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TREM2 regulation of microglial dynamics

Josef Kittler (UCL), Damian Crowther (AstraZeneca)

This studentship is focused on understanding the cellular basis of microglial function through the study of TREM2, with the aim of opening up new avenues for intervention in disease. You will be part of a multidisciplinary collaboration between University College London and Astrazeneca. You will be based in the Department of Neuroscience, Physiology and Pharmacology at UCL and collaborate with the AZ Neuroscience Innovative Medicines Unit in Cambridge.

 

Microglia, as the brain’s resident immune cells, monitor neuronal damage and the entry of pathogens into the brain and regulate inflammatory signaling. In addition, microglia and their highly dynamic fine processes can detect and rapidly migrate to areas of neuronal damage where they can phagocytose cellular debris and pathological material.

Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane protein with an extracellular immunoglobulin domain whose expression in the brain is restricted to microglia. A subset of heterozygous loss of function TREM2 variants are associated with an increased risk of developing Alzheimer’s disease. TREM2 plays an important role in microglial damage response, migration and phagocytic activation, providing an important genetic link between neuro-inflammatory response and dementia. The aim of the project is to further elucidate key aspects of TREM2 regulatory control of healthy and pathological microglial function. To further understand the role of TREM2 signalling and impact of its altered function in regulating microglial dynamics the project will combine methods to label and image the morphology of microglia in rodent brain slices with new ways to drive both gain and loss of TREM2 function. Live cell two-photon microscopy will also be used to record microglial dynamics upon selective activation or inhibition of TREM2 in brain slices. The project will provide new insight into the role of TREM2 in the regulation of microglial dynamics under healthy and pathological conditions.

Reference

Thornton et al., 2017 TREM2 shedding by cleavage at the H157-S158 bond is accelerated for the Alzheimer’s disease-associated H157Y variant. EMBO Mol Med. 9:1366-1378.