Finding New Ways How to Control BACE1.

Abstract

Recently, all applications of BACE1 inhibitors failed as therapeutical targets for Alzheimer´s disease (AD) due to severe side effects. Therefore, alternative ways for treatment development are a hot research topic. The present analysis investigates BACE1 protein-protein interaction networks and attempts to solve the absence of complete knowledge about pathways involving BACE1. A bioinformatics analysis matched the functions of the non-substrate interaction network with Voltage-gated potassium channels, which also appear as top priority protein nodes. Targeting BACE1 interactions with PS1 and GGA-s, blocking of BACE1 access to APP by BRI3 and RTN-s, activation of Wnt signaling and upregulation of β-catenin, and brain delivery of the extracellular domain of p75NTR, are the main alternativesto the use of BACE 1 inhibitors highlighted by the analysis. The pathway enrichment analysis also emphasized substrates and substrate candidates with essential biological functions, which cleavage must remain controlled. They include ephrin receptors, ROBO1, ROBO2, CNTN-s, CASPR-s, CD147, CypB, TTR, APLP1/APLP2, NRXN-s, and PTPR-s. The analysis of the interaction subnetwork of BACE1 functionally related to inflammation identified a connection to three cardiomyopathies, which supports the hypothesis of the common molecular mechanisms with AD. A lot of potential shows the regulation of BACE1 activity through post-translational modifications. The interaction network of BACE1 and its phosphorylation enzyme CSNK1D functionally match the Circadian clock, p53, and Hedgehog signaling pathways. The regulation of BACE1 glycosylation could be achieved through N-acetylglucosamine transferases, α-(1→6)-fucosyltransferase, β-galactoside α-(2→6)-sialyltransferases, galactosyltransferases, and mannosidases suggested by the interaction network analysis of BACE1-MGAT3. The present analysis proposes possibilities for the alternative control of AD pathology.