Elevated TREM2 Gene Dosage Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer's Disease Models

C Y Daniel Lee; Anthony Daggett; Xiaofeng Gu; Lu-Lin Jiang; Peter Langfelder; Xiaoguang Li; Nan Wang; Yingjun Zhao; Chang Sin Park; Yonatan Cooper; Isabella Ferando; Istvan Mody; Giovanni Coppola; Huaxi Xu; X William Yang

doi:10.1016/j.neuron.2018.02.002

Elevated TREM2 Gene Dosage Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer's Disease Models

Neuron. 2018 Mar 7;97(5):1032-1048.e5. doi: 10.1016/j.neuron.2018.02.002.

Authors

Affiliations

¹ 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.
² Neuroscience and Aging Research Center, Sanford-Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
³ Center for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁵ 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.
⁶ 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.
⁷ 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.

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.

Keywords: Alzheimer’s disease; BAC; RNA-sequencing; TREM2; amyloid plaque; gene dosage; microglia; mouse; neuroinflammation; reprogramming.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

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*

Substances

Membrane Glycoproteins
Receptors, Immunologic
Trem2 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding