title: Expression of microRNA-34a in Alzheimer's disease brain targets genes linked to synaptic plasticity, energy metabolism, and resting state network activity.
abstract: Polygenetic risk factors and reduced expression of many genes in late-onset Alzheimer's disease (AD) impedes identification of a target(s) for disease-modifying therapies. We identified a single microRNA, miR-34a that is over expressed in specific brain regions of AD patients as well as in the 3xTg-AD mouse model. Specifically, increased miR-34a expression in the temporal cortex region compared to age matched healthy control correlates with severity of AD pathology. miR-34a over expression in patient's tissue and forced expression in primary neuronal culture correlates with concurrent repression of its target genes involved in synaptic plasticity, oxidative phosphorylation and glycolysis. The repression of oxidative phosphorylation and glycolysis related proteins correlates with reduced ATP production and glycolytic capacity, respectively. We also found that miR-34a overexpressed neurons secrete miR-34a containing exosomes that are taken up by neighboring neurons. Furthermore, miR-34a targets dozens of genes whose expressions are known to be correlated with synchronous activity in resting state functional networks. Our analysis of human genomic sequences from the tentative promoter of miR-34a gene shows the presence of NFκB, STAT1, c-Fos, CREB and p53 response elements. Together, our results raise the possibilities that pathophysiology-induced activation of specific transcription factor may lead to increased expression of miR-34a gene and miR-34a mediated concurrent repression of its target genes in neural networks may result in dysfunction of synaptic plasticity, energy metabolism, and resting state network activity. Thus, our results provide insights into polygenetic AD mechanisms and disclose miR-34a as a potential therapeutic target for AD.
authors.affiliation: Center for Basic and Translational Stroke Research, Department of Physiology and Pharmacology, West Virginia University, Morgantown, WV 26506, United States.
authors.forename: S
authors.initials: S
authors.lastname: Sarkar
authors.affiliation: Center for Basic and Translational Stroke Research, Department of Physiology and Pharmacology, West Virginia University, Morgantown, WV 26506, United States.
authors.forename: S
authors.initials: S
authors.lastname: Jun
authors.affiliation: Center for Basic and Translational Stroke Research, Department of Physiology and Pharmacology, West Virginia University, Morgantown, WV 26506, United States.
authors.forename: S
authors.initials: S
authors.lastname: Rellick
authors.affiliation: Center for Basic and Translational Stroke Research, Department of Physiology and Pharmacology, West Virginia University, Morgantown, WV 26506, United States.
authors.forename: D D
authors.initials: DD
authors.lastname: Quintana
authors.affiliation: Center for Basic and Translational Stroke Research, Department of Physiology and Pharmacology, West Virginia University, Morgantown, WV 26506, United States.
authors.forename: J Z
authors.initials: JZ
authors.lastname: Cavendish
authors.affiliation: Center for Basic and Translational Stroke Research, Department of Physiology and Pharmacology, West Virginia University, Morgantown, WV 26506, United States. Electronic address: jwsimpkins@hsc.wvu.edu.
authors.forename: J W
authors.initials: JW
authors.lastname: Simpkins
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004734:Energy Metabolism; D005260:Female; D006019:Glycolysis; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009473:Neuronal Plasticity; D009474:Neurons / Q000378:metabolism; D010085:Oxidative Phosphorylation; D061251:Primary Cell Culture
chemical_list: C522425:MIRN34 microRNA, human; D035683:MicroRNAs
keywords: Alzheimer's disease; Glycolysis; MiR-34a; MicroRNAs; Oxidative phosphorylation; Resting state network; Synaptic plasticity