Abstract
Alzheimer’s disease (AD) of the brain neocortex and age-related macular degeneration (AMD) of the retina are two complex neurodegenerative disorders, which (i) involve the progressive dysregulation and deterioration of multiple neurobiological signaling pathways, (ii) exhibit the temporal accumulation of pro-inflammatory lesions including the amyloid beta (Aβ) peptide-containing senile plaques of AD and the drusen of AMD, and (iii) culminate in an insidious inflammatory neurodegeneration ending, respectively, in neural cell atrophy and death and progressive loss of cognition and central visual function. Recent independent research studies have indicated that AD and AMD share common, pathological signaling defects and disease mechanisms at the molecular genetic level. Using high-integrity total RNA samples pooled from AD brain and AMD retina, microfluidic hybridization miRNA arrays, and bioinformatics, the current study was undertaken to quantify microRNA (miRNA) speciation and complexity common to both AD and AMD. These small non-coding (sncRNAs) are known to post-transcriptionally regulate multiple neurobiological pathways and an abundance of research information has already been generated on the roles of these miRNAs in pathological situations involving inflammatory neuropathology and neural cell decline. Here, for the first time, we report the sequence and abundance of a septet of sncRNAs including miRNA-7, miRNA-9-1, miRNA-23a/miRNA-27a, miRNA-34a, miRNA-125b-1, miRNA-146a, and miRNA-155 that are significantly increased in abundance and common to both AD-affected superior temporal lobe neocortex (Brodmann A22) and the AMD-affected macular region of the retina. Bioinformatics, miRNA–mRNA complementarity, next-gen RNA sequencing, and feature alignment analysis further indicate that these 7 up-regulated miRNAs have the potential to interact with and down-regulate ~ 9460 target messenger RNAs (mRNAs; about 3.5% of the genome) involved in the synchronization of amyloid production and clearance, phagocytosis, innate-immune, pro-inflammatory, and neurotrophic signaling and/or synaptogenesis in diseased tissues.
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Acknowledgements
The work reported in this paper was presented in part at the Vavilov Institute of General Genetics Autumn 2016 Seminar Series (Инcтитyт oбщeй гeнeтики имeни Baвилoвa Oceнь 2016 Ceминap cepии) in Moscow, RUSSIA October 2016 and at the Society for Neuroscience (SFN) Annual Meeting, Washington DC, USA November 2017. Sincere thanks are extended to Drs PN Alexandrov, JG Cui, F Culicchia, W Poon, K Navel, C Hebel, C Eicken, and the late Dr. JM Hill to for helpful discussions in this research area, for short post-mortem interval (PMI) human brain and retinal tissues or extracts, and for initial bioinformatics and data interpretation, and to D Guillot for expert technical assistance and medical artwork. Thanks are also extended to the University of California at Irvine Brain Bank, the University of Maryland Brain and Tissue Bank, and the LSU School of Medicine-archived brain nucleic acid source, and the many neuropathologists, physicians, and researchers of the US and Canada who have provided high-quality, short post-mortem interval (PMI) human CNS or extracted tissue fractions for scientific study. Research on the microRNAs, pro-inflammatory and pathogenic signaling in the Lukiw laboratory involving the microbiome, the innate-immune response, neuroinflammation, and amyloidogenesis in AD, prion, and in other neurological diseases was supported through an unrestricted grant to the LSU Eye Center from Research to Prevent Blindness (RPB), the Louisiana Biotechnology Research Network (LBRN), and NIH grants NEI EY006311, NIA AG18031, and NIA AG038834 (WJL). Additional data related to this paper may be requested from the authors.
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All procedures involving post-mortem human neocortical and retinal tissues were followed and handled in strict accordance with the ethics review board policies at donor institutions, and the Institutional Biosafety Committee/Institutional Review Board (IBC/IRB) Committee’s ethical guidelines (IBC#12323; IRB#6774) at the Louisiana State University Health Sciences Center, School of Medicine, New Orleans LA 70112 USA.
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Pogue, A.I., Lukiw, W.J. Up-regulated Pro-inflammatory MicroRNAs (miRNAs) in Alzheimer’s disease (AD) and Age-Related Macular Degeneration (AMD). Cell Mol Neurobiol 38, 1021–1031 (2018). https://doi.org/10.1007/s10571-017-0572-3
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DOI: https://doi.org/10.1007/s10571-017-0572-3