Potassium channel dysfunction and altered neuronal excitability potentially contribute to cognitive decline in amyloid-β (Aβ) pathology. In particular, the accumulation of intracellular Aβ, preceding extracellular plaque deposition, has been implicated in dysregulated excitability and early-stage neuronal stress. However, the molecular mechanisms linking intracellular Aβ to altered neuronal excitability remain incompletely understood. This study aimed to identify a mediator of intracellular Aβ toxicity contributing to neuronal dysfunction in Aβ pathology. We performed a genome-wide human protein chip assay, followed by in vitro binding assays, surface plasmon resonance, and in vivo colocalization analysis using postmortem Alzheimer’s disease (AD) brain tissues in which Aβ pathology is observed. We generated neuronal cell lines stably expressing mRFP-Aβ to model intracellular Aβ accumulation and investigate its pathogenic effects. In addition, we evaluated potassium channel activity and neurotoxicity in Aβ-treated neuronal cells and assessed neuronal excitability and cognitive functions in APPNL−G−F knock-in mice using electrophysiological recordings and behavioral tests. Voltage-gated potassium channel β2 (Kvβ2) was identified as a novel intracellular Aβ-binding protein. Aβ directly bound to the N-terminus of Kvβ2, disrupting its interaction with EB1 and impairing Kv1-Kvβ2 localization to the axon initial segment. In neuronal cell lines expressing intracellular mRFP-Aβ, Kvβ2 colocalized with Aβ in the cytosol, and Kv1 trafficking to the plasma membrane was markedly reduced. Consistent with this observation, colocalization of Aβ and Kvβ2 was confirmed in the brains of AD patients. In addition, enforced expression of Kvβ2, but not Aβ-binding-defective Kvβ2 ∆(2–18) mutant, rescued potassium channel dysfunction and suppressed neurotoxicity in Aβ-treated neuronal cells. Furthermore, lentiviral delivery of Kvβ2 into APPNL−G−F mice reduced neuronal hyperexcitability, rescued activity-related neuronal markers, and ameliorated memory deficits, whereas the Kvβ2 ∆(2–18) mutant did not. These findings suggest that the interaction between Kvβ2 and Aβ mediates neuronal hyperexcitability and memory impairment in APPNL−G−F mice, elucidating a potential mechanism underlying Kv1 channel dysfunction in Aβ pathology.
Cho et al. (Tue,) studied this question.