Unique molecular characteristics and microglial origin of Kv1.3 channel-positive brain myeloid cells in Alzheimer's disease

Supriya Ramesha, Sruti Rayaprolu, Christine A. Bowen, Cynthia R. Giver, Sara Bitarafan, Hai M. Nguyen, Tianwen Gao, Michael J. Chen, Ngozi Nwabueze, Eric B. Dammer, Amanda K. Engstrom, Hailian Xiao, Andrea Pennati, Nicholas T. Seyfried, David J. Katz, Jacques Galipeau, Heike Wulff, Edmund K. Waller, Levi B. Wood, Allan I. LeveySrikant Rangaraju

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article numbere2013545118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number11
DOIs
StatePublished - Mar 16 2021

Keywords

  • Alzheimer's disease
  • Microglia
  • Neurodegeneration
  • Neuroinflammation
  • Potassium channel

ASJC Scopus subject areas

  • General

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