Microglial TAM Receptors as Modulators of Alzheimer’s Pathology

2018

Unrestrained inflammation of the central nervous system (CNS) precipitates and exacerbates a wide range of debilitating neurodegenerative diseases, including Alzheimer’s disease (AD). Our understanding of the mechanisms that regulate neuroinflammation is incomplete. Microglia perform two activities that are crucial to the regulation of neuroinflammation: 1) the inhibition of neurotoxic inflammatory cytokines and chemokines; and 2) the engulfment of dead cells and membranes. Multiple lines of evidence demonstrate that these microglial activities are controlled by signaling through TAM (Tyro3, Axl, Mer) receptor tyrosine kinases. Receptors for TAM are called Axl and Mer. In Alzheimer’s disease, the expression of these genes in microglia is elevated. This elevation is thought to be in order to restrain the disease. Through experiments supported by Cure Alzheimer’s Fund, it was found that a key ligand of TAM associates with plaques. The loss of a TAM receptor, Mer, in the APP/PS1 mouse model of Alzheimer’s seriously worsens the disease. Several drugs that inhibit TAM inhibitors are given to patients as a cancer therapy without considering the effect on Alzheimer’s disease. This research will address the role of microglial TAM receptors in the engulfment of Alzheimer’s-related plaques.

2017

Protein aggregates of amyloid beta peptides accumulate in the brain in Alzheimer’s disease and contribute to disease pathology by directly damaging neurons and by activating microglia, the resident immune cells of the brain. We will employ genetic methods to study the function of TAM receptors expressed in microglia, and hypothesize that TAMs act to dampen the activation of these immune cells and therefore prevent inflammation in the brain during Alzheimer’s disease. We furthermore hypothesize that these TAM receptors enable microglia to ingest amyloid beta aggregates as they are forming and thereby indirectly protect neurons against aggregate-mediated damage. Boosting TAM activation or expression in microglia may therefore be of therapeutic benefit in Alzheimer’s disease.