Scott-Solache, James; (2024) TREM2 signaling regulates microglial homeostatic functions. Doctoral thesis (Ph.D), UCL (University College London.

Text JSS_THESIS_FINAL.pdf - Accepted Version Access restricted to UCL open access staff until 1 April 2027. Download (46MB)

Abstract

Microglia, the immune cells of the central nervous system (CNS), serve as crucial guardians of CNS health. They continuously monitor their local environments, adjusting neuronal activity and structure and clearing damaged synapses. Their remarkable adaptability is evident when responding to pathology in neurodegenerative diseases, such as Alzheimer's Disease (AD). Triggering receptor expressed on myeloid cells 2 (TREM2) is a crucial protein in governing this response to pathology and the potential of TREM2 as a therapeutic target for AD is gaining significant attention. However, its contribution to microglial homeostatic functions remains less understood. TREM2 is known to exert various effects depending on the ligand it interacts with. This thesis utilised novel monoclonal antibodies to investigate the downstream effects of TREM2 signaling under non-disease conditions. In experiments using BV2 cells, Ab_1 activated the canonical pathway, promoting the phosphorylation of AKT and MTOR, whereas Ab_2 activated the alternative pathway, dephosphorylating multiple proteins involved in actin remodelling and endocytosis. These contrasting outcomes could be attributed to Ab_1's enhancing and Ab_2’s inhibition of TREM2 endocytosis. Following an hour of treatment in acute brain slices, Ab_1 and Ab_2 had opposite effects on microglial surveillance due to modifications to cell morphology. Ab_1 decreased overall cell size and ramification while Ab_2 increased these features and promoted the growth of filopodia. Prolonged antibody treatments on organotypic hippocampal slice cultures unveiled alterations in synapse phagocytosis. Ab_1 decreased phagocytosis of excitatory pre-synapses compared to Ab_2, and both antibodies reduced the uptake of phosphatidylserine, a signal for damaged synapses. This work is the first to demonstrate that TREM2 stimulation can trigger two distinct signaling pathways that result in different outcomes on microglial morphology, surveillance activity, and synapse phagocytosis. These findings provide new avenues for investigating TREM2's role in homeostatic microglial functions, with potential applications in the development of future AD therapeutics.

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