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[P3–196]: MICRORNA EXPRESSION IN ALZHEIMER DISEASE: A SYSTEMATIC REVIEW OF THE LITERATURE AND META‐ANALYSIS
Author(s) -
Takousis Petros,
Schulz Jessica,
Lill Christina M.,
Perneczky Robert,
Bertram Lars
Publication year - 2017
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2017.06.1408
Subject(s) - microrna , meta analysis , biology , gene expression , gene , disease , bioinformatics , messenger rna , computational biology , genetics , medicine
EOAD and late onset AD share amyloid and tau pathology but there are important differences between the two with respect to age of onset, speed of progression and presenting symptoms. Since EOAD is only rarely caused by autosomal dominant mutation inheritance, there are currently no distinguishing biomarkers for EOAD alone. MicroRNAs (miRNAs) are short non-coding RNAs involved in the degradation or translational repression of several mRNA targets. MiRNAs are packaged into exosomes, released by cells into the extracellular milieu and biofluids, including cerebrospinal fluid (CSF), and are implicated in cell-to-cell communication. We hypothesized that uncovering significantly altered exosomal miRNAs in the CSF of EOAD patients would reveal novel biomarkers, provide insight into disease mechanism, and guide therapeutic development. Methods: CSF was obtained by lumbar puncture from patients diagnosed with EOAD (N1⁄417, 60.8864.62 years) and healthy controls (N1⁄412; 67.0867.83 years). The miRCURYExosome Isolation Kit (Exiqon) was used to isolate exosomes from 1.0mL of input CSF. Subsequently, the miRNA was purified from each exosomal prep and converted into cDNA. For the discovery phase of the study, each sample underwent real-time PCR on two 384 well plates with 752 miRNA primer sets (Exiqon Human Panels I and II), whereby candidate differentially expressed miRNAs were revealed. For the validation phase, candidate miRNAs are being confirmed by independent real-time PCR experiments. Results: Preliminary data from the discovery phase revealed that of 52 miRNAs expressed in at least 75% of all samples, 7 were up-regulated and 10 were down-regulated in the exosomal CSF from EOAD compared with healthy controls (all p<0.05). To date, the down-regulation of miR-451a in EOAD has been validated (p<0.01). Computational modeling is being performed to assess whether multiple differentially expressed miRNAs can predict EOAD diagnosis. Also, a bioinformatics analysis is being conducted to identify putative mRNA targets and pathways altered in EOAD. Conclusions:This study identified novel differentially expressed exosomal miRNAs from CSF isolated from EOAD patients. These miRNAs may differentiate EOAD from other forms of AD, elucidate disease mechanism, and contribute novel targets for therapeutics.