Harnessing Escherichia coli’s Dark Genome to Produce Anti-Alzheimer Peptides

Abstract

Alzheimer’s disease (AD) is characterized by progressive neurodegeneration. The critical molecular trigger is believed to be the accumulation of Aβ neurotoxic oligomers. Given the proteolytic processing of Amyloid Precursor Protein (APP) by β-secretase (beta-site APP cleaving enzyme 1, BACE1) as the key step in the building up of Aβ oligomers, BACE inhibitors come with therapeutic prospects of preventing or delaying the onset of Alzheimer’s. To find inhibitory peptides against BACE1, a library of ‘dark peptides’ was constructed from 4400 intergenic DNA sequences of Escherichia coli. The sequence level analysis was followed by protein structure predictions, molecular docking, and simulation. Based on bioinformatics analysis, 5 potential peptides were screened for experimental validation. Out of these two peptides were identified as lead molecules based on BACE1 inhibitory activity, followed by FRET inhibitory assay, western blot, and RT-PCR. An 86.7 % drop in BACE1 level was observed in the presence of the ECOI2 peptide. Though encouraging results were obtained from in-silico and in-vitro studies, more work is required to study the efficacy of these peptides in suitable animal models.