Amyloid beta (1‐42) peptide suppression of macroscopic homomeric Kv1.2 and heteromeric Kv1.1/1.2 currents is calcium‐ and calcineurin‐dependent: Implications for Alzheimer’s disease

Background The roles of Aβ in the pathogenesis of Alzheimer ’s disease (AD) include disruption of: 1) Ca2+ homeostasis, 2) synaptic communication, and 3) learning‐ and memory‐related synaptic plasticity and neuronal excitability mechanisms. Exactly how these abnormalities arise is incompletely under...

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Published in:Alzheimer's & dementia 2023-12, Vol.19 (S13), p.n/a
Main Authors: Jamshidi, Dina, DeBoeuf, Kristi, Farley, Joseph
Format: Article
Language:English
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Summary:Background The roles of Aβ in the pathogenesis of Alzheimer ’s disease (AD) include disruption of: 1) Ca2+ homeostasis, 2) synaptic communication, and 3) learning‐ and memory‐related synaptic plasticity and neuronal excitability mechanisms. Exactly how these abnormalities arise is incompletely understood. Our lab has focused on the involvement of voltage‐gated potassium channels (VGKCs) in several of these processes. VGKCs are activated during an action potential and regulate Ca2+ influx. Inhibition of VGKCs can lead to synapto‐ and neuro‐toxicity. Kv1.x family subunits can assemble as functional homomers or select heteromers; Kv1.1 is often co‐expressed with Kv1.2. We’ve previously found that: 1) Aβ peptides suppress both Kv1.1 and Kv1.2 homomeric channel activities, as well as Kv1.1/1.2 heteromeric activity, 2) Aβ suppression of Kv1.1 was partially (∼ 50%) dependent on intracellular calcium [Ca2+]i, being reduced by exposure of cells to the calcium chelator BAPTA‐AM, as well as by cyclosporine A (CsA), an inhibitor of PP2B/calcineurin (CaN). Here we asked if Aβ‐suppression of Kv1.2 and Kv1.1/1.2 currents was similarly dependent on [Ca2+]i, and CaN in the case of Kv1.2. Methods Stage V/VI Xenopus laevis oocytes from Ecocyte Bioscience (Austin, TX) were injected with Kv1.2 cRNA for homomeric expression. Heteromeric expression was produced by co‐injection of Kv1.1 and 1.2 cRNAs. Macroscopic currents were measured 2‐3 days later using TEVC. Results Bath application (1 μM) of Aβ(1‐42) produced significant suppression of Kv1.2 (46%, n = 10) and Kv1.1/1.2 (41%, n = 8), 30 min following Aβ application. These suppressions were significantly greater than those of DMSO‐exposed control cells: 2% for Kv1.2 (n = 15), p< .002; 11% (n = 7) for Kv1.1/1.2, p
ISSN:1552-5260
1552-5279
DOI:10.1002/alz.080156