Figure 2.

Phagocytic construction of dense-core plaques via activation of microglial TAM receptors. (A) The tripartite signaling arrangement assumed by the TAM receptor RTKs, their ligands, and PtdSer in all settings. In the brain, Mer and Axl are prominently expressed by activated microglia. The TAM ligands Gas6 and Pros1 are produced by many neural cells, including microglia and neurons. The critical phospholipid PtdSer is externalized on the surface of plasma membrane derived from cells damaged and/or killed by Aβ exposure. PtdSer, without which the kinase activity of TAM receptors cannot be effectively stimulated, binds to the amino terminus of Gas6 and Pros1. (B) Engagement of the microglial TAM system at the halo (yellow) of dystrophic PtdSer-rich membrane that contains Aβ oligomers and proto-fibrils. This halo surrounds the Thio S⁺ dense cores (red) that contain highly polymerized, aggregated, and compacted Aβ. TAM-mediated phagocytosis results in the internalization of Aβ oligomers and proto-fibrils into early microglial endosomes. (C) Aβ polymerization, aggregation, and compaction. Maturation of early microglial endosomes to lysosomes results in acidification of the organelle, which promotes Aβ aggregation. This aggregation is also promoted by the endosomal concentration of Aβ oligomers and proto-fibrils that is achieved by phagocytosis. Many Aβ-laden cells will die by apoptosis, and thereby deposit aggregated Aβ polymers into growing dense-core plaques. Some microglia may deliver aggregated Aβ to the cores of these plaques by exocytosis.