TREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in Alzheimer’s Disease

Jul 15, 2019Neuron

TREM2 may influence brain immune cell problems after CD33 in Alzheimer's disease

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Abstract

Knocking out CD33 in 5xFAD mice improved cognition and reduced amyloid beta pathology, but these effects were negated by additional knockout of TREM2.

CD33 knockout was associated with reduced amyloid beta pathology and improved cognitive performance in a mouse model of Alzheimer's disease.
Additional knockout of TREM2 reversed the cognitive and pathological benefits observed with CD33 knockout.
TREM2 knockout in 5xFAD mice worsened amyloid beta pathology and neurodegeneration, while reducing certain immune cell numbers.
Gene profiling indicated that CD33 and TREM2 influence the expression of genes related to immune response and cell signaling.
The interaction between CD33 and TREM2 appears to regulate inflammatory pathways, including the IL-1β/IL-1RN axis.

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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 Iba1cell 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;CD33and downregulated in 5xFAD;TREM2mice. Differential gene expression in 5xFAD;CD33microglia 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. + -/--/--/-

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TREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in Alzheimer’s Disease

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