Microglia TREM2R47H Alzheimer-linked variant enhances excitatory transmission and reduces LTP via increased TNF-α levels

  1. Siqiang Ren
  2. Wen Yao
  3. Marc D Tambini
  4. Tao Yin
  5. Kelly A Norris
  6. Luciano D'Adamio  Is a corresponding author
  1. Rutgers, The State University of New Jersey, United States

Abstract

To study the mechanisms by which the p.R47H variant of the microglia gene and Alzheimer's disease (AD) risk factor TREM2 increases dementia risk, we created Trem2R47H KI rats. Trem2R47H rats were engineered to produce human Aβ to define human-Aβ-dependent and -independent pathogenic mechanisms triggered by this variant. Interestingly, pre- and peri-adolescent Trem2R47H rats present increased brain concentrations of TNF-α, augmented glutamatergic transmission, suppression of Long-term-Potentiation (LTP), an electrophysiological surrogate of learning and memory, but normal Ab levels. Acute reduction of TNF-α activity with a neutralizing anti-TNF-α antibody occludes the boost in amplitude of glutamatergic transmission and LTP suppression observed in young Trem2R47H/R47H rats. Thus, the microglia-specific pathogenic Trem2 variant boosts glutamatergic neuronal transmission and suppresses LTP by increasing brain TNF-α concentrations, directly linking microglia to neuronal dysfunction. Future studies will determine whether this phenomenon represents an early, Aβ-independent pathway that facilitates dementia pathogenesis in humans.

Data availability

All data generated or analyzed during this study are included in the Source data files have been provided for all Figures.

Article and author information

Author details

  1. Siqiang Ren

    Department of Pharmacology, Physiology and Neuroscience, Rutgers, The State University of New Jersey, Newark, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Wen Yao

    Department of Pharmacology, Physiology and Neuroscience, Rutgers, The State University of New Jersey, Newark, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Marc D Tambini

    Department of Pharmacology, Physiology and Neuroscience, Rutgers, The State University of New Jersey, Newark, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4461-586X
  4. Tao Yin

    Department of Pharmacology, Physiology and Neuroscience, Rutgers, The State University of New Jersey, Newark, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Kelly A Norris

    Department of Pharmacology, Physiology and Neuroscience, Rutgers, The State University of New Jersey, Newark, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Luciano D'Adamio

    Department of Pharmacology, Physiology and Neuroscience, Rutgers, The State University of New Jersey, Newark, United States
    For correspondence
    luciano.dadamio@rutgers.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2204-9441

Funding

National Institute on Aging (R01AG063407)

  • Luciano D'Adamio

National Institute on Aging (RF1AG064821)

  • Luciano D'Adamio

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experiments were done according to policies on the care and use of laboratory animals of theEthical Guidelines for Treatment of Laboratory Animals of the NIH. The procedures were describedand approved by the Rutgers Institutional Animal Care and Use Committee (IACUC) (protocol number 201702513). All efforts were made to minimize animal suffering and reduce the number of animals used. The animals were housed two per cage under controlled laboratory conditions with a 12hr dark light cycle, a temperature of 22 {plus minus} 2{degree sign}C. Rats had free access to standard rodent diet and tapwater.

Reviewing Editor

  1. Margaret M McCarthy, University of Maryland School of Medicine, United States

Version history

  1. Received: April 2, 2020
  2. Accepted: June 23, 2020
  3. Accepted Manuscript published: June 24, 2020 (version 1)
  4. Version of Record published: July 6, 2020 (version 2)

Copyright

© 2020, Ren et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Siqiang Ren
  2. Wen Yao
  3. Marc D Tambini
  4. Tao Yin
  5. Kelly A Norris
  6. Luciano D'Adamio
(2020)
Microglia TREM2R47H Alzheimer-linked variant enhances excitatory transmission and reduces LTP via increased TNF-α levels
eLife 9:e57513.
https://doi.org/10.7554/eLife.57513

Share this article

https://doi.org/10.7554/eLife.57513

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