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

Ana Griciuc1, Shaun Patel1, Anthony N Federico1

  • 1Genetics 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.

Neuron
|July 15, 2019
PubMed

Insights

CD33 and TREM2 receptors influence Alzheimer's disease (AD) pathology. CD33 knockout improved cognition in mice, but TREM2 knockout reversed these benefits, indicating TREM2 acts downstream of CD33 in AD progression.

Area of Science:

  • Neuroscience
  • Immunology
  • Genetics

Background:

  • Microglial receptors CD33 and TREM2 are implicated in Alzheimer's disease (AD) risk.
  • Understanding the interplay between these receptors is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the functional crosstalk between CD33 and TREM2 in the context of Alzheimer's disease.
  • To elucidate the molecular mechanisms underlying their interaction.

Main Methods:

  • Utilized 5xFAD mouse models with genetic knockouts of CD33 and TREM2.
  • Performed RNA-sequencing (RNA-seq) profiling of microglia.
  • Analyzed amyloid beta (Aβ) pathology, neurodegeneration, and cognitive function.

Main Results:

  • CD33 knockout attenuated Aβ pathology and improved cognition, effects abrogated by TREM2 knockout.
  • TREM2 knockout exacerbated Aβ pathology and neurodegeneration, with no rescue by CD33 knockout.
  • RNA-seq revealed differential gene expression in microglia, with TREM2 acting downstream of CD33.
  • Identified crosstalk involving the IL-1β/IL-1RN axis and chemokine receptor activity.

Conclusions:

  • TREM2 functions downstream of CD33 in regulating microglial responses in AD.
  • Findings provide insights into the CD33-TREM2 axis, offering potential therapeutic targets for Alzheimer's disease.
Keywords:
Alzheimer'sCD33IL-1betaRNA-seqTREM2amyloid betamicroglianeuroinflammationpathway analysistranscriptomics

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