14564
title and abstract
Grb10-mediated Negative Regulation of IGF1R-Activated Signalling Pathway Results in Cognitive Disorder in Diabetic Rats.
Growth factor receptor-bound protein 10(Grb10)is a Src homology 2 (SH2) domain-containing protein and one of the binding partners for several trans-membrane tyrosine-kinase receptors, including insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1-R). The hippocampus, which is critical for cognitive functions, is one of the main distribution areas of Grb10 in the central nervous system. In recent years, diabetic encephalopathy has been defined as a third type of diabetes and the IGF1-IR pathway has been shown to be critical for the neuropathogenic process of cognitive disorder in diabetes. However, the role of endogenous Grb10 in regulating the IGF1-IR pathway and neurobehavioral changes is not explicit. The objective of this study was to determine the in vivo function of endogenous Grb10 in diabetic encephalopathy and the underlying mechanisms. Using stereotaxic surgical techniques and lentiviral vectors expressing specific short hairpin RNA (shRNA), we could steadily knock down Grb10 expression in the hippocampus. More importantly, we demonstrated that hippocampus-specific modulation of Grb10 protein levels led to a prominent remission of cognitive disorder, including improvements in both ultrastructural pathology and abnormal neurobehavioural changes. Our findings indicate that endogenous overexpression of Grb10 functions as a suppressor of the IGF1-IR pathway, which may represent an important mechanism that regulates cognitive disorder in diabetes. This article is protected by copyright. All rights reserved.