Neuron
Volume 103, Issue 5, 4 September 2019, Pages 820-835.e7
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Article
TREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in Alzheimer’s Disease

https://doi.org/10.1016/j.neuron.2019.06.010Get rights and content
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Highlights

  • Mitigation of Aβ pathology in 5xFAD;CD33−/− mice is abrogated by knocking out TREM2

  • Reduction of Iba1+ cells in 5xFAD;TREM2−/− mice is not rescued by knocking out CD33

  • CD33 and TREM2 knockout increase and reduce microglial activation, respectively

  • Gene expression changes in 5xFAD;CD33−/− microglia depend on the presence of TREM2

Summary

The microglial receptors CD33 and TREM2 have been associated with risk for Alzheimer’s disease (AD). Here, we investigated crosstalk between CD33 and TREM2. We showed that knockout of CD33 attenuated amyloid beta (Aβ) pathology and improved cognition in 5xFAD mice, both of which were abrogated by additional TREM2 knockout. Knocking out TREM2 in 5xFAD mice exacerbated Aβ pathology and neurodegeneration but reduced Iba1+ cell numbers, all of which could not be rescued by additional CD33 knockout. RNA-seq profiling of microglia revealed that genes related to phagocytosis and signaling (IL-6, IL-8, acute phase response) are upregulated in 5xFAD;CD33−/− and downregulated in 5xFAD;TREM2−/− mice. Differential gene expression in 5xFAD;CD33−/− microglia depended on the presence of TREM2, suggesting TREM2 acts downstream of CD33. Crosstalk between CD33 and TREM2 includes regulation of the IL-1β/IL-1RN axis and a gene set in the “receptor activity chemokine” cluster. Our results should facilitate AD therapeutics targeting these receptors.

Keywords

CD33
TREM2
microglia
amyloid beta
neuroinflammation
Alzheimer's
RNA-seq
transcriptomics
pathway analysis
IL-1beta

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