Targeting Microtubule-associated Protein Tau (MAPT) Interactors for Novel Therapeutic Interventions for Rapidly Progressive Alzheimer’s Disease

Abstract

Rapidly Progressive Alzheimer's disease (rpAD) is a disease characterized by rapid cognitive loss. It progresses quickly over the course of weeks to months and sometimes may take up to two to three years. It’s rare and difficult to diagnose although accurate diagnosis is extremely crucial for its treatment. Recent evidence suggests Tau as a promising therapeutic agent for the development of disease-modifying drugs for rpAD due to the involvement of Tau abnormalities in rpAD neurodegeneration. To determine whether Tau is a suitable therapeutic target, in silico tools were used to analyse the interaction of proteins isolated by Tau IP. It is identified that proteins interact with MAPT during the pathology of disease and play a role in progression of rpAD. The specific interaction between the MAPT region belonging from the MTB domain 2MZ7 and its interactors Neuromodulin, Synaptophysin and RhoA were investigated using molecular docking and visualization tools like PyRx, PyMOL, Discovery Studio, and LigPlot+ and binding energies and bonding between the amino acids was observed and evaluated. Protein network analysis revealed an aberration towards apoptotic pathway and signaling pathway. Furthermore, binding of different drug compounds including Methamphetamine, Ascorbic acid and Doxorubicin were evaluated through docking in silico. Doxorubicin showed the highest binding energy of -6.0 kcal/mol with 2MZ7. These drug compounds and their interaction with 2MZ7 yielding high binding affinity shows that binding site of MAPT can be blocked using Doxorubicin to prevent the interaction of pathological proteins that are involved in the accelerated progression of rpAD.