Microglia use TAM receptors to detect and engulf amyloid β plaques

Youtong Huang1,2, Kaisa E Happonen1, Patrick G Burrola1, Carolyn O'Connor3, Nasun Hah4, Ling Huang5, Axel Nimmerjahn6, Greg Lemke7

  1. Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA.
  2. Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA.
  3. Flow Cytometry Core, The Salk Institute for Biological Studies, La Jolla, CA, USA.
  4. Chapman Foundations Genomic Sequencing Core, The Salk Institute for Biological Studies, La Jolla, CA, USA.
  5. Razavi Newman Integrative Genomics and Bioinformatics Core, The Salk Institute for Biological Studies, La Jolla, CA, USA.
  6. Waitt Advanced Biophotonics Center, The Salk Institute for Biological Studies, La Jolla, CA, USA.
  7. Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA. lemke@salk.edu.

Abstract

Two microglial TAM receptor tyrosine kinases, Axl and Mer, have been linked to Alzheimer's disease, but their roles in disease have not been tested experimentally. We find that in Alzheimer's disease and its mouse models, induced expression of Axl and Mer in amyloid plaque-associated microglia was coupled to induced plaque decoration by the TAM ligand Gas6 and its co-ligand phosphatidylserine. In the APP/PS1 mouse model of Alzheimer's disease, genetic ablation of Axl and Mer resulted in microglia that were unable to normally detect, respond to, organize or phagocytose amyloid-β plaques. These major deficits notwithstanding, TAM-deficient APP/PS1 mice developed fewer dense-core plaques than APP/PS1 mice with normal microglia. Our findings reveal that the TAM system is an essential mediator of microglial recognition and engulfment of amyloid plaques and that TAM-driven microglial phagocytosis does not inhibit, but rather promotes, dense-core plaque development.

Presented By Youtong Huang | ORCID iD

NeuroscienceNicholas Liao2021-05 (May)