Elevated TREM2 Gene Dosage Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer's Disease Models
Variants of TREM2 are associated with Alzheimer's disease (AD). To study whether increasing TREM2 gene dosage could modify the disease pathogenesis, we developed BAC transgenic mice expressing human TREM2 (BAC-TREM2) in microglia. We found that elevated TREM2 expression reduced amyloid burden i...
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| Vydáno v: | Neuron (Cambridge, Mass.) Ročník 97; číslo 5; s. 1032 |
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| Hlavní autoři: | , , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
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United States
07.03.2018
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| Témata: | |
| ISSN: | 1097-4199, 1097-4199 |
| On-line přístup: | Zjistit podrobnosti o přístupu |
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| Abstract | Variants of TREM2 are associated with Alzheimer's disease (AD). To study whether increasing TREM2 gene dosage could modify the disease pathogenesis, we developed BAC transgenic mice expressing human TREM2 (BAC-TREM2) in microglia. We found that elevated TREM2 expression reduced amyloid burden in the 5xFAD mouse model. Transcriptomic profiling demonstrated that increasing TREM2 levels conferred a rescuing effect, which includes dampening the expression of multiple disease-associated microglial genes and augmenting downregulated neuronal genes. Interestingly, 5xFAD/BAC-TREM2 mice showed further upregulation of several reactive microglial genes linked to phagocytosis and negative regulation of immune cell activation. Moreover, these mice showed enhanced process ramification and phagocytic marker expression in plaque-associated microglia and reduced neuritic dystrophy. Finally, elevated TREM2 gene dosage led to improved memory performance in AD models. In summary, our study shows that a genomic transgene-driven increase in TREM2 expression reprograms microglia responsivity and ameliorates neuropathological and behavioral deficits in AD mouse models. |
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| AbstractList | Variants of TREM2 are associated with Alzheimer's disease (AD). To study whether increasing TREM2 gene dosage could modify the disease pathogenesis, we developed BAC transgenic mice expressing human TREM2 (BAC-TREM2) in microglia. We found that elevated TREM2 expression reduced amyloid burden in the 5xFAD mouse model. Transcriptomic profiling demonstrated that increasing TREM2 levels conferred a rescuing effect, which includes dampening the expression of multiple disease-associated microglial genes and augmenting downregulated neuronal genes. Interestingly, 5xFAD/BAC-TREM2 mice showed further upregulation of several reactive microglial genes linked to phagocytosis and negative regulation of immune cell activation. Moreover, these mice showed enhanced process ramification and phagocytic marker expression in plaque-associated microglia and reduced neuritic dystrophy. Finally, elevated TREM2 gene dosage led to improved memory performance in AD models. In summary, our study shows that a genomic transgene-driven increase in TREM2 expression reprograms microglia responsivity and ameliorates neuropathological and behavioral deficits in AD mouse models. Variants of TREM2 are associated with Alzheimer's disease (AD). To study whether increasing TREM2 gene dosage could modify the disease pathogenesis, we developed BAC transgenic mice expressing human TREM2 (BAC-TREM2) in microglia. We found that elevated TREM2 expression reduced amyloid burden in the 5xFAD mouse model. Transcriptomic profiling demonstrated that increasing TREM2 levels conferred a rescuing effect, which includes dampening the expression of multiple disease-associated microglial genes and augmenting downregulated neuronal genes. Interestingly, 5xFAD/BAC-TREM2 mice showed further upregulation of several reactive microglial genes linked to phagocytosis and negative regulation of immune cell activation. Moreover, these mice showed enhanced process ramification and phagocytic marker expression in plaque-associated microglia and reduced neuritic dystrophy. Finally, elevated TREM2 gene dosage led to improved memory performance in AD models. In summary, our study shows that a genomic transgene-driven increase in TREM2 expression reprograms microglia responsivity and ameliorates neuropathological and behavioral deficits in AD mouse models.Variants of TREM2 are associated with Alzheimer's disease (AD). To study whether increasing TREM2 gene dosage could modify the disease pathogenesis, we developed BAC transgenic mice expressing human TREM2 (BAC-TREM2) in microglia. We found that elevated TREM2 expression reduced amyloid burden in the 5xFAD mouse model. Transcriptomic profiling demonstrated that increasing TREM2 levels conferred a rescuing effect, which includes dampening the expression of multiple disease-associated microglial genes and augmenting downregulated neuronal genes. Interestingly, 5xFAD/BAC-TREM2 mice showed further upregulation of several reactive microglial genes linked to phagocytosis and negative regulation of immune cell activation. Moreover, these mice showed enhanced process ramification and phagocytic marker expression in plaque-associated microglia and reduced neuritic dystrophy. Finally, elevated TREM2 gene dosage led to improved memory performance in AD models. In summary, our study shows that a genomic transgene-driven increase in TREM2 expression reprograms microglia responsivity and ameliorates neuropathological and behavioral deficits in AD mouse models. |
| Author | Wang, Nan Ferando, Isabella Gu, Xiaofeng Daggett, Anthony Yang, X William Cooper, Yonatan Park, Chang Sin Jiang, Lu-Lin Langfelder, Peter Zhao, Yingjun Coppola, Giovanni Li, Xiaoguang Mody, Istvan Lee, C Y Daniel Xu, Huaxi |
| Author_xml | – sequence: 1 givenname: C Y Daniel surname: Lee fullname: Lee, C Y Daniel organization: Center for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA – sequence: 2 givenname: Anthony surname: Daggett fullname: Daggett, Anthony organization: Center for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA – sequence: 3 givenname: Xiaofeng surname: Gu fullname: Gu, Xiaofeng organization: Center for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA – sequence: 4 givenname: Lu-Lin surname: Jiang fullname: Jiang, Lu-Lin organization: Neuroscience and Aging Research Center, Sanford-Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA – sequence: 5 givenname: Peter surname: Langfelder fullname: Langfelder, Peter organization: Center for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA – sequence: 6 givenname: Xiaoguang surname: Li fullname: Li, Xiaoguang organization: Neuroscience and Aging Research Center, Sanford-Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA – sequence: 7 givenname: Nan surname: Wang fullname: Wang, Nan organization: Center for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA – sequence: 8 givenname: Yingjun surname: Zhao fullname: Zhao, Yingjun organization: Neuroscience and Aging Research Center, Sanford-Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA – sequence: 9 givenname: Chang Sin surname: Park fullname: Park, Chang Sin organization: Center for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA – sequence: 10 givenname: Yonatan surname: Cooper fullname: Cooper, Yonatan organization: Center for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA – sequence: 11 givenname: Isabella surname: Ferando fullname: Ferando, Isabella organization: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA – sequence: 12 givenname: Istvan surname: Mody fullname: Mody, Istvan organization: Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA; Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA – sequence: 13 givenname: Giovanni surname: Coppola fullname: Coppola, Giovanni organization: Center for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA; Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA – sequence: 14 givenname: Huaxi surname: Xu fullname: Xu, Huaxi organization: Neuroscience and Aging Research Center, Sanford-Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA – sequence: 15 givenname: X William surname: Yang fullname: Yang, X William email: xwyang@mednet.ucla.edu organization: Center for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: xwyang@mednet.ucla.edu |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/29518357$$D View this record in MEDLINE/PubMed |
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| Copyright | Copyright © 2018 Elsevier Inc. All rights reserved. |
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| DOI | 10.1016/j.neuron.2018.02.002 |
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| Issue | 5 |
| Keywords | RNA-sequencing reprogramming mouse Alzheimer’s disease BAC neuroinflammation TREM2 amyloid plaque gene dosage microglia |
| Language | English |
| License | Copyright © 2018 Elsevier Inc. All rights reserved. |
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| PublicationTitle | Neuron (Cambridge, Mass.) |
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| PublicationYear | 2018 |
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| Snippet | Variants of TREM2 are associated with Alzheimer's disease (AD). To study whether increasing TREM2 gene dosage could modify the disease pathogenesis, we... |
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| SubjectTerms | Alzheimer Disease - genetics Alzheimer Disease - pathology Animals Animals, Newborn Cells, Cultured Cellular Reprogramming Techniques - methods Disease Models, Animal Female Gene Dosage - genetics Humans Male Membrane Glycoproteins - biosynthesis Membrane Glycoproteins - genetics Memory - physiology Mice Mice, Inbred C57BL Mice, Transgenic Microglia - pathology Microglia - physiology Organ Culture Techniques Phenotype Receptors, Immunologic - biosynthesis Receptors, Immunologic - genetics |
| Title | Elevated TREM2 Gene Dosage Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer's Disease Models |
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