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Cited by 37Alzheimer's disease research and treatmentsMicroRNA in disease regulationNeuroinflammation and Neurodegeneration Mechanisms

miR155 regulation of behavior, neuropathology, and cortical transcriptomics in Alzheimer's disease

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Readhead, Ben, Haure-Mirande, Jean-Vianney, Mastroeni, Diego, Audrain, Mickael, Fanutza, Tomas, Kim, Soong H., Blitzer, Robert D., Gandy, Sam +2 more·2020·Acta Neuropathologica
DOI 10.1007/s00401-020-02185-zPMC PMC8414561
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Abstract

MicroRNAs are recognized as important regulators of many facets of physiological brain function while also being implicated in the pathogenesis of several neurological disorders. Dysregulation of miR155 is widely reported across a variety of neurodegenerative conditions, including Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, and traumatic brain injury. In previous work, we observed that experimentally validated miR155 gene targets were consistently enriched among genes identified as differentially expressed across multiple brain tissue and disease contexts. In particular, we found that human herpesvirus-6A (HHV-6A) suppressed miR155, recapitulating reports of miR155 inhibition by HHV-6A in infected T-cells, thyrocytes, and natural killer cells. In earlier studies, we also reported the effects of constitutive deletion of miR155 on accelerating the accumulation of Aβ deposits in 4-month-old APP/PSEN1 mice. Herein, we complete the cumulative characterization of transcriptomic, electrophysiological, neuropathological, and learning behavior profiles from 4-, 8- and 10-month-old WT and APP/PSEN1 mice in the absence or presence of miR155. We also integrated human post-mortem brain RNA-sequences from four independent AD consortium studies, together comprising 928 samples collected from six brain regions. We report that gene expression perturbations associated with miR155 deletion in mouse cortex are in aggregate observed to be concordant with AD-associated changes across these independent human late-onset AD (LOAD) data sets, supporting the relevance of our findings to human disease. LOAD has recently been formulated as the clinicopathological manifestation of a multiplex of genetic underpinnings and pathophysiological mechanisms. Our accumulated data are consistent with such a formulation, indicating that miR155 may be uniquely positioned at the intersection of at least four components of this LOAD "multiplex": (1) innate immune response pathways; (2) viral response gene networks; (3) synaptic pathology; and (4) proamyloidogenic pathways involving the amyloid β peptide (Aβ).

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  • Constitutive deletion of miR155, which should increase SHIP1, led to an increase in amyloid plaques.

    “Finally, Inpp5d was identified as a target of miR155, and constitutive deletion of miR155, which should increase SHIP1, led to an increase in amyloid plaques.40,41”

    From Microglial <i>INPP5D</i> limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [41]

    The Results section (“Absence of miR155 increases Aß deposition in 8-month-old APP/PSEN1 mice”) reports increased amyloid plaque deposition after constitutive miR155 deletion in APP/PSEN1 mice. The passages from our copy do not establish that the deletion increases SHIP1 or identify Inpp5d as a miR155 target; searches for SHIP1 and Inpp5d did not locate support for those parts of the citing sentence. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Numerous studies targeting members of the TREM2/TYROBP pathway (Trem2, Tyrobp, and miR155) support beneficial outcomes associated with maintenance and/or restoration of homeostatic functions of microglia.

    “Support for beneficial outcomes associated with maintenance and/or restoration of homeostatic functions of microglia comes from the numerous studies targeting the members of this pathway, including Trem2,48,50–52 Tyrobp,53,54 and miR155.41,55”

    From Microglial <i>INPP5D</i> limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [41]

    The Discussion (page unavailable) reports that miR155 deletion largely benefited learning and partially rescued synaptic plasticity in APP/PSEN1 mice. It does not establish that these benefits came from maintaining or restoring homeostatic microglial function; the Results (page unavailable) found no change in the measured microglial activation markers. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Inpp5d was identified as a target of miR155.

    “Finally, Inpp5d was identified as a target of miR155, and constitutive deletion of miR155, which should increase SHIP1, led to an increase in amyloid plaques.40,41”

    From Microglial <i>INPP5D</i> limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [41]

    The Results and Discussion describe effects of miR155 deletion, including increased amyloid plaques in APP/PSEN1 mice, but do not identify Inpp5d as a miR155 target. Searches of our copy for “Inpp5d” and “SHIP1” found no passage establishing that relationship; the plaque finding does not verify the specific claim being audited. No page numbers are available in the indexed copy. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

  • Increased miR-155 expression has been observed in mouse models of AD and in hippocampal tissue from AD donors.

    “Additionally, increased miR-155 expression has been observed in mouse models of AD and in hippocampal tissue from AD donors 28,47 .”

    From Identification of a protective microglial state mediated by miR-155 and interferon-γ signaling in a mouse model of Alzheimer’s disease (2023) · cites this paper as [28]

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References 85 · Cited by 37

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Authors
Readhead, B., Haure-Mirande, J.-V., Mastroeni, D., Audrain, M., Fanutza, T., Kim, S. H., Blitzer, R. D., Gandy, S., Dudley, J. T., & Ehrlich, M. E.
Affiliations
  • Arizona State University (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • James J. Peters VA Medical Center (US)
Corresponding author
  • Dudley, Joel T.
  • Ehrlich, Michelle E.
ORCID
Venue
Acta Neuropathologica
Publisher
Springer Science and Business Media LLC
Published
2020-07-14
Volume
140
Issue
3
Pages
295-315
ISSN
  • 0001-6322 (ISSN-L)
  • 1432-0533
DOI
10.1007/s00401-020-02185-z
PMC
PMC8414561
OpenAlex
W3043576616
Cited by
37
References
85
Citations by year
2026: 3 · 2025: 4 · 2024: 8 · 2023: 11 · 2022: 9 · 2021: 2
FWCI
3.20
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Aging (AG046170, 1\R56AG058469, 1R01AG058469, R21AG63968, U01AG061835, R21AG063068)
  • Katherine Gehl and George B. Link, Jr., Foundation
  • Alzheimer's Association (AARGD-17-529197)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
miR-155, Alzheimer's disease, HHV-6A, amyloid-beta, innate immune response, synaptic pathology, learning behavior, electrophysiology, neuropathology
MeSH terms
Alzheimer Disease, Animals, Brain, Disease Models, Animal, Humans, Mice, Transgenic, Nervous System Diseases, Amyloid beta-Peptides, MicroRNAs, Gene Regulatory Networks, Plaque, Amyloid, Transcriptome

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