Abundant evidence supports the idea that progressive up-regulation of complex pro-inflammatory signaling, A?42 peptide evolution, and loss of neurotrophic support underlie the initiation and propagation of Alzheimer's disease (AD). Micro RNA (miRNA)-mediated messenger RNA (mRNA) interference is a newly discovered genetic mechanism involved in the regulation of gene expression at the post-transcriptional level. The major mode of miRNA action is to target and bind to the 3'un-translated region of specific mRNAs and in doing so, quench expression of that mRNA, thereby acting as a negative regulator of gene expression. AD affects only specific areas of the brain, and mis-regulated miRNA expression is strongly linked to altered gene expression within these regions. In AD models, these same AD-enriched miRNAs induce specific pathological changes that are strikingly similar to those observed in AD brain. Accumulating evidence strongly suggests that altered miRNA-mediated processing of specific mRNA populations triggers the pathogenic expression of genes that drive the AD process. The overall goal of this project is to significantly move the miRNAin- AD field forward, and impact the scientific understanding of AD, by defining mechanistically how specific miRNAs induce molecular-genetic mechanisms that result in AD-type change. Human brains utilize only a fraction of all known miRNA species;and only a subset of these are altered in AD brain. Increases in the expression of a specific NF-?B-sensitive miRNA-146a down-regulates the abundance of at least three major mRNA targets, complement factor H (CFH), interleukin-1 receptor associated kinase (IRAK) and tetraspanin 12 (TSPAN12), that encode key modulators of the brain's innate immune system, inflammatory response and the generation of neurotrophic or neurotoxic amyloid peptides. Down-regulated TSPAN12 restricts ADAM10 (a-secretase) dependent cleavage of beta-amyloid precursor protein (?APP). Stressed human brain cells up-regulate miRNA-146a in parallel with increased amyloidogenesis and shedding of A?42 peptides. Hypothesis: up-regulated miRNA-146a contributes to altered innate immune and inflammatory responses, increased A?42 peptide generation and decreased neurotrophic support.
Three Specific Aims test predicted outcomes based on this hypothesis in AD, in stressed human brain primary cells, and in specific transgenic models of AD.
These Specific Aims i nclude (1) identification of alterations in miRNA-146a abundance in AD brain;(2) testing whether stressed human neuronal, astrocyte or microglial cells exhibit miRNA changes similar to those conducive to inflammatory neurodegeneration and A?42 peptide generation in AD tissues, and testing if added exogenous miRNA-146a or anti-miRNA-146a oligonucleotides will promote or neutralize these changes;and (3) testing whether miRNA-146a, anti-miRNA-146a and modulation of CFH, IRAK or TSPAN12 expression are key regulators of the inflammatory response and amyloidogenesis in amyloid over-expressing Tg2576 mice.
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|Hill, James M; Zhao, Yuhai; Bhattacharjee, Surjyadipta et al. (2014) miRNAs and viroids utilize common strategies in genetic signal transfer. Front Mol Neurosci 7:10|
|Pogue, Aileen I; Hill, James M; Lukiw, Walter J (2014) MicroRNA (miRNA): sequence and stability, viroid-like properties, and disease association in the CNS. Brain Res 1584:73-9|
|Jones, Brandon M; Bhattacharjee, Surjyadipta; Dua, Prerna et al. (2014) Regulating amyloidogenesis through the natural triggering receptor expressed in myeloid/microglial cells 2 (TREM2). Front Cell Neurosci 8:94|
|Ball, Melvyn J; Lukiw, Walter J; Kammerman, Eli M et al. (2013) Intracerebral propagation of Alzheimer's disease: strengthening evidence of a herpes simplex virus etiology. Alzheimers Dement 9:169-75|
|Hill, James M; Stern, Ethan M; Bhattacharjee, Partha S et al. (2013) The antimicrobial agent C31G is effective for therapy for HSV-1 ocular keratitis in the rabbit eye model. Antiviral Res 100:14-9|
|Bhattacharjee, Surjyadipta; Zhao, Yuhai; Hill, James M et al. (2013) Selective accumulation of aluminum in cerebral arteries in Alzheimer's disease (AD). J Inorg Biochem 126:35-7|
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