Presenter: Yi Lu
Paper: TREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in Alzheimer’s Disease
Authors: Ana Griciuc, Shaun Patel, Anthony N. Federico, ..., Joseph El Khoury, Marco Colonna, Rudolph E. Tanzi
Abstract: 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 attenu-ated amyloid beta (Ab) pathology and improved cognition in 5xFAD mice, both of which were abro-gated by additional TREM2 knockout. Knocking out TREM2 in 5xFAD mice exacerbated Ab pathology and neurodegeneration but reduced Iba1+ cell numbers, all of which could not be rescued by addi-tional CD33 knockout. RNA-seq proﬁling of microglia revealed that genes related to phagocytosis and signaling (IL-6, IL-8, acute phase response) are upre-gulated in 5xFAD;CD33 and downregulated in 5xFAD;TREM2 mice. Differential gene expression in 5xFAD;CD33 microglia depended on the pres-ence of TREM2, suggesting TREM2 acts downstream of CD33. Crosstalk between CD33 and TREM2 in-cludes regulation of the IL-1b/IL-1RN axis and a gene set in the ‘‘receptor activity chemokine’’ cluster. Our results should facilitate AD therapeutics target-ing these receptors.
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