Microglia in Neurodegeneration

A glial cell subtype, microglia are the main arbiters of the neuroimmune system in the central nervous system (CNS). With structurally dynamic processes, microglia constantly scan their environment, acting both as housekeepers involved in neuronal maintenance and synaptic pruning and as defenders against acute and chronic insult. In the context of Alzheimer’s disease (AD), microglia have been observed to surround amyloid plaques and initiate clearance via phagocytosis while spatially restricting plaque proliferation. In particular, mutations of the microglial triggering receptor expressed on myeloid cells 2 (TREM2) are associated with significantly increased risk of late-onset AD. TREM2 is a cell surface immunoreceptor whose activation by a number of polyanionic ligands, including ApoE and Aβ, initiates intracellular signaling cascades through its adaptor protein DAP12. Normally, TREM2 activation promotes chemotaxis, phagocytosis, proliferation, and maintenance activities of microglia that are essential to their neuroprotective function. More specifically, normal TREM2 ligand binding will lead to PI3K and downstream mTOR activation, which inhibits microglial autophagy, a process that is critical to keeping microglia active and in a high metabolic state as they surround Aβ plaques. This role is likely impaired in the absence of TREM2 as Trem2-/- microglia show increased levels of autophagic vesicles. In AD phenotypes, initial impaired microglial clearance of Aβ generates extracellular buildup of aggregates, which trigger a chronic microglial inflammatory response, yielding neurotoxic effects that contribute to AD-associated neurodegeneration.

Selected Reviews:

• Hansen, D. V., Hanson, J. E., & Sheng, M. (2018). Microglia in Alzheimer’s disease. The Journal of Cell Biology 217(2), 459–472.
• Hickman, S., Izzy, S., Sen, P., Morsett, L., & Khoury, J. E. (2018). Microglia in neurodegeneration. Nature Neuroscience 21(10), 1359–1369.
• Yeh, F. L., Hansen, D. V., & Sheng, M. (2017). TREM2, Microglia, and Neurodegenerative Diseases. Trends in Molecular Medicine 23(6), 512–533.
• Zhou, Y., Ulland, T. K., & Colonna, M. (2018). TREM2-Dependent Effects on Microglia in Alzheimer’s Disease. Frontiers in Aging Neuroscience 10.