Loss of TREM2 confers resilience to synaptic and cognitive impairment in aged mice

Wenhui Qu, Ling Li

Research output: Contribution to journalArticlepeer-review

Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2), a receptor exclusively expressed by microglia in the brain, modulates microglial immune homeostasis. Human genetic studies have shown that the loss-of-function mutations in TREM2 signaling are strongly associated with an elevated risk of age-related neurodegenerative diseases including Alzheimer's disease (AD). Numerous studies have investigated the impact of TREM2 deficiency in the pathogenic process of AD. However, the role of TREM2 in shaping neuronal and cognitive function during normal aging is underexplored. In the present study, we employed behavioral, electrophysiological, and biochemical approaches to assess cognitive and synaptic function in male and female young and aged TREM2-deficient (Trem22/2) mice compared with age-matched, sex-matched, and genetic background-matched wild-type (WT) C57BL/6J controls. Young Trem22/2 mice exhibited normal cognitive function and synaptic plasticity but had increased dendritic spine density compared with young WT. Unexpectedly, aged Trem22/2 mice showed superior cognitive performance compared with aged WT controls. Consistent with the behavioral data, aged Trem22/2 mice displayed significantly enhanced hippocampal long-term potentiation (LTP) and increased dendritic spine density and synaptic markers compared with aged WT mice. Taken together, these findings suggest that loss of TREM2 affects the neuronal structure and confers resilience to age-related synaptic and cognitive impairment during non-pathogenic aging.

Original languageEnglish (US)
Pages (from-to)9552-9563
Number of pages12
JournalJournal of Neuroscience
Volume40
Issue number50
DOIs
StatePublished - Dec 9 2020

Bibliographical note

Funding Information:
Received Aug. 20, 2020; revised Oct. 12, 2020; accepted Oct. 27, 2020. Author contributions: L.L. designed research; W.Q. performed research; W.Q. analyzed data; W.Q. and L.L. wrote the paper. This work was supported in part by grants from the National Institute on Aging of the National Institutes of Health (AG056976 and AG058081) and the College of Pharmacy at the University of Minnesota. We thank Dr. Marco Colonna at Washington University for providing the original breeding pairs of Trem2−/− mice and Andrea Gram for maintaining and genotyping the experimental mice. The authors declare no competing financial interests. Correspondence should be addressed to Ling Li at lil@umn.edu. https://doi.org/10.1523/JNEUROSCI.2193-20.2020 Copyright © 2020 the authors

Publisher Copyright:
© 2020 the authors

Keywords

  • Aging
  • Dendritic spine density
  • Learning and memory
  • Long-term potentiation
  • Synaptic plasticity
  • TREM2

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