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

Ana Griciuc; Shaun Patel; Anthony N Federico; Se Hoon Choi; Brendan J Innes; Mary K Oram; Gea Cereghetti; Danielle McGinty; Anthony Anselmo; Ruslan I Sadreyev; Suzanne E Hickman; Joseph El Khoury; Marco Colonna; Rudolph E Tanzi

doi:10.1016/j.neuron.2019.06.010

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

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

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acute-Phase Reaction / genetics
Alzheimer Disease / genetics*
Alzheimer Disease / metabolism
Alzheimer Disease / pathology
Amyloid beta-Peptides / metabolism*
Animals
Brain / metabolism*
Brain / pathology
Cognition*
Disease Models, Animal
Gene Expression Regulation
Interleukin-6 / metabolism
Interleukin-8 / metabolism
Membrane Glycoproteins / genetics*
Mice
Mice, Knockout
Microglia / metabolism*
Microglia / pathology
Phagocytosis / genetics
Plaque, Amyloid / pathology*
Receptors, Immunologic / genetics*
Sialic Acid Binding Ig-like Lectin 3 / genetics*

Substances

Amyloid beta-Peptides
Cd33 protein, mouse
Interleukin-6
Interleukin-8
Membrane Glycoproteins
Receptors, Immunologic
Sialic Acid Binding Ig-like Lectin 3
Trem2 protein, mouse
interleukin-6, mouse

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

Authors

Affiliations

Abstract

Publication types

MeSH terms

Substances

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