Selective neutralization of APP-C99 with monoclonal antibodies reduces the production of Alzheimer's Aβ peptides.
The toxic amyloid-β (Aβ) 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 Aβ production. Furthermore, they significantly decreased brain Aβ 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 Aβ peptides implicated in AD.
Laboratory of Molecular and Cellular Biology of Alzheimer's Disease, Brain Mind Institute and School of Life Sciences, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland.
Jemila
J
Houacine
Tristan
T
Bolmont
Lorène
L
Aeschbach
Mustapha
M
Oulad-Abdelghani
Patrick C
PC
Fraering
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001921:Brain / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D051379:Mice; D008807:Mice, Inbred BALB C
D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D053829:Amyloid Precursor Protein Secretases