Selective neutralization of APP-C99 with monoclonal antibodies reduces the production of Alzheimer's Aß peptides.
Neurobiol Aging
; 33(11): 2704-14, 2012 Nov.
Article
en En
| MEDLINE
| ID: mdl-22317957
ABSTRACT
The toxic amyloid-ß (Aß) peptides involved in Alzheimer's disease (AD) are produced after processing of the amyloid precursor protein-C-terminal fragment APP-C99 by γ-secretase. Thus, major therapeutic efforts have been focused on inhibiting the activity of this enzyme. However, preclinical and clinical trials testing γ-secretase inhibitors revealed adverse side effects most likely attributed to impaired processing of the Notch-1 receptor, a γ-secretase substrate critically involved in cell fate decisions. Here we report an innovative approach to selectively target the γ-secretase-mediated processing of APP-C99 with monoclonal antibodies neutralizing this substrate. Generated by immunizing mice with natively folded APP-C99, these antibodies bound N- or C-terminal accessible epitopes of this substrate, and decorated extracellular amyloid deposits in AD brain tissues. In cell-based assays, the same antibodies impaired APP-C99 processing by γ-secretase, and reduced Aß production. Furthermore, they significantly decreased brain Aß levels in the APPPS1 mouse model of AD after intracerebroventricular injection. Together, our findings support APP-C99 substrate-targeting antibodies as new immunotherapeutic and Notch-sparing agents to lower the levels of Aß peptides implicated in AD.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Péptidos beta-Amiloides
/
Enfermedad de Alzheimer
/
Anticuerpos Monoclonales
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Neurobiol Aging
Año:
2012
Tipo del documento:
Article
País de afiliación:
Suiza