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

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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/Ly6clow monocytes. 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. Significance The potassium channel Kv1.3 in brain myeloid cells represents a promising therapeutic target for Alzheimer’s disease (AD). The patterns of expression and functional roles of Kv1.3 channels in brain myeloid subpopulations and the microglial-versus-peripheral myeloid origin of Kv1.3-expressing cells in AD remain unclear. Here, we show that in mice, Kv1.3 is selectively up-regulated in an Aβ-dependent manner by a subset of microglia-derived cells, expresses higher levels of proinflammatory genes, and confirms the presence of Kv1.3-expressing microglial subpopulations in human AD. Furthermore, blocking Kv1.3 in an AD model reduces Aβ neuropathology, increases synaptic protein expression, and skews the microglial transcriptome toward pro-phagocytic and protective phenotypes. Our findings strengthen the preclinical rationale for targeting microglial Kv1.3 channels for therapeutic immunomodulation in AD.
Funding Information
  • Alzheimer's Association (37102)
  • NIH NINDS NIA (K08-NS099474-1, R01 NS114130-01A1)
  • NIH (R01AG053960, R01AG061800, RF1AG057471, RF1AG057470, RF1AG062181, R01AG057339)
  • NIA (F32AG064862)
  • NIH (1R01NS087142)
  • NIH (R01NS100294)
  • NIA (U01AG061357)

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