Compounds That Bind APP and Inhibit Aβ Processing in Vitro Suggest a Novel Approach to Alzheimer Disease Therapeutics

Abstract Extracellular deposits of aggregated amyloid-β (Aβ) peptides are a hallmark of Alzheimer disease; thus, inhibition of Aβ production and/or aggregation is an appealing strategy to thwart the onset and progression of this disease. The release of Aβ requires processing of the amyloid precursor protein (APP) by both β- and γ-secretase. Using an assay that incorporates full-length recombinant APP as a substrate for β-secretase (BACE), we have identified a series of compounds that inhibit APP processing, but do not affect the cleavage of peptide substrates by BACE1. These molecules also inhibit the processing of APP and Aβ by BACE2 and selectively inhibit the production of Aβ42 species by γ-secretase in assays using CTF99. The compounds bind directly to APP, likely within the Aβ domain, and therefore, unlike previously described inhibitors of the secretase enzymes, their mechanism of action is mediated through APP. These studies demonstrate that APP binding agents can affect its processing through multiple pathways, providing proof of concept for novel strategies aimed at selectively modulating Aβ production.