title: MicroRNA Profiling of CSF Reveals Potential Biomarkers to Detect Alzheimer`s Disease.
abstract: The miRBase-21 database currently lists 1881 microRNA (miRNA) precursors and 2585 unique mature human miRNAs. Since their discovery, miRNAs have proved to present a new level of epigenetic post-transcriptional control of protein synthesis. Initial results point to a possible involvement of miRNA in Alzheimer's disease (AD). We applied OpenArray technology to profile the expression of 1178 unique miRNAs in cerebrospinal fluid (CSF) samples of AD patients (n = 22) and controls (n = 28). Using a Cq of 34 as cut-off, we identified positive signals for 441 miRNAs, while 729 miRNAs could not be detected, indicating that at least 37% of miRNAs are present in the brain. We found 74 miRNAs being down- and 74 miRNAs being up-regulated in AD using a 1.5 fold change threshold. By applying the new explorative "Measure of relevance" method, 6 reliable and 9 informative biomarkers were identified. Confirmatory MANCOVA revealed reliable miR-100, miR-146a and miR-1274a as differentially expressed in AD reaching Bonferroni corrected significance. MANCOVA also confirmed differential expression of informative miR-103, miR-375, miR-505#, miR-708, miR-4467, miR-219, miR-296, miR-766 and miR-3622b-3p. Discrimination analysis using a combination of miR-100, miR-103 and miR-375 was able to detect AD in CSF by positively classifying controls and AD cases with 96.4% and 95.5% accuracy, respectively. Referring to the Ingenuity database we could identify a set of AD associated genes that are targeted by these miRNAs. Highly predicted targets included genes involved in the regulation of tau and amyloid pathways in AD like MAPT, BACE1 and mTOR.
authors.affiliation: Department of Psychiatry and Psychotherapy, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Denk
authors.affiliation: Department of Psychiatry and Psychotherapy, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Boelmans
authors.affiliation: Institute for Cardiac Diagnostics and Therapy (IKDT), Berlin, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Siegismund
authors.affiliation: Institute for Cardiac Diagnostics and Therapy (IKDT), Berlin, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Lassner
authors.affiliation: Department of Psychiatry and Psychotherapy, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Sönke
authors.initials: S
authors.lastname: Arlt
authors.affiliation: Department of Psychiatry and Psychotherapy, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Jahn
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000134:cerebrospinal fluid / Q000235:genetics; D016282:Aspartic Acid Endopeptidases / Q000134:cerebrospinal fluid / Q000235:genetics; D015415:Biomarkers / Q000134:cerebrospinal fluid; D016002:Discriminant Analysis; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000134:cerebrospinal fluid / Q000235:genetics*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000134:cerebrospinal fluid / Q000235:genetics; D016875:tau Proteins / Q000134:cerebrospinal fluid / Q000235:genetics
chemical_list: D015415:Biomarkers; C054369:MAPT protein, human; C544266:MIRN100 microRNA, human; C544749:MIRN103 microRNA, human; C540933:MIRN375 microRNA, human; D035683:MicroRNAs; D016875:tau Proteins; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human