Premium
miR‐146a Contributes to Dementia‐Like Pathology by Upregulation of Prion Protein in type‐2 diabetes
Author(s) -
Kalani Anuradha,
Mallonee Carissa J,
Chu Guoxin,
Tyagi Neetu
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.707.4
Subject(s) - dementia , western blot , downregulation and upregulation , medicine , endocrinology , diabetes mellitus , immunohistochemistry , biology , alpha synuclein , gene knockdown , type 2 diabetes , pathology , neuroscience , gene , parkinson's disease , disease , genetics
Although the association of type‐2 diabetes as a risk factor to develop dementia is reported; however, underlying mechanisms are not clearly understood. Recently, the greater role of cellular prion protein was reported over other proteins that intensify cognitive dysfunctions. However, involvement and regulation of prion in diabetic dementia‐like pathology is under‐explored. We used obese diabetic db/db (leptin receptor knockout) and db/+ control mice for the experiments. Novel object recognition and Y‐maze tests were used to determine short‐term memory and behavior impairments, respectively. Diabetic db/db mice showed compromised short‐term memory and abrupt spontaneous behavior as compared to db/+ control littermates that suggest dementia‐like pathology in diabetic db/db mice. The association of diabetes to dementia‐like pathology was further confirmed by Western blot analysis that showed enhanced expression of phosphorylated tau and altered expression of glycogen synthase kinase‐3 proteins in diabetic db/db mice as compared to control littermates. We next observed enhanced expression of prion in diabetic db/db brain, as defined by Western blot and Immunohistochemistry analysis. After analyzing several microRNAs on qRT 2 ‐PCR array, designed for neurological diseases, we determined significant reduction in transcript expression of microRNA‐146a (miR‐146a) in diabetic db/db brain as compared to control. The sequence matching tools validated the binding of miR‐146a to a conserved domain of prion gene. Moreover, in order to establish the cause and effect relationship, we administered miR‐146a mimic sequences encapsulated in exosomes, which were derived from mouse brain endothelial cells. Innovatively, administration of miR‐146 mimics through exosomes decreased prion expression in db db mice as compared to db/db, which were administered with scramble (control) miRNAs. Alongside, we also observed improvement in novel object recognition task performed by miR‐146a administered db/db mice as compared to scramble‐administered mice. Altogether, study results suggest a novel role of miR‐146a in regulating prion and highlighted novel delivery of therapeutic non‐coding RNAs through exosomes that helped in alleviating cognitive functions in diabetic db/db mice. Support or Funding Information This work was supported by NIH grant HL107640‐NT. HypothesisDiabetic db/db mice brains have altered regulation of prion protein which is associated with down‐regulation of miR‐146a. Microtubule associated proteins are also involved in dementia‐like pathology. Administration of exosomes loaded with miR‐146a rescued prion expression and dementia‐like pathology.