Nuclear Shuttling of IGF1R/INSR in Alzheimer’s disease and its corresponding role in regulation of neurodegeneration

Abstract Background Alzheimer’s disease (AD) has been long associated with ageing and Insulin dysregulation. The receptors and ligands of the Insulin family including Insulin, IGF1, INSR, and IGF1R mainly has been explored over the years. However, their differential distribution in terms of compartmentalization and trafficking requires investigation. Method We started this study with SHSY5Y cells and checked for differential distribution in nucleus and cytoplasm in case of AD model. We repeated the study in N2A cells. To understand the nuclear shuttling better, we extended our study in differentiated SHSY5Y (into the Acetylcholinergic lineage) and exploited super resolution microscopy for imaging and trafficking. We fractionated the cellular compartments for biochemical evidence. To ascertain the partners and forms of protein that shuttles, antibody based assays were performed. For validation of this phenomena as of uniform occurrence, mice brain tissues and human primary neurons were utilized for imaging studies. Result Ligand independent shuttling into the nucleus occurs in case of AD models in presence of amyloid beta (1‐42). There is a 6.4 fold increase in phosphorylation in cytosolic pIGF1R/INSR in case of AD and a 2.5 fold increase in nuclear fractions. The occurrence correlated with the increase in Cyclin D1 production as suggested by ChIP studies. Upon treatment with Sumoylation inhibitor which blocks IGF1R transit into the nucleus, Cyclin D1 levels lowered validating transcriptional control of Cyclin D1 by IGF1R in AD scenario. Thus cell cycle can be directly influenced through interaction of IGF1R with binding partners LEF and TCF in AD. Conclusion Canonical ligand independent shuttling of phosphorylated IGF1R/INSR influences the cell cycle in AD thus triggering cell cycle through a direct control mechanism.