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Addressing Alzheimer’s Disease (AD) Neuropathology Using Anti-microRNA (AM) Strategies

Abstract

Disruptions in multiple neurobiological pathways and neuromolecular processes have been widely implicated in the etiopathology of Alzheimer’s disease (AD), a complex, progressive, and ultimately lethal neurological disorder whose current incidence, both domestically and globally, is reaching epidemic proportions. While only a few percent of all AD cases appear to have a strong genetic or familial component, the major form of this disease, known as idiopathic or sporadic AD, displays a multi-factorial pathology and represents one of the most complex and perplexing neurological disorders known. More effective and innovative pharmacological strategies for the successful intervention and management of AD might be expected: (i) to arise from strategic-treatments that simultaneously address multiple interrelated AD targets that are directed at the initiation, development, and/or propagation of this disease and (ii) those that target the “neuropathological core” of the AD process at early or upstream stages of AD. This “Perspectives paper” will review current research involving microRNA (miRNA)-mediated, messenger RNA (mRNA)-targeted gene expression pathways in sporadic AD and address the potential implementation of evolving anti-microRNA (AM) strategies in the amelioration and clinical management of AD. This novel-therapeutic approach: (i) incorporates a system involving the restoration of multiple miRNA-regulated mRNA-targets via the use of selectively-stabilized AM species; and (ii) that via implementation of synthetic AMs, the abundance of only relatively small-families of miRNAs need be modulated or neutralized to re-establish neural-homeostasis in the AD-affected brain. In doing so, these strategic approaches will jointly and interactively address multiple AD-associated processes such as the disruption of synaptic communication, defects in amyloid peptide clearance and amyloidogenesis, tau pathology, deficits in neurotrophic support, alterations in the innate immune response, and the proliferation of neuroinflammatory signaling.

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Acknowledgments

The analytical, experimental and statistical work in this research report was presented in part at the Vavilov Institute of General Genetics autumn seminar series (Серия осенних семинаров) in Moscow RUSSIA November 2018 and at the Society for Neuroscience (SFN) Annual Meeting November 2018, San Diego CA, USA. Sincere thanks are extended to the late Drs. JM Hill (JMH; Louisiana State University), TPA Kruck (TPAK; University of Toronto), C. Bergeron (CB, University of Toronto) for helpful discussions on this research area and to F Culicchia, C Eicken, C Hebel, B. Krishnan, K Navel, and L. Wong for short postmortem interval (PMI) human and other mammalian brain tissues or extracts and data interpretation and to D Guillot for expert technical assistance. Thanks are also extended to the many neuropathologists, physicians and researchers of the US, Canada, Europe and Russia who have provided high quality, short postmortem interval (PMI) human CNS or extracted brain tissue fractions for scientific study. We would like to further thank the following 18 domestic and international brain banks, and their continuing cooperation, for access to high quality postmortem tissues and valuable analytical advice: the Autism Brain Net, Los Angeles CA, USA; the Harvard University/McLean Hospital Tissue Center, Boston MA, USA; Louisiana State University, New Orleans LA, USA; the Lomonosov Institute, Moscow State University, Moscow, Russian Federation; the National Disease Research Interchange, Philadelphia PA, USA; the National Institutes of Health NIH NeuroBioBank, comprised of tissues from the National Institute of Mental Health (NIMH), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Neurological Disorders and Stroke (NINDS), Bethesda MD USA; the Netherlands Brain Research Institute, Amsterdam, Netherlands; the New York State Institute for Basic Research, Staten Island NY, USA; the Oregon Health Sciences University, Portland OR, USA; the Southern Eye Bank, Metairie LA, USA; the University of California, Irvine CA, USA; the University of Kentucky Alzheimer’s disease Brain Bank, Lexington KY, USA; the University of Maryland Brain and Tissue Bank, Baltimore MD, USA; the University of Massachusetts, Worcester MA, USA; University of Pennsylvania School of Medicine, Philadelphia PA, USA, and the University of Toronto Brain Bank, Toronto ON, Canada. All authors agree on the content of this publication. Research on AM design and potential treatment strategies, metal neurotoxicity, human and murine microRNAs, small noncoding RNA (sncRNA), proinflammatory and pathogenic signaling in the Lukiw laboratory involving the innate-immune response, neuroinflammation and amyloidogenesis in AD, PrD and in other human neurological disorders was supported through an unrestricted grant to the LSU Eye Center from Research to Prevent Blindness (RPB); the Louisiana Biotechnology Research Network (LBRN), the Alzheimer Association and NIH grants NEI EY006311, NIA AG18031 and NIA AG038834 (WJL).

Funding

Research on AM design and potential treatment strategies, metal neurotoxicity, human and murine microRNAs, small non-coding RNA, pro-inflammatory and pathogenic signaling in the Lukiw laboratory involving the innate immune response, neuroinflammation, and amyloidogenesis in AD and PrD and in other human neurological disorders was financially supported through an unrestricted grant to the LSU Eye Center from Research to Prevent Blindness (RPB) and by the Louisiana Biotechnology Research Network (LBRN), the Alzheimer’s Association, and NIH grants NEI EY006311, NIA AG18031, and NIA AG038834 (WJL).

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Contributions

VRJ, YZ, NMS, and WJL performed all microRNA and messenger RNA analysis, miRNA-mRNA verification and linking, and preliminary AM experiments, organized and tabulated all the data, and performed statistical analysis from age-, gender-, and PMI-matched control and AD brains, and collaborated interactively in the synthesis of the material presented in this Frontiers “Perspective” article. WJL wrote the paper. YZ and WJL have published in excess of 50 peer-reviewed manuscripts into this research area. All authors agree on the content of this publication.

Corresponding author

Correspondence to Walter J. Lukiw.

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Ethics Statement

All acquisition, handling, experimental, and analytical procedures involving postmortem human brain tissues were carried out in an ethical manner in strict accordance with the ethics review board policies at brain and tissue donor institutions and at the Louisiana State University (LSU) Health Sciences Center. Informed consent from next of kin was obtained at brain and tissue donor institutions for all tissue samples prior to autopsy and donation; coded postmortem brain tissue samples (containing no personal identifying information of the donors) were obtained from the 18 brain and tissue banks listed in the “Acknowledgments” section above. The ethical use of postmortem human brain tissues and their analyses were also carried out in strict accordance with the Institutional Biosafety Committee and the Institutional Review Board Committee (IBC/IRBC) ethical guidelines IBC#18059 and IRBC#6774 at the LSU Health Sciences Center, New Orleans, LA 70112, USA.

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Jaber, V.R., Zhao, Y., Sharfman, N.M. et al. Addressing Alzheimer’s Disease (AD) Neuropathology Using Anti-microRNA (AM) Strategies. Mol Neurobiol 56, 8101–8108 (2019). https://doi.org/10.1007/s12035-019-1632-0

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Keywords

  • Alzheimer’s disease
  • microRNA (miRNA)
  • messenger RNA (mRNA)
  • miRNA-mRNA linkage analysis
  • miRNA-7
  • miRNA-9
  • miRNA-34a
  • miRNA-125b
  • miRNA-146a
  • miRNA-155