Department of Life Sciences, University of Bath, Bath, UK.
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA.
Br J Pharmacol. 2024 Sep;181(17):3172-3191. doi: 10.1111/bph.16381. Epub 2024 May 8.
Oligomeric amyloid β (oAβ) exhibits agonist-like action at human α7- and α7β2-containing nicotinic receptors. The N-terminal amyloid β fragment (N-Aβ fragment) modulates presynaptic calcium and enhances hippocampal-based synaptic plasticity via α7-containing nicotinic receptors. Further, the N-Aβ fragment and its core sequence, the N-amyloid-beta core hexapeptide (N-Aβcore), protect against oAβ-associated synapto- and neurotoxicity. Here, we investigated how oAβ, the N-Aβ fragment, and the N-Aβcore regulate the single-channel properties of α7- and α7β2-nicotinic receptors.
Single-channel recordings measured the impact of acetylcholine, oAβ, the N-Aβ fragment, and the N-Aβcore on the unitary properties of human α7- and α7β2-containing nicotinic receptors expressed in nicotinic-null SH-EP1 cells. Molecular dynamics simulations identified potential sites of interaction between the N-Aβ fragment and orthosteric α7+/α7- and α7+/β2- nicotinic receptor binding interfaces.
The N-Aβ fragment and N-Aβcore induced α7- and α7β2-nicotinic receptor single-channel openings. Relative to acetylcholine, oAβ preferentially enhanced α7β2-nicotinic receptor single-channel open probability and open-dwell times. Co-application with the N-Aβcore neutralized these effects. Further, administration of the N-Aβ fragment alone, or in combination with acetylcholine or oAβ, selectively enhanced α7-nicotinic receptor open probability and open-dwell times (compared to acetylcholine or oAβ).
Amyloid-beta peptides demonstrate functional diversity in regulating α7- and α7β2-nicotinic receptor function, with implications for a wide range of nicotinic receptor-mediated functions in Alzheimer's disease. The effects of these peptides on α7- and/or α7β2-nicotinic receptors revealed complex interactions with these subtypes, providing novel insights into the neuroprotective actions of amyloid β-derived fragments against the toxic effects of oAβ.
寡聚淀粉样β（oAβ）在人α7 和包含α7β2 的烟碱型乙酰胆碱受体上表现出激动剂样作用。N 端淀粉样β 片段（N-Aβ 片段）通过包含α7 的烟碱型乙酰胆碱受体调节突触前钙并增强海马突触可塑性。此外，N-Aβ 片段及其核心序列 N-淀粉样β核心六肽（N-Aβcore）可防止 oAβ 相关的突触和神经毒性。在这里，我们研究了 oAβ、N-Aβ 片段和 N-Aβcore 如何调节α7 和α7β2-烟碱型乙酰胆碱受体的单通道特性。
单通道记录测量了乙酰胆碱、oAβ、N-Aβ 片段和 N-Aβcore 对在烟碱型乙酰胆碱受体缺失的 SH-EP1 细胞中表达的人α7 和包含α7β2 的烟碱型乙酰胆碱受体的单位特性的影响。分子动力学模拟确定了 N-Aβ 片段与正位α7+/α7-和α7+/β2-烟碱型乙酰胆碱受体结合界面之间潜在的相互作用位点。
N-Aβ 片段和 N-Aβcore 诱导α7 和α7β2-烟碱型乙酰胆碱受体单通道开放。与乙酰胆碱相比，oAβ 优先增强α7β2-烟碱型乙酰胆碱受体单通道开放概率和开放持续时间。与 N-Aβcore 共同应用中和了这些作用。此外，单独给予 N-Aβ 片段或与乙酰胆碱或 oAβ 联合给药，选择性地增强了α7-烟碱型乙酰胆碱受体的开放概率和开放持续时间（与乙酰胆碱或 oAβ 相比）。
淀粉样β 肽在调节α7 和α7β2-烟碱型乙酰胆碱受体功能方面表现出功能多样性，这对阿尔茨海默病中广泛的烟碱型乙酰胆碱受体介导的功能具有重要意义。这些肽对α7 和/或α7β2-烟碱型乙酰胆碱受体的影响揭示了与这些亚型的复杂相互作用，为淀粉样β 衍生片段对 oAβ 毒性作用的神经保护作用提供了新的见解。
