title: Dementia-like pathology in type-2 diabetes: A novel microRNA mechanism.
abstract: Although type-2 diabetes (T2D) has been reported to increase the risk of cognitive dysfunction and dementia, the underlying mechanisms remain unclear. Dementia-like pathology is attributed to the accumulation of cellular prion protein (PrPc) which plays a role in cognitive dysfunction. However, its involvement and regulation in diabetic dementia-like pathology is not well understood. Using T2D db/db (leptin receptor knockout) mice subjected to object recognition and Y-maze behavioral tests, we determined that short-term memory was compromised and that the mice displayed abrupt spontaneous behaviour compared to db/m control mice. MicroRNA analysis using qRT2-PCR array demonstrated a significant reduction in the transcript expression of microRNA-146a (miR-146a) in the brain of T2D db/db mice as compared to db/m controls. The sequence matching tools validated the binding of miR-146a to a conserved domain of the PrPcgene. Administration of mouse brain endothelial cell-derived exosomes (BECDEs) loaded with miR-146a into the brain's ventricle of T2D db/db mice attenuated brain PrPclevels and restored short-term memory function though not significant. Also, we observed hyperphosphorylation of tau through decreased expression of glycogen synthase kinase-3 in T2D db/db brains that regulates microtubule organization and memory function. We conclude that underexpression of miR-146a upregulates PrPcproduction in T2D db/db mice and the delivery of BECDEs loaded with a miR-146a can down regulate PrPclevels and restore short term memory function up to a certain extent.
authors.affiliation: Department of Physiology, School of Medicine, University of Louisville, Louisville, KY 40202, USA. Electronic address: a0kala02@louisville.edu.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Kalani
authors.affiliation: Department of Physiology, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Chaturvedi
authors.affiliation: Department of Physiology, School of Medicine, University of Louisville, Louisville, KY 40202, USA; Department of Surgery, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Claudio
authors.initials: C
authors.lastname: Maldonado
authors.affiliation: Department of Surgery, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Bauer
authors.affiliation: Department of Physiology, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Irving G
authors.initials: IG
authors.lastname: Joshua
authors.affiliation: Department of Physiology, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Suresh C
authors.initials: SC
authors.lastname: Tyagi
authors.affiliation: Department of Physiology, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
authors.forename: Neetu
authors.initials: N
authors.lastname: Tyagi
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D003704:Dementia / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000494:pharmacology / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D000072002:Prion Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D054411:Receptors, Leptin / Q000172:deficiency / Q000235:genetics; D021641:Recognition, Psychology / Q000502:physiology; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016228:Endothelial Growth Factors; D035683:MicroRNAs; D008869:Microtubule-Associated Proteins; C534190:Mirn146 microRNA, mouse; D000072002:Prion Proteins; D012333:RNA, Messenger; D054411:Receptors, Leptin; D016875:tau Proteins; D038362:Glycogen Synthase Kinase 3
keywords: Cellular prion protein; Dementia; Diabetes; Memory; microRNA