title: MicroRNA-195 protects against dementia induced by chronic brain hypoperfusion via its anti-amyloidogenic effect in rats.
abstract: Previous studies have demonstrated that chronic brain hypoperfusion (CBH) causes Aβ aggregation by upregulating expression of amyloid precursor protein (APP) and β-site APP cleaving enzyme 1 (BACE1) protein, which is accompanied by cognitive impairment, but the mechanisms are not fully understood. In this study, we evaluated the effect of microRNA on memory impairment in rats induced by CBH. We show here that CBH generated by bilateral common carotid artery occlusion (2VO) significantly decreased the learning and memory ability in rats, as assessed by Morris water maze, and upregulated expression of APP and BACE1 proteins in the hippocampus and cortex of rats, as evaluated by Western blot and immunofluorescence. In reciprocal, qRT-PCR analysis showed that microRNA-195 (miR-195) was downregulated in both the hippocampus and cortex of rats following CBH, and in the plasma of dementia patients. APP and BACE1 proteins were downregulated by miR-195 overexpression, upregulated by miR-195 inhibition, and unchanged by binding-site mutation or miR-masks, indicating that APP and BACE1 are two potential targets for miR-195. Knockdown of endogenous miR-195 by lentiviral vector-mediated overexpression of its antisense molecule (lenti-pre-AMO-miR-195) elicited dementia in rats, whereas overexpression of miR-195 using lenti-pre-miR-195 reduced dementia vulnerability triggered by 2VO. Additionally, chromatin immunoprecipitation analysis showed that NFκB was bound to the promoter region of miR-195 and inhibited its expression. We conclude that miR-195 may play a key role in determining dementia susceptibility in 2VO rats by regulating APP and BACE1 expression at the post-transcriptional level, and exogenous complement of miR-195 may be a potentially valuable anti-dementia approach.
authors: Department of Pharmacology, Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China, 150081. a.z.hrbmu@gmail.com
authors: Jing
authors: J
authors: Ai
authors: Li-Hua
authors: LH
authors: Sun
authors: Hui
authors: H
authors: Che
authors: Rong
authors: R
authors: Zhang
authors: Tian-Zhu
authors: TZ
authors: Zhang
authors: Wan-Chen
authors: WC
authors: Wu
authors: Xiao-Lin
authors: XL
authors: Su
authors: Xin
authors: X
authors: Chen
authors: Guang
authors: G
authors: Yang
authors: Kang
authors: K
authors: Li
authors: Ning
authors: N
authors: Wang
authors: Tao
authors: T
authors: Ban
authors: Ya-Nan
authors: YN
authors: Bao
authors: Fei
authors: F
authors: Guo
authors: Hui-Fang
authors: HF
authors: Niu
authors: Yu-Lan
authors: YL
authors: Zhu
authors: Xiu-Ying
authors: XY
authors: Zhu
authors: Shi-Guang
authors: SG
authors: Zhao
authors: Bao-Feng
authors: BF
authors: Yang
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000097:blood / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D002340:Carotid Artery Diseases / Q000150:complications*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D003704:Dementia / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D035683:MicroRNAs / Q000096:biosynthesis / Q000097:blood / Q000627:therapeutic use*; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000378:metabolism / Q000627:therapeutic use*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016282:Aspartic Acid Endopeptidases; D008070:Lipopolysaccharides; D035683:MicroRNAs; D018696:Neuroprotective Agents; D016376:Oligonucleotides, Antisense; D010446:Peptide Fragments; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D000097782:NF-kappaB-Inducing Kinase; C552722:MIRN195 microRNA, human; C075222:amyloid beta-protein (1-42); C509280:BACE1 protein, human