Microglia TREM2R47H Alzheimer-linked variant enhances excitatory transmission and reduces LTP via increased TNF-α levels
- 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.
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All data generated or analyzed during this study are included in the Source data files have been provided for all Figures.
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Author details
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.
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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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
