TAM-ping down amyloid in Alzheimer's disease

Abstract

The TAM receptor kinases Axl and Mer are critical for microglial recognition and clearance of accumulating amyloid in transgenic models of Alzheimer’s disease.

In Alzheimer’s disease, plaque-associated microglia (PAM) express high levels of the TAM receptor tyrosine kinases, Axl and Mer. Lemke and colleagues show in preclinical models of AD amyloid deposition that microglia engage Aβ plaques using the TAM system (inset), whereby microglia TAM receptors are activated by Gas6 in the presence of phosphatidyl serine (PtdSer) bound to the GLA domain. PtdSer+ dystrophic membranes are present in fibrillar Aβ halos surrounding dense core plaques, thus allowing an anchor for TAM-expressing microglia to construct a Gas6-PtdSer bridge in order to detect, phagocytose, and compact Aβ plaques. Note to artist on Figure: We envision a scene within an Alzheimer’s brain, that shows angry Aβ plaques with activated microglia clustered around them (see sketch). These microglia should be classically activated, with shortened arms, enlarged soma, etc. Further away, microglia should have a more ramified shape, with elaborated processes, similar to surveilling microglia. Microglia in close proximity to Aβ plaques should express Axl and Mer on their surface, while distant microglia should express on Mer, which is constitutively expressed. In some configuration, we would like to include an inset (see PDF attached) to depict the TAM receptor bridge with plaque PtdSer and Gas6. We want to convey how harried the AD brain environment is – think: No Man’s Land, in World War 1. This will hopefully highlight how specialized the TAM system is to be able to function in such a complex environment.