Microglia use TAM receptors to detect and engulf amyloid β plaques

Youtong Huang; Kaisa E Happonen; Patrick G Burrola; Carolyn O'Connor; Nasun Hah; Ling Huang; Axel Nimmerjahn; Greg Lemke

doi:10.1038/s41590-021-00913-5

Microglia use TAM receptors to detect and engulf amyloid β plaques

Nat Immunol. 2021 May;22(5):586-594. doi: 10.1038/s41590-021-00913-5. Epub 2021 Apr 15.

Authors

Youtong Huang^{1

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

Affiliations

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. [email protected].

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.

Publication types

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

MeSH terms

Alzheimer Disease / immunology*
Alzheimer Disease / pathology
Amyloid beta-Peptides / metabolism
Amyloid beta-Protein Precursor / genetics
Animals
Axl Receptor Tyrosine Kinase
Brain / cytology
Brain / diagnostic imaging
Brain / pathology
Disease Models, Animal
Female
Humans
Intravital Microscopy
Male
Mice
Mice, Knockout
Microglia / immunology
Microglia / pathology*
Microscopy, Confocal
Microscopy, Fluorescence, Multiphoton
Phagocytosis / immunology
Presenilin-1 / genetics
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism*
RNA-Seq
Receptor Protein-Tyrosine Kinases / genetics
Receptor Protein-Tyrosine Kinases / metabolism*
Single-Cell Analysis
c-Mer Tyrosine Kinase / genetics
c-Mer Tyrosine Kinase / metabolism*

Substances

APP protein, mouse
Amyloid beta-Peptides
Amyloid beta-Protein Precursor
Presenilin-1
Proto-Oncogene Proteins
presenilin 1, mouse
MERTK protein, human
Mertk protein, mouse
Receptor Protein-Tyrosine Kinases
c-Mer Tyrosine Kinase
Axl Receptor Tyrosine Kinase

Abstract

Publication types

MeSH terms

Substances

Grants and funding