The Role of TREM2 in Microglial Activation, Phagocytic Function, and the Pathogenesis of Alzheimer’s Disease
Introduction: Alzheimer’s disease, the sixth leading cause of death and most common, known cause of dementia, displays molecular hallmarks including neurotoxic amyloid plaques and neurofibrillary tau tangles, resulting in brain atrophy, cognitive decline, and memory loss.1,2 Microglia, resident immune cells of the brain, have been noted to potentially play a role in the propagation of AD pathology via the neuroinflammation hypothesis. Triggering receptor expressed on myeloid cells 2, TREM2, is a transmembrane receptor inducing microglial activation, migration, and metabolism.3 The rare R47H TREM2 variant confers loss of function, which is commonly associated with increased risk of AD.2 Methods: A transgenic mouse line overexpressing TREM2 (BAC-TREM2) and crossed with 5x familial AD (5xFAD) mouse was fed polystyrene beads as phagocytic bait to observe changes in microglial phagocytic function.4 Recombinant soluble TREM2 (sTREM2) or vehicle were stereotactically injected into the hippocampus of 5xFAD mice, and immunohistochemical analysis was conducted.5 To test the role of microglia as inflammatory mediators in vivo, PLX3397, which depletes microglia via inhibition of colony-stimulating factor 1 receptor (CSF1R), was administered.5 Lastly, sTREM2 was expressed in 5xFAD mice using AAV to investigate long-term effects of sTREM2 on AD pathology.5 Morris water maze behavior studies were conducted.5 Results: In vitro phagocytosis assay revealed an increase in phagocytosis with TREM2 overexpression (40% population in BAC-TREM2 mice compared to 25% in WT, n=3,4, p<0.05).4 Stereotactic injection of sTREM2 reduced amyloid plaque load in 5xFAD mice when compared with vehicle (n=6, p<0.05).5 Depletion of microglia with PLX3397 reversed the protective effect of sTREM2 on plaque load (ns, n=5).5 5xFAD mice with long-term expression of sTREM2 showed a reduced plaque load relative to WT (n=5, p<0.05).5 Morris water maze results revealed that sTREM2 expression rescued spatial learning and memory function to a more WT-like phenotype while 5xFAD mice spent more time in search of the platform (20s reduction in escape latency at day 5, p<0.001, 20s increased time spent in the target quadrant, p<0.05).5 Significance: These findings suggest a gene dosage effect of TREM2 and its role in mediating microglial phagocytosis and activation in AD pathology. Specifically, increased gene dosage of TREM2 might be protective. sTREM2 displays a protective effect on AD pathology and cognitive decline, which are at least in part microglia-mediated. These data have implications for therapeutic strategies by which targeting this pathway or delivering sTREM2 as treatment might provide an opportunity to drive a specific, protective microglial phenotype.
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- van der Kant, R., Goldstein, L.S.B. & Ossenkoppele, R. Amyloid-β-independent regulators of tau pathology in Alzheimer disease. Nat Rev Neurosci21, 21–35 (2020). https://doi.org/10.1038/s41583-019-0240-3
- Shi, Y., Holtzman, D.M. Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight. Nat Rev Immunol18, 759–772 (2018). https://doi.org/10.1038/s41577-018-0051-1
- Lee, C. Y. et al. Elevated TREM2 gene dosage reprograms microglia responsivity and ameliorates pathological phenotypes in Alzheimer’s disease models. Neuron 97, 1032–1048 (2018). 1016/j.neuron.2018.02.002
- Zhong, L., Xu, Y., Zhuo, R. et al.Soluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer’s disease model. Nat Commun 10, 1365 (2019). https://doi-org.srv-proxy2.library.tamu.edu/10.1038/s41467-019-09118-9