Peptides of Presenilin-1 Bind the Amyloid Precursor Protein Ectodomain and Offer a Novel and Specific Therapeutic Approach to Reduce β-Amyloid in Alzheimer's Disease

Dewji NN, et al., 10(4):e0122451, PLoS One, 2015

Alzheimer's disease (AD) pathogenesis is widely accepted to be triggered by the accumulation of the amyloid-β (Aβ) in the brain. Aβ is a set of oligopeptides each of which is proteolytically cleaved from β-amyloid precursor protein (APP) by β-secretase and γ-secretase. Presenilin (PS)-1 or -2 act as the catalyst in this process. Most of the current approaches used to treat AD aim to inhibit the effects of Aβ by altering the activities of β- or γ-secretase. This article reveals a novel and completely different approach to reduce the production of Aβ without affecting the catalytic activities of β- or γ-secretase. The binding affinities of synthetic peptides P1, scrambled P1, P4, P5, P7 and P8 for the soluble ectodomain of APP or control IgG were studied by Bio-Layer Interferometry (BLI) on a Pall ForteBio Octet RED96 instrument. Streptavidin (SA) Biosensor probes were immobilized with biotinylated peptides. Biosensor tips were then immersed in various concentrations of APPs. Kinetic parameters (KD, kon, and koff) were determined for each binding interaction. Overall findings of this study demonstrate that the two small peptides from PS-1 NH2-terminal domain, P4 and P8 effectively reduce the production of Aβ in AD model systems. These peptides and their derivatives offer promising new drug leads for the development of future AD therapeutics.

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