. The biological function of APP is however still not elucidated. APP is a transmembrane
proteine and there is now accumulating evidence that APP operates as a transduction unit. We
have previously reported that antibody binding to the cell surface APP (APP-Ab) causes
neuronal cell death via a GTP binding protein G0 that forms complexes with the APP
cytoplasmic domain (Mbebi et al., 2002). Anatomopathological studies revealed increased
cathepsins levels in Alzheimer brain tissues and preliminary studies from our laboratory
showed that APP-Ab are sufficient to increase cathepsins in primary culture of cortical
neurones.
In the study presented here, we delineate the relationship between the APP cytotoxic
functions and cathepsin S expression. We provide evidence that acting directly and
specifically upon neuronal APP through APP-Ab binding, stimulates the synthesis of
cathepsin S. In addition, a Jun-Kinase inhibitor could reverse cathepsin S activation. Finally,
following APP-Ab treatment, the addition of a specific inhibitor of cathepsin S reverse APP-
Ab dependent cell death. Taken together, our results show that cathepsin S is a crucial
executor of APP neurotoxicity. These findings raise the possibility that the lysosomal
pathway may contribute to neuronal cell death in AD.
Supported by Alsace Alzheimer 68.
- 473 -