| Literature DB >> 31301936 |
Ana Griciuc1, Shaun Patel1, Anthony N Federico1, Se Hoon Choi1, Brendan J Innes1, Mary K Oram1, Gea Cereghetti2, Danielle McGinty1, Anthony Anselmo3, Ruslan I Sadreyev3, Suzanne E Hickman4, Joseph El Khoury4, Marco Colonna5, Rudolph E Tanzi6.
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 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.Entities:
Keywords: Alzheimer's; CD33; IL-1beta; RNA-seq; TREM2; amyloid beta; microglia; neuroinflammation; pathway analysis; transcriptomics
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Year: 2019 PMID： 31301936 PMCID： PMC6728215 DOI： 10.1016/j.neuron.2019.06.010
Source DB: PubMed Journal: Neuron ISSN： 0896-6273 Impact factor: 17.173