Decoding the non‐canonical role of Discoidin Domain Receptor 2 and its plausible interaction with Amyloid beta in Alzheimer’s Disease

Abstract

AbstractBackgroundReceptor tyrosine kinases (RTK) that perform versatile roles in the disease landscape have been extensively studied in proliferative signaling, but their role in degeneration remains quite unexplored. Interestingly several of these RTKs are perturbed in Alzheimer’s Disease (AD), of which Discoidin Domain Receptor 2 (DDR2) is an interesting candidate. DDR2 belongs to a unique set of RTKs that act as sensors of the Extracellular matrix (ECM) and mediate downstream signaling by binding to its ligand collagen.MethodWe investigated the expression and activity of DDR2 in our AD‐like cell model. We also looked for the expression of collagen levels which are well‐established ligands of DDR2. Docking studies were performed between Amyloid beta and DDR2 ectodomain to predict interactions between the two and some important residues were screened which are further being validated by site‐directed mutagenesis. We also performed Immunocytochemistry studies to investigate the localization of DDR2 under disease conditions.ResultThere is a significant upregulation in the DDR2 expression and activity as observed from western blot analysis and qRT PCR. There were no significant changes observed in the mRNA expression level of collagens in the control versus AD scenario. From the Molecular Docking studies between DDR2 and Aβ, we chose the best‐fitted model and screened a few interacting residues in the protein‐protein interface which were validated by site‐directed mutagenesis. Next, from Immunocytochemistry studies, we observed that DDR2 is naturally localized inside the nucleus of neuroblastoma cells and also present in the nucleus in AD‐like scenarios.ConclusionHeightened expression and activity of DDR2 in the absence of collagen, possibly in the presence of Aβ, results in its dysregulated trans‐compartmental distribution across the nucleocytoplasmic interfaces to commence AD‐like pathology. This study overall depicts a preliminary picture of DDR2 playing an essential role in AD and sheds light on its non‐canonical mode of signaling triggered by Aβ which needs further experimental validation.