A Systems Biological Approach to the Identification of Exosomal NTRK1 as a Potent Biomarker for Prolonged type II Diabetes-Induced Alzheimer’s Disease

Abstract

A prolonged diabetic state leading to Alzheimer’s disease (AD), attributable to diminished insulin action in the brain, is  referred to as “type 3 diabetes”(DMIII). Recent studies have confirmed that signaling extracellular vesicles (EVs) or exosomes serve as potential biomarkers for AD and is also involved in the neuropathology of brain diabetes. They provide a possible link between DMII and AD, which remains unknown due to complex pathophysiological mechanism,  and a lack of an integrative approach to identify novel molecular pathways. To elucidate the biological pathways, we used a systems biological method that integrates genes, interactomes and biological pathways involved, to reveal the underlying molecular mechanisms and also candidate biomarkers. Causative genes were identified from the literature and databases for AD, diabetes and exosomes, to create protein interactomes which were examined to find 214 common molecular signatures. Analysis of the subnetwork provides functional modules representing various mechanistic molecular and cellular pathway including tyrosine kinase signaling, apoptosis, cyclin-dependent kinase signaling and  the homeostatic pathway. Furthermore, the prioritization of functional modules identifies NTRK1, as a potential candidate marker. These results support the possible use of these candidate biomarkers for diagnosis of diabetic-mediated AD. Overall, our molecular annotations of exosome reveal the pathophysiology of AD, to identify circulating markers for diagnosis. More studies are required to validate NTRK1 as a biomarker, in vivo and in vitro.