title: Growth factor receptor-bound protein 10-mediated negative regulation of the insulin-like growth factor-1 receptor-activated signalling pathway results in cognitive disorder in diabetic rats.
abstract: Growth factor receptor-bound protein 10 (Grb10) is a Src homology 2 domain-containing protein and one of the binding partners for several transmembrane 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 was 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 neurobehavioural changes is not explicit. The present study aimed 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, we could steadily knockdown 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 for regulating cognitive disorder in diabetes.
authors.affiliation: Department of Gerontology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China.
authors.forename: L
authors.initials: L
authors.lastname: Ma
authors.forename: Q
authors.initials: Q
authors.lastname: Wei
authors.forename: H
authors.initials: H
authors.lastname: Deng
authors.forename: Q
authors.initials: Q
authors.lastname: Zhang
authors.forename: G
authors.initials: G
authors.lastname: Li
authors.forename: N
authors.initials: N
authors.lastname: Tang
authors.forename: J
authors.initials: J
authors.lastname: Xie
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D003072:Cognition Disorders / Q000150:complications*; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D051383:GRB10 Adaptor Protein / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D018782:Maze Learning; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D051383:GRB10 Adaptor Protein; D017526:Receptor, IGF Type 1