Impact of TREM2R47H variant on tau pathology–induced gliosis and neurodegeneration
| Autor: | Marie-Ève Tremblay, Cheryl E. G. Leyns, Jason D. Ulrich, Terrance T. Kummer, Marco Colonna, Monica Xiong, Andrew D. Sauerbeck, Nayeon Kim, Marie-Kim St-Pierre, Javier Remolina Serrano, David M. Holtzman, Maud Gratuze |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Mutation Missense tau Proteins Context (language use) Neuropathology Biology Mice 03 medical and health sciences 0302 clinical medicine Atrophy Alzheimer Disease medicine Humans Animals Gliosis Receptors Immunologic Mice Knockout Membrane Glycoproteins Microglia TREM2 Neurodegeneration General Medicine medicine.disease Disease Models Animal 030104 developmental biology medicine.anatomical_structure Amino Acid Substitution 030220 oncology & carcinogenesis Tauopathy medicine.symptom Neuroscience Research Article |
| Zdroj: | J Clin Invest |
| ISSN: | 1558-8238 0021-9738 |
| DOI: | 10.1172/jci138179 |
| Popis: | Alzheimer’s disease (AD) is characterized by plaques containing amyloid-β (Aβ) and neurofibrillary tangles composed of aggregated, hyperphosphorylated tau. Beyond tau and Aβ, evidence suggests that microglia play an important role in AD pathogenesis. Rare variants in the microglia-expressed triggering receptor expressed on myeloid cells 2 (TREM2) gene increase AD risk 2- to 4-fold. It is likely that these TREM2 variants increase AD risk by decreasing the response of microglia to Aβ and its local toxicity. However, neocortical Aβ pathology occurs many years before neocortical tau pathology in AD. Thus, it will be important to understand the role of TREM2 in the context of tauopathy. We investigated the impact of the AD-associated TREM2 variant (R47H) on tau-mediated neuropathology in the PS19 mouse model of tauopathy. We assessed PS19 mice expressing human TREM2(CV) (common variant) or human TREM2(R47H). PS19-TREM2(R47H) mice had significantly attenuated brain atrophy and synapse loss versus PS19-TREM2(CV) mice. Gene expression analyses and CD68 immunostaining revealed attenuated microglial reactivity in PS19-TREM2(R47H) versus PS19-TREM2(CV) mice. There was also a decrease in phagocytosis of postsynaptic elements by microglia expressing TREM2(R47H) in the PS19 mice and in human AD brains. These findings suggest that impaired TREM2 signaling reduces microglia-mediated neurodegeneration in the setting of tauopathy. |
| Databáze: | OpenAIRE |
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