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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 CD11bCD45 CNS-MPs acutely isolated from an Aβ mouse model (5xFAD) as well as fresh postmortem human AD brain. Transcriptomic profiling of purified CD11bKv1.3 CNS-MPs, CD11bCD45 Kv1.3 microglia, and peripheral monocytes from 5xFAD mice revealed that Kv1.3-high CNS-MPs highly express canonical microglial markers (, ) and are distinct from peripheral Ly6c/Ly6c monocytes. Unlike homeostatic microglia, Kv1.3-high CNS-MPs express relatively lower levels of homeostatic genes, higher levels of , 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 (). 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.
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http://dx.doi.org/10.1073/pnas.2013545118 | DOI Listing |
Proc Natl Acad Sci U S A
March 2021
Department of Neurology, Emory University, Atlanta, GA 30322;
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.
View Article and Find Full Text PDFJ Vis Exp
June 2020
Department of Neurology, Emory University;
Microglia and central nervous system (CNS)-infiltrating macrophages, collectively called CNS mononuclear phagocytes (CNS-MPs), play central roles in neurological diseases including neurodegeneration and stroke. CNS-MPs are involved in phagocytic clearance of pathological proteins, debris and neuronal synapses, each with distinct underlying molecular pathways. Characterizing these phagocytic properties can provide a functional readout that compliments molecular profiling of microglia using traditional flow cytometry, transcriptomics and proteomics approaches.
View Article and Find Full Text PDFJ Neuroinflammation
June 2019
Department of Neurology, Emory University, Atlanta, GA, USA.
Background: Microglia and CNS-infiltrating monocytes/macrophages (CNS-MPs) perform pro-inflammatory and protective anti-inflammatory functions following ischemic stroke. Selective inhibition of pro-inflammatory responses can be achieved by Kv1.3 channel blockade, resulting in a lower infarct size in the transient middle cerebral artery occlusion (tMCAO) model.
View Article and Find Full Text PDFFront Immunol
June 2019
Department of Neurology, Emory University, Atlanta, GA, United States.
In the central nervous system (CNS), microglia are innate immune mononuclear phagocytes (CNS MPs) that can phagocytose infectious particles, apoptotic cells, neurons, and pathological protein aggregates, such as Aβ in Alzheimer's disease (AD). While CD11bCD45 microglia account for the majority of CNS MPs, a small population of CD11bCD45 CNS MPs is also recognized in AD that surround Aβ plaques. These transcriptionally and pathologically unique CD45 cells have unclear origin and undefined phagocytic characteristics.
View Article and Find Full Text PDFInteract Cardiovasc Thorac Surg
April 2006
Department of Cardiovascular Surgery, University Hospital, 3010 Berne, Switzerland.
It is well known that malperfusion syndrome (MPS) increases early mortality of patients suffering from acute type A aortic dissection (AADA). The aim of the present study was to analyze the outcome of patients who survived after surgical treatment of AADA with or without MPS. Data of 227 consecutive patients, who underwent surgery for AADA, were analyzed.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!