Amyloid β and Amyloid Precursor Protein Synergistically Suppress Large-Conductance Calcium-Activated Potassium Channel in Cortical Neurons.

Kenji Yamamoto,Nobuo Kato,Ryo Yamamoto

doi:10.3389/fnagi.2021.660319

Kenji Yamamoto, Nobuo Kato + Show 1 more

Open Access

https://doi.org/10.3389/fnagi.2021.660319

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Abstract

Intracellular amyloid β (Aβ) injection suppresses the large-conductance calcium-dependent potassium (BK) channel in cortical pyramidal cells from wild-type (WT) mice. In 3xTg Alzheimer’s disease (AD) model mice, intraneuronal Aβ is genetically programed to accumulate, which suppresses the BK channel. However, the mode of BK channel suppression remained unclarified. The present report revealed that only one (11A1) of the three anti-Aβ-oligomer antibodies that we examined, but not anti-monomer-Aβ-antibodies, was effective in recovering BK channel activity in 3xTg neurons. Antibodies against amyloid precursor protein (APP) were also found to be effective, suggesting that APP plays an essential part in this Aβ-oligomer-induced BK channel suppression in 3xTg neurons. In WT neurons, by contrast, APP suppressed BK channels by itself, which suggests that either APP or Aβ is sufficient to block BK channels, thus pointing to a different co-operativity of Aβ and APP in WT and 3xTg neurons. To clarify this difference, we relied on our previous finding that the scaffold protein Homer1a reverses the BK channel blockade in both WT and 3xTg neurons. In cortical neurons from 3xTg mice that bear Homer1a knockout (4xTg mice), neither anti-APP antibodies nor 11A1, but only the 6E10 antibody that binds both APP and Aβ, rescued the BK channel suppression. Given that Homer1a expression is activity dependent and 3xTg neurons are hyperexcitable, Homer1a is likely to be expressed sufficiently in 3xTg neurons, thereby alleviating the suppressive influence of APP and Aβ on BK channel. A unique way that APP modifies Aβ toxicity is thus proposed.

Highlights

Alzheimer’s disease (AD) is a focus of global concern
Our previous studies showed that intracellular amyloid β (Aβ) renders the descending limb of action potentials less steep by blocking BK channels, but no AP4-sensitive K channels are blocked (Yamamoto et al, 2011)
We adopted the spike broadening as an index of BK channel activity and, thereby, demonstrated that up- and down-regulation of BK channel activities are well correlated with cognitive amelioration and decline in 3xTg AD model mice, respectively, in our previous studies (Wang F. et al, 2015; Wang L. et al, 2015)

Summary

Introduction

Alzheimer’s disease (AD) is a focus of global concern. no causal therapy is available yet, general anticipation is widespread toward potential interventions at the early stage, especially targeting the amyloidogenic pathway leading to amyloid β (Aβ) production (LaFerla et al, 2007; Perrin et al, 2009). In pre-Aβ-deposit 3xTg mice, we have shown that a class of potassium channel, the large-conductance calcium-activated potassium (BK) channel, is suppressed in cortical pyramidal neurons. This channel, called slo, BK, maxiK, or KCa1.1, is widely expressed and is regarded, if defective, to cause numerous diseases (Ghatta et al, 2006; Salkoff et al, 2006; Nardi and Olesen, 2008; Griguoli et al, 2016). In WT mouse neurons, intracellular injection of Aβ suppressed BK channel, widened spikes, and enhanced spike-induced calcium entry (Yamamoto et al, 2011)

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