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Neuron. 2019 Sep 4;103(5):820-835.e7. doi: 10.1016/j.neuron.2019.06.010. Epub 2019 Jul 10.

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

Author information

1
Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
2
Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA; Institute of Biochemistry, Department of Biology, ETH Zürich, 8093 Zürich, Switzerland.
3
Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
4
Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
5
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
6
Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA. Electronic address: tanzi@helix.mgh.harvard.edu.

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.

KEYWORDS:

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

PMID:
31301936
PMCID:
PMC6728215
[Available on 2020-09-04]
DOI:
10.1016/j.neuron.2019.06.010

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