Immunomodulation of AβPP Processing Alleviates Amyloid-β-Related Pathology in Alzheimer's Disease Transgenic Mice

Abstract

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.