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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG038834-04
Application #
8700279
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Petanceska, Suzana
Project Start
2011-08-01
Project End
2016-05-31
Budget Start
2014-08-01
Budget End
2015-05-31
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Louisiana State Univ Hsc New Orleans
Department
Neurosciences
Type
Schools of Medicine
DUNS #
City
New Orleans
State
LA
Country
United States
Zip Code
70112
Alexandrov, Peter N; Pogue, Aileen I; Lukiw, Walter J (2018) Synergism in aluminum and mercury neurotoxicity. Integr Food Nutr Metab 5:
Alexandrov, P N; Percy, M E; Lukiw, Walter J (2018) Chromosome 21-Encoded microRNAs (mRNAs): Impact on Down's Syndrome and Trisomy-21 Linked Disease. Cell Mol Neurobiol 38:769-774
Zhao, Yuhai; Jaber, Vivian; Percy, Maire E et al. (2017) A microRNA cluster (let-7c, miRNA-99a, miRNA-125b, miRNA-155 and miRNA-802) encoded at chr21q21.1-chr21q21.3 and the phenotypic diversity of Down's syndrome (DS; trisomy 21). J Nat Sci 3:
Zhao, Yuhai; Jaber, Vivian; Lukiw, Walter J (2017) Secretory Products of the Human GI Tract Microbiome and Their Potential Impact on Alzheimer's Disease (AD): Detection of Lipopolysaccharide (LPS) in AD Hippocampus. Front Cell Infect Microbiol 7:318
Alexandrov, Peter N; Zhao, Yuhai; Jaber, Vivian et al. (2017) Deficits in the Proline-Rich Synapse-Associated Shank3 Protein in Multiple Neuropsychiatric Disorders. Front Neurol 8:670
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Zhao, Yuhai; Cong, Lin; Lukiw, Walter J (2017) Lipopolysaccharide (LPS) Accumulates in Neocortical Neurons of Alzheimer's Disease (AD) Brain and Impairs Transcription in Human Neuronal-Glial Primary Co-cultures. Front Aging Neurosci 9:407
Jaber, V; Zhao, Y; Lukiw, W J (2017) Alterations in micro RNA-messenger RNA (miRNA-mRNA) Coupled Signaling Networks in Sporadic Alzheimer's Disease (AD) Hippocampal CA1. J Alzheimers Dis Parkinsonism 7:
Pogue, A I; Jaber, V; Zhao, Y et al. (2017) Systemic Inflammation in C57BL/6J Mice Receiving Dietary Aluminum Sulfate; Up-Regulation of the Pro-Inflammatory Cytokines IL-6 and TNF?, C-Reactive Protein (CRP) and miRNA-146a in Blood Serum. J Alzheimers Dis Parkinsonism 7:
Zhao, Yuhai; Jaber, Vivian; Lukiw, Walter J (2016) Over-Expressed Pathogenic miRNAs in Alzheimer's Disease (AD) and Prion Disease (PrD) Drive Deficits in TREM2-Mediated A?42 Peptide Clearance. Front Aging Neurosci 8:140

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