Immunomodulation of AβPP processing alleviates amyloid-β-related pathology in Alzheimer's disease transgenic mice.
Among the different paradigms aimed at interfering with amyloid-β (Aβ)-related pathology, the attenuation of amyloid-β protein precursor (AβPP) processing to limit Aβ levels seems to be a promising one. Along with the development of BACE1 inhibitors, and the generation of its knock-out mice, accumulating data raise concerns regarding a total inhibition of the enzyme as it shares the processing of other substrates. We described a novel approach to interfere with the specific interaction between AβPP and BACE1 using monoclonal antibodies directed to the β-secretase cleavage site upon the substrate, AβPP. Such antibodies limit AβPP cleavage in a cellular model of Alzheimer's disease (AD) and avoid the total inhibition of BACE1. Here, we demonstrate the ability of AβPP β-site antibodies to interfere with Aβ production in vivo. Systemic antibody treatment diminished Aβ plaques, membrane-associated oligomers, and intracellular Aβ accumulation, all of which have been implicated in cellular death and synaptic loss, suggesting that this approach may be an applicable strategy for AD treatment.
Arbel-Ornath
Michal
M
Department of Molecular Microbiology & Biotechnology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv, Israel.
Becker
Maria
M
Rabinovich-Toidman
Polina
P
Gartner
Myra
M
Solomon
Beka
B
D000544:Alzheimer Disease / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000276:immunology* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000911:Antibodies, Monoclonal; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human