Differential effects of partial and complete loss of TREM2 on microglial injury response and tauopathy
| Autor: | Claire D. Clelland, Fuying Gao, Li Gan, David Le, Connor H. Ludwig, Dimitrios Davalos, Yonatan A. Cooper, Katerina Akassoglou, Maria Telpoukhovskaia, Giovanni Coppola, Yaqiao Li, Lay Kodama, Faten A. Sayed, Lihong Zhan, Yungui Zhou, Axel Hauduc |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Pathology medicine.medical_specialty Aging Mutation Missense Haploinsufficiency Microgliosis 03 medical and health sciences Mice 0302 clinical medicine Atrophy Alzheimer Disease Medicine Animals Receptors Immunologic Loss function Hemizygote Mice Knockout Multidisciplinary Membrane Glycoproteins Microglia business.industry TREM2 Neurodegeneration neurodegeneration Biological Sciences medicine.disease 030104 developmental biology medicine.anatomical_structure motility inflammation Tauopathy RNA-seq business 030217 neurology & neurosurgery Neuroscience tau inclusions |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 |
| Popis: | Significance Late-onset Alzheimer’s disease is the most common form of dementia. A rare hemizygous variant in a microglial-expressed gene, Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), significantly increases risk for late-onset Alzheimer’s disease. This variant is thought to cause loss of function, inducing TREM2 haploinsufficiency. The ramifications of TREM2 haploinsufficiency on microglial function and tau pathology are major gaps in the field. We find that, in contrast to the protective effects of complete TREM2 deficiency, TREM2 haploinsufficiency exacerbates tau pathology, inflammation, and atrophy at a late stage of disease in a mouse model of tauopathy. The differential effects of partial and complete loss of TREM2 are important considerations for TREM2-targeted therapeutic strategies. Alzheimer’s disease (AD), the most common form of dementia, is characterized by the abnormal accumulation of amyloid plaques and hyperphosphorylated tau aggregates, as well as microgliosis. Hemizygous missense variants in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) are associated with elevated risk for developing late-onset AD. These variants are hypothesized to result in loss of function, mimicking TREM2 haploinsufficiency. However, the consequences of TREM2 haploinsufficiency on tau pathology and microglial function remain unknown. We report the effects of partial and complete loss of TREM2 on microglial function and tau-associated deficits. In vivo imaging revealed that microglia from aged TREM2-haploinsufficient mice show a greater impairment in their injury response compared with microglia from aged TREM2-KO mice. In transgenic mice expressing mutant human tau, TREM2 haploinsufficiency, but not complete loss of TREM2, increased tau pathology. In addition, whereas complete TREM2 deficiency protected against tau-mediated microglial activation and atrophy, TREM2 haploinsufficiency elevated expression of proinflammatory markers and exacerbated atrophy at a late stage of disease. The differential effects of partial and complete loss of TREM2 on microglial function and tau pathology provide important insights into the critical role of TREM2 in AD pathogenesis. |
| Databáze: | OpenAIRE |
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