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

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.

细胞内注射淀粉样β蛋白（Aβ）可抑制野生型（WT）小鼠皮质锥体细胞中的大电导钙依赖性钾（BK）通道。在3xTg阿尔茨海默病（AD）模型小鼠中，神经元内的Aβ通过基因编程积累，从而抑制BK通道。然而，BK通道被抑制的方式仍不明确。本研究报告显示，我们所检测的三种抗Aβ寡聚体抗体中只有一种（11A1），而非抗单体Aβ抗体，可有效恢复3xTg神经元中BK通道的活性。还发现抗淀粉样前体蛋白（APP）抗体也有效，这表明APP在3xTg神经元中这种由Aβ寡聚体诱导的BK通道抑制中起关键作用。相比之下，在WT神经元中，APP自身可抑制BK通道，这表明APP或Aβ都足以阻断BK通道，从而表明在WT和3xTg神经元中Aβ和APP具有不同的协同作用。为了阐明这种差异，我们依据之前的发现，即支架蛋白Homer1a可逆转WT和3xTg神经元中BK通道的阻断。在携带Homer1a基因敲除的3xTg小鼠（4xTg小鼠）的皮质神经元中，抗APP抗体和11A1均无效，只有同时结合APP和Aβ的6E10抗体可挽救BK通道的抑制。鉴于Homer1a的表达依赖于神经元活动，且3xTg神经元具有高兴奋性，Homer1a可能在3xTg神经元中充分表达，从而减轻APP和Aβ对BK通道的抑制作用。因此提出了APP改变Aβ毒性的一种独特方式。