CD33 and TREM2 regulation of microglial functions
type: CreativeWork
description: Microglia are macrophages resident in the central nervous system (CNS). Microglia contribute to CNS development, homeostasis and pathology, and microglial dysfunction has been associated with several neurodegenerative diseases. CD33 and triggering receptor expressed on myeloid cells 2 (TREM2) are microglial receptors, variants of which affect Alzheimer’s disease (AD) risk, and therefore are potential targets for therapeutic intervention in AD. In this work, I show a conserved inhibitory role of CD33, a sialic acid-binding immunoglobulin-type lectin (Siglec) in both mice and human microglial cells. Knock down of CD33 in a mouse microglial cell line, BV-2, resulted in increased phagocytosis of several targets and increased migration towards ATP. Human CD33 has two distinct variants: CD33M, associated with increased risk of developing AD, and CD33m, associated with decreased risk of developing AD by genome wide association studies (GWAS). However, how these variants confer differential risk of AD was unclear. By overexpression of the receptors in CHME-3 cells, I show that CD33M inhibits phagocytosis, migration and proliferation, but increases adhesion to components of the extracellular matrix when highly overexpressed, similar to mouse CD33. In contrast, CD33m, increases phagocytosis, migration and proliferation but decreases adhesion to components of the extracellular matrix. This suggests that CD33m has gained (rather than lost) function relative to CD33M, and that CD33m may be protective by providing efficient removal of toxic substrates such as neuronal debris. CD33 may oppose the signalling function of the phagocytic receptor TREM2. Humans with rare TREM2 variants (particularly R47H) have increased risk of developing AD. In this work I show a potential novel gain of function role of the R47H variant of TREM2, which results in increased loss of neurons, inflammation and phagocytosis of isolated synapses. This gain of function could explain why individuals heterozyg…
abstract: Microglia are macrophages resident in the central nervous system (CNS). Microglia contribute to CNS development, homeostasis and pathology, and microglial dysfunction has been associated with several neurodegenerative diseases. CD33 and triggering receptor expressed on myeloid cells 2 (TREM2) are microglial receptors, variants of which affect Alzheimer’s disease (AD) risk, and therefore are potential targets for therapeutic intervention in AD. In this work, I show a conserved inhibitory role of CD33, a sialic acid-binding immunoglobulin-type lectin (Siglec) in both mice and human microglial cells. Knock down of CD33 in a mouse microglial cell line, BV-2, resulted in increased phagocytosis of several targets and increased migration towards ATP. Human CD33 has two distinct variants: CD33M, associated with increased risk of developing AD, and CD33m, associated with decreased risk of developing AD by genome wide association studies (GWAS). However, how these variants confer differential risk of AD was unclear. By overexpression of the receptors in CHME-3 cells, I show that CD33M inhibits phagocytosis, migration and proliferation, but increases adhesion to components of the extracellular matrix when highly overexpressed, similar to mouse CD33. In contrast, CD33m, increases phagocytosis, migration and proliferation but decreases adhesion to components of the extracellular matrix. This suggests that CD33m has gained (rather than lost) function relative to CD33M, and that CD33m may be protective by providing efficient removal of toxic substrates such as neuronal debris. CD33 may oppose the signalling function of the phagocytic receptor TREM2. Humans with rare TREM2 variants (particularly R47H) have increased risk of developing AD. In this work I show a potential novel gain of function role of the R47H variant of TREM2, which results in increased loss of neurons, inflammation and phagocytosis of isolated synapses. This gain of function could explain why individuals heterozyg…
author: Butler, Claire
language: eng
keywords: Microglia, Neuroinflammation, Alzheimer's Disease
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2021-12-22
date modified: 2026-07-22T22:24:08Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.83729