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O3‐05‐03: Micro RNA (miRNA) signaling in Alzheimer's disease
Author(s) -
Lukiw Walter
Publication year - 2011
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.2011.05.1418
Subject(s) - microrna , biology , messenger rna , untranslated region , gene , gene expression , epigenetics , rna , regulation of gene expression , genetics , microbiology and biotechnology
Background: Micro RNAs (miRNAs) are a recently described family of small, non-coding RNAs that regulate the post-transcriptional expression of genes. Their major mode of epigenetic action is to bind to complimentary nucleic acid sequences in the 3’ un-translated region (3’-UTR) of messenger RNA (mRNA), and thereby act as a repressor of that mRNA’s expression. Hence, up-regulated miRNAs down-regulate their mRNA targets. Increased miRNA abundance is associated with neurodegenerative disorders including Alzheimer’s disease (AD) and prion-mediated neurode generation. Perhaps the most interesting property of miRNAs is their ability to interact with multiple mRNAs, and thereby down-regulate the abundance of interrelated families of disease-relevant genes. Methods: 5xFAD Tg-AD models; bioinformatics; DNA array; primary human brain cell culture; miRNA array; miRNA-promoter-reporter assays; NF-kB inhibitors; Northern dot blot concentration technique; primary human brain cell culture; RT-PCR; Tg2576 Tg-AD models; Western analysis. Results: The brainenrichedmicro RNAsmiRNA-125b and miRNA-146a were found to be significantly up-regulated in 108 short post-mortem interval control and AD brains, in human primary brain cells (neuronal-glial co-cultures) and in specific amyloid over-expressing Tg-AD models. Specific AD-relevant mRNA targets were predicted and tested for relevance; gene expression for these mRNA targets were analyzed at the mRNA and protein level; highly interactive NF-kB-miRNA mechanisms were identified. Conclusions: Our recent work characterizes the signaling mechanism of two NF-kB-sensitivemiRNAs -miRNA-125b andmiRNA-146a that are significantly up-regulated (a) in AD brain, (b) in stressed human brain cells in primary culture, and (c) in transgenic murine models of AD (Tg-AD) including the Tg2576 and 5xFAD Tg-AD murine models. These brain enriched miRNAs represent a critical epigenetic control that down-regulates the expression of specific disease-related brain genes in AD and in AD models; down-regulation of these multiple, AD-relevant brain genes affect (a) the innate immune and inflammatory response, (b) neurotrophism and amyloid generation, and (c) synaptogenesis.