Antibody-bound beta-amyloid precursor protein stimulates the production of tumor necrosis factor-alpha and monocyte chemoattractant protein-1 by cortical neurons.
Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by the accumulation of extracellular depositions of fibrillar beta-amyloid (A beta), which is derived from the alternative processing of beta-amyloid precursor protein (APP). Although APP is thought to function as a cell surface receptor, its mode of action still remains elusive. In this study, we found that the culture medium derived from cortical neurons treated with an anti-APP antibody triggers the death of naive neurons. Biochemical and immunocytochemical analyses revealed the presence, both in the conditioned medium and in neurons, of increased levels of tumor necrosis factor-alpha and monocyte chemoattractant protein-1. Furthermore, the expression of these proinflammatory mediators occurred through a c-Jun N-terminal protein kinase/c-Jun-dependent mechanism. Taken together, our findings provide evidence for a novel mechanism whereby neuronal APP in its full-length configuration induces neuronal death. Such a mechanism might be relevant to neuroinflammatory processes as those observed in AD.
Mbebi
Corinne
C
Laboratoire de Signalisations Moléculaires et Neurodégénérescence, INSERM, U692, Université Louis Pasteur, Faculté de Médecine, 11, rue Humann, 67085 Strasbourg cedex, France.
González de Aguilar
Jose-Luis
JL
Sée
Violaine
V
Dupuis
Luc
L
Frossard
Nelly
N
Mercken
Luc
L
Pradier
Laurent
L
Larmet
Yves
Y
Loeffler
Jean-Philippe
JP
D016564:Amyloid beta-Protein Precursor / Q000276:immunology* / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001666:Binding Sites, Antibody / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000235:genetics; D017077:Culture Media, Conditioned / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
D016564:Amyloid beta-Protein Precursor; D018932:Chemokine CCL2; D017077:Culture Media, Conditioned; D014409:Tumor Necrosis Factor-alpha