TY - JOUR
T1 - Activated microglia mitigate aβ-associated tau seeding and spreading
AU - Gratuze, Maud
AU - Chen, Yun
AU - Parhizkar, Samira
AU - Jain, Nimansha
AU - Strickland, Michael R.
AU - Serrano, Javier Remolina
AU - Colonna, Marco
AU - Ulrich, Jason D.
AU - Holtzman, David M.
N1 - Funding Information:
This study was supported by the BrightFocus Foundation (grant A2020257F to M. Gratuze), the National Institutes of Health (NIH; grant AG047644), the JPB Foundation, the Charles and Helen Schwab Foundation (D.M. Holtzman), and the Edward N. and Della L. Thome Memorial Foundation, Bank of America, N.A., Trustee (D.M. Holtzman). Confocal data were generated on a Zeiss LSM 880 Airyscan Confocal Microscope, which was purchased with support from the Office of Research Infrastructure Programs, a part of the NIH Office of the Director under grant OD021629, and in part with support from the Washington University Center for Cellular Imaging, which is supported by Washington University School of Medicine, The Children’s Discovery Institute of Washington University, St. Louis Children’s Hospital (CDI-CORE-2015-505 and CDI-CORE-2019-813), and the
Funding Information:
Foundation for Barnes-Jewish Hospital (3770 and 4642). The Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine is partially supported by the National Cancer Institute (cancer center support grant P30 CA91842 to the Siteman Cancer Center) and the National Center for Research Resources, a component of the NIH, and NIH Roadmap for Medical Research (Institute of Clinical and Translational Sciences/Clinical and Translational Sciences Award grant UL1 TR000448). This publication is solely the responsibility of the authors and does not necessarily represent the official view of the National Center for Research Resources or NIH.
Funding Information:
Scanning of IHC was performed on the NanoZoomer digital pathology system courtesy of the Hope Center Alafi Neuroimaging Laboratory. We thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for help with genomic analysis. This study was supported by the BrightFocus Foundation (grant A2020257F to M. Gratuze), the National Institutes of Health (NIH; grant AG047644), the JPB Foundation, the Charles and Helen Schwab Foundation (D.M. Holtzman), and the Edward N. and Della L. Thome Memorial Foundation, Bank of America, N.A., Trustee (D.M. Holtzman). Confocal data were generated on a Zeiss LSM 880 Airyscan Confocal Microscope, which was purchased with support from the Office of Research Infrastructure Programs, a part of the NIH Office of the Director under grant OD021629, and in part with support from the Washington University Center for Cellular Imaging, which is supported by Washington University School of Medicine, The Children?s Discovery Institute of Washington University, St. Louis Children?s Hospital (CDI-CORE-2015-505 and CDI-CORE-2019-813), and the Foundation for Barnes-Jewish Hospital (3770 and 4642). The Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine is partially supported by the National Cancer Institute (cancer center support grant P30 CA91842 to the Siteman Cancer Center) and the National Center for Research Resources, a component of the NIH, and NIH Roadmap for Medical Research (Institute of Clinical and Translational Sciences/Clinical and Translational Sciences Award grant UL1 TR000448). This publication is solely the responsibility of the authors and does not necessarily represent the official view of the National Center for Research Resources or NIH. Author contributions: M. Gratuze, M. Colonna, J.D. Ulrich, and D.M. Holtzman designed the study. M. Gratuze, Y. Chen, S. Parhizkar, N. Jain, and M.R. Strickland performed the experiments and analyzed the data. M. Gratuze, J.D. Ulrich, and D.M. Holtzman wrote the manuscript. All authors discussed the results and commented on the manuscript. 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.
Publisher Copyright:
© 2021 Gratuze et al.
PY - 2021/8/2
Y1 - 2021/8/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85108021185&partnerID=8YFLogxK
U2 - 10.1084/jem.20210542
DO - 10.1084/jem.20210542
M3 - Article
C2 - 34100905
AN - SCOPUS:85108021185
SN - 0022-1007
VL - 218
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 8
M1 - e20210542
ER -