Extended Data Fig. 7: TAM (Mer) signaling promotes dense-core Aβ plaque accumulation with functional consequences.
From: Microglia use TAM receptors to detect and engulf amyloid β plaques
a, Thio S plaque density in APP/PS1 (gray) versus APP/PS1Axl−/−Mertk−/− (red) cortex for plaques of the indicated size at 12 months. b, Thio S+ plaque density (all plaque sizes) in APP/PS1 (gray) versus APP/PS1Axl−/−Mertk−/− (red) hippocampus at 12 months. c, Soluble Aβ42 levels quantified in APP/PS1 (gray) versus APP/PS1Axl−/−Mertk−/− (red) cortex and hippocampus at 4 and 12 mo, as indicated. n = 5-6 per genotype. d, Quantitative LI-COR western blot measurement of APP protein levels in the 12 mo cortex of 3 cohorts of mice (4 genotypes each cohort) of the indicated genotypes demonstrates no change in APP expression in APP/PS1 mice upon mutation of Axl and Mertk. Blots left and quantification right. e, ThioS+ plaque density (all plaque sizes) in APP/PS1 (gray) versus APP/PS1Mertk−/− (pink) cortex and hippocampus at 12 months. f, Thio S+ plaque density (all plaque sizes) in APP/PS1 (gray) versus APP/PS1Axl−/− (white) cortex and hippocampus at 12 months. Data points represent plaque density in n = 6-8 mice of the indicated genotypes averaged from N ≥ 5 cortical sections for each brain. Mann-Whitney test (a, c, d) and Student’s t-test (b, e, f). Data are represented as mean ±1 STD. g, TAM-mediated microglial recognition, phagocytosis, and consolidation of Aβ plaques. Microglial Axl and Mer are bridged to the PtdSer-rich dystrophic membranes of plaques via TAM ligands, whose amino-terminal and carboxy-terminal domains bind PtdSer and Axl/Mer, respectively3,26. Gas6 is shown, but a role for the Mer ligand Pros126 is not excluded. Engagement of the PtdSer-TAM ligand-TAM receptor complex activates the TAM tyrosine kinases (TK), which drives phagocytosis of forming plaque material. Internalized phagocytic cargo is eventually transferred to lysosomes, whose acidic interiors promote the aggregation of large, insoluble Aβ fibrils. Exocytosis or microglial death then delivers this aggregated material to growing dense-core plaques.
