In Alzheimer’s disease (AD) models, AD risk variants in the microglial-expressed TREM2 gene decrease Aβ plaque–associated microgliosis and increase neuritic dystrophy as well as plaque-associated seeding and spreading of tau aggregates. Whether this Aβ-enhanced tau seeding/spreading is due to loss of microglial function or a toxic gain of function in TREM2-deficient microglia is unclear. Depletion of microglia in mice with established brain amyloid has no effect on amyloid but results in less spine and neuronal loss. Microglial repopulation in aged mice improved cognitive and neuronal deficits. In the context of AD pathology, we asked whether microglial removal and repopulation decreased Aβ-driven tau seeding and spreading. We show that both TREM2KO and microglial ablation dramatically enhance tau seeding and spreading around plaques. Interestingly, although repopulated microglia clustered around plaques, they had a reduction in disease-associated microglia (DAM) gene expression and elevated tau seeding/spreading. Together, these data suggest that TREM2-dependent activation of the DAM phenotype is essential in delaying Aβ-induced pathological tau propagation.
Activated microglia mitigate Aβ-associated tau seeding and spreading
Disclosures: M. Colonna reported "other" from Vigil Neuroscience, and grants from Ono and Pfizer outside the submitted work; in addition, M. Colonna had a patent to TREM2 pending. J.D. Ulrich reported a patent to anti-TREM2 agonist antibodies pending. D.M. Holtzman reported grants from NIH, JPB Foundation, Charles and Helen Schwab Foundation, and Edward N. and Della L. Thome Memorial Foundation during the conduct of the study; "other" from C2N Diagnostics; and personal fees from Denali, Genentech, Merck, Cajal Neurosciences, and Takeda outside the submitted work; in addition, D.M. Holtzman had a patent to anti-tau antibodies licensed and a provisional patent on anti-TREM2 antibodies pending. No other disclosures were reported.
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Maud Gratuze, Yun Chen, Samira Parhizkar, Nimansha Jain, Michael R. Strickland, Javier Remolina Serrano, Marco Colonna, Jason D. Ulrich, David M. Holtzman; Activated microglia mitigate Aβ-associated tau seeding and spreading. J Exp Med 2 August 2021; 218 (8): e20210542. doi: https://doi.org/10.1084/jem.20210542
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