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Spreading of Alzheimer's disease inflammatory signaling through soluble micro-RNA.

ABSTRACT: Alzheimer's disease is a progressive, neurodegenerative disorder that develops within the limbic system, spreading radially into anatomically linked brain association areas as the disease progresses. Analysis of temporal-lobe association of neocortex-derived extracellular fluid and cerebrospinal fluid from Alzheimer's disease patients shows an abundant presence of micro-RNA (miRNA), including the proinflammatory miRNA-146a and miRNA-155. Using a novel and highly sensitive LED-Northern dot-blot focusing technique, we detected the secretion of potentially pathogenic amounts of miRNA-146a and miRNA-155 from stressed human primary neural cells. A conditioned medium containing miRNA-146a and miRNA-155 was found to induce Alzheimer-type gene expression changes in control brain cells. These included downregulation in the expression of an important repressor of the innate immune response, complement factor H (CFH). These effects were neutralized using anti-miRNA strategies. Anti-miRNA-based therapeutics may provide a novel and efficacious treatment to stem the miRNA-mediated spreading of inflammatory signaling involved in Alzheimer's disease.

SUBMITTER: Lukiw WJ

PROVIDER: S-EPMC4467540 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Spreading of Alzheimer's disease inflammatory signaling through soluble micro-RNA.

Lukiw Walter J WJ Alexandrov Peter N PN Zhao Yuhai Y Hill James M JM Bhattacharjee Surjyadipta S

Neuroreport 20120701 10

Alzheimer's disease is a progressive, neurodegenerative disorder that develops within the limbic system, spreading radially into anatomically linked brain association areas as the disease progresses. Analysis of temporal-lobe association of neocortex-derived extracellular fluid and cerebrospinal fluid from Alzheimer's disease patients shows an abundant presence of micro-RNA (miRNA), including the proinflammatory miRNA-146a and miRNA-155. Using a novel and highly sensitive LED-Northern dot-blot f ...[more]

PMID: 22660168

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Project description:Alzheimer's disease (AD) is a tragic, progressive, age-related neurological dysfunction, representing one of the most prevalent neurodegenerative disorders in industrialized societies. Globally, 5 million new cases of AD are diagnosed annually, with one new AD case being reported every 7?s. Most recently there has been a surge in the study of the regulatory mechanisms of the AD process, and the particular significance of small non-coding ?22 ribonucleotide RNAs called micro RNAs (miRNAs). Abundant data have profiled miRNA patterns in healthy, aging brain, in mild cognitive impairment (MCI), and in the moderate- and late-stages of AD. The major mode of action of miRNA is to interact, via base-pair complementarity, with ribonucleotides located within the 3' untranslated region (3'-UTR) of multiple target messenger RNAs (mRNAs), and in doing so decrease the capability of that specific mRNA to be expressed. Many miRNAs are highly cell- and tissue-specific. The human brain appears to use only a highly specific fraction of all known human miRNAs, whose speciation and complexity are defined as a discrete subset of all known small non-coding RNAs (sncRNAs) in the brain. In general, in contrast to normally, aging human brain, in AD a family of pathogenically up-regulated miRNAs appear to be down-regulating the expression certain brain-essential mRNA targets, including key regulatory genes involved interactively in neuroinflammation, synaptogenesis, neurotrophic functions, and amyloidogenesis. These up-regulated, NF-kB-sensitive miRNAs, involved in the innate immune and inflammatory response and synaptic, neurotrophic, and amyloidogenic functions include miRNA-9, miRNA-125b, miRNA-146a, and miRNA-155. Other miRNAs of the miRNA-15/107 family, miRNA-153 and miRNA-190, and others, will be discussed. Overall, this manuscript will review the known contribution of miRNAs to aging brain function and the role they appear to play in the incidence and progression of AD.

Dataset Information

Spreading of Alzheimer's disease inflammatory signaling through soluble micro-RNA.

Publications

Spreading of Alzheimer's disease inflammatory signaling through soluble micro-RNA.

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