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 V. Nwabueze, Eric B. Dammer, Amanda Engstrom, Hailian Xiao, Andrea Pennati, Nicholas T. Seyfried, David J. Katz, Jacques Galipeau, Heike Wulff, Edmund K. Waller, Levi B. Wood, Allan I. Levey, Srikant Rangaraju
Abstract
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.