气候变化领域集成服务门户(CCPortal): Unique molecular characteristics and microglial origin of Kv1.3 channel-positive brain myeloid cells in Alzheimer's disease

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DOI	10.1073/pnas.2013545118
	Unique molecular characteristics and microglial origin of Kv1.3 channel-positive brain myeloid cells in Alzheimer's disease
	Ramesha S.; Rayaprolu S.; Bowen C.A.; Giver C.R.; Bitarafan S.; Nguyen H.M.; Gao T.; Chen M.J.; Nwabueze N.; Dammer E.B.; Engstrom A.K.; Xiao H.; Pennati A.; Seyfried N.T.; Katz D.J.; Galipeau J.; Wulff H.; Waller E.K.; Wood L.B.; Levey A.I.; Rangaraju S.
发表日期	2021
ISSN	00278424
卷号	118 期号:11
英文摘要	Kv1.3 potassium channels, expressed by proinflammatory central nervous system mononuclear phagocytes (CNS-MPs), are promising therapeutic targets for modulating neuroinflammation in Alzheimer's disease (AD). The molecular characteristics of Kv1.3-high CNS-MPs and their cellular origin from microglia or CNS-infiltrating monocytes are unclear. While Kv1.3 blockade reduces amyloid beta (Aβ) burden in mouse models, the downstream immune effects on molecular profiles of CNS-MPs remain unknown. We show that functional Kv1.3 channels are selectively expressed by a subset of CD11b+CD45+CNS-MPs acutely isolated from an Aβ mouse model (5xFAD) as well as fresh postmortem human AD brain. Transcriptomic profiling of purified CD11b+Kv1.3+CNS-MPs, CD11b+CD45int Kv1.3neg microglia, and peripheral monocytes from 5xFAD mice revealed that Kv1.3-high CNS-MPs highly express canonical microglial markers (Tmem119, P2ry12) and are distinct from peripheral Ly6chigh/Ly6clowmonocytes. Unlike homeostatic microglia, Kv1.3-high CNS-MPs express relatively lower levels of homeostatic genes, higher levels of CD11c, and increased levels of glutamatergic transcripts, potentially representing phagocytic uptake of neuronal elements. Using irradiation bone marrow CD45.1/CD45.2 chimerism in 5xFAD mice, we show that Kv1.3+CNS-MPs originate from microglia and not blood-derived monocytes. We show that Kv1.3 channels regulate membrane potential and early signaling events in microglia. Finally, in vivo blockade of Kv1.3 channels in 5xFAD mice by ShK-223 reduced Aβ burden, increased CD11c+CNS-MPs, and expression of phagocytic genes while suppressing proinflammatory genes (IL1b). Our results confirm the microglial origin and identify unique molecular features of Kv1.3-expressing CNS-MPs. In addition, we provide evidence for CNS immunomodulation by Kv1.3 blockers in AD mouse models resulting in a prophagocytic phenotype. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Alzheimer's disease; Microglia; Neurodegeneration; Neuroinflammation; Potassium channel
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180299
作者单位	Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, United States; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, United States; George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30313, United States; Department of Pharmacology, School of Medicine, University of California, Davis, CA 95616, United States; Department of Neurology, Emory University, Atlanta, GA 30322, United States; Pritzker School of Medicine, University of Chicago, Chicago, IL 60637, United States; Department of Biochemistry, Emory University, Atlanta, GA 30322, United States; Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, United States; Department of Medicine, University of Wisconsin-Madison, Madison, WI 53706, United States
推荐引用方式 GB/T 7714	Ramesha S.,Rayaprolu S.,Bowen C.A.,et al. Unique molecular characteristics and microglial origin of Kv1.3 channel-positive brain myeloid cells in Alzheimer's disease[J],2021,118(11).
APA	Ramesha S..,Rayaprolu S..,Bowen C.A..,Giver C.R..,Bitarafan S..,...&Rangaraju S..(2021).Unique molecular characteristics and microglial origin of Kv1.3 channel-positive brain myeloid cells in Alzheimer's disease.Proceedings of the National Academy of Sciences of the United States of America,118(11).
MLA	Ramesha S.,et al."Unique molecular characteristics and microglial origin of Kv1.3 channel-positive brain myeloid cells in Alzheimer's disease".Proceedings of the National Academy of Sciences of the United States of America 118.11(2021).