Kv1.3 inhibition alleviates neuropathology via neuroinflammatory and resilience pathways in a mouse model of Aβ pathology

ABSTRACT: Kv1.3, a voltage-gated potassium channel, is a therapeutic target in various neuropathological conditions. In rodent models, Kv1.3 inhibitors have been shown to inhibit disease-induced neuroinflammation. However, the cellular mechanisms of disease-modification by Kv1.3 blockers and the signaling pathways regulated by Kv1.3 and are unclear. In this -study, we aim to delineate the major protective mechanisms of Kv1.3 blockade in Alzheimer’s disease (AD) pathology by investigating the brain-derived bulk and single nuclear transcriptomes (snRNAseq) and bulk proteomes, along with neurobehavioral and pathological changes in 5xFAD mice. Following 3 months of Kv1.3 blockade via either small molecule PAP-1 or ShK-223 peptide, we observed Ab plaque reduction with both drugs and improved behavior with PAP-1. snRNAseq of brain nuclei identified neuronal and glial populations with expected AD-related changes in microglia. Pseudo-bulk analyses showed that PAP-1 disproportionately impacted oligodendrocytes and microglia while ShK-223 had more pronounced effects on glutamatergic neurons. PAP-1 also increased expression of myelination genes in oligodendrocytes and synaptic genes in neurons, with distinct effects on excitatory and inhibitory neurons. Cell-cell communication analyses suggested that PAP-1 increased crosstalk between neurons and astrocytes with endothelial cells. Bulk brain transcriptomics and proteomics with PAP-1 showed increased levels of synaptic and cognitive resilience-associated proteins while decreasing glial activation and interferon (IFN) responsive genes/proteins. PAP-1 also decreased STAT1 phosphorylation in the 5xFAD brain. To gain further mechanistic insight into Kv1.3's role in interferon signaling in microglia, we confirmed physical interactions between Kv1.3 and STAT1 and STAT3 in BV2 microglia overexpressing Kv1.3. We also found that Kv1.3 blockade (PAP-1) specifically reduced type 2 IFN but not type 1 IFN-induced phosphorylation of STAT1/3, a finding with further validated in another microglial cell line as well as in primary microglia derived from wild-type or Kv1.3-knockout mice. Lastly, we identified novel proteomic changes occurring in cerebrospinal fluid that reflect disease-modification by Kv1.3 blockers. This study reveals cell type-specific effects of Kv1.3 blockers in AD pathology that correspond with reduced neuropathology and neuroinflammation, augmentation of resilience pathways and neuro-vascular coupling and translationally relevant biofluid biomarkers of therapeutic effect. We also provide novel mechanistic insights into functional coupling between Kv1.3 channels and type-2 IFN signaling pathways in microglia.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

DISEASE(S): Alzheimer's Disease

SUBMITTER: UPASNA SRIVASTAVA  

LAB HEAD: upasna srivastava

PROVIDER: PXD071599 | Pride | 2026-07-13

REPOSITORIES: Pride