Alzheimer’s disease (AD) is the most common cause of senile dementia and one of the greatest medical, social, and economic challenges. According to a dominant theory, amyloid-β (Aβ) peptide is a key AD pathogenic factor. Aβ-soluble species interfere with synaptic functions, aggregate gradually, form plaques, and trigger neurodegeneration. The AD-associated pathology affects numerous systems, though the substantial loss of cholinergic neurons and α7 nicotinic receptors (α7AChR) is critical for the gradual cognitive decline. Aβ binds to α7AChR under various experimental settings; nevertheless, the functional significance of this interaction is ambiguous. Whereas the capability of low Aβ concentrations to activate α7AChR is functionally beneficial, extensive brain exposure to high Aβ concentrations diminishes α7AChR activity, contributes to the cholinergic deficits that characterize AD. Aβ and snake α-neurotoxins competitively bind to α7AChR. Accordingly, we designed a chemically modified α-cobratoxin (mToxin) to inhibit the interaction between Aβ and α7AChR. Subsequently, we examined mToxin in a set of original in silico, in vitro, ex vivo experiments, and in a murine AD model. We report that mToxin reversibly inhibits α7AChR, though it attenuates Aβ-induced synaptic transmission abnormalities, and upregulates pathways supporting long-term potentiation and reducing apoptosis. Remarkably, mToxin demonstrates no toxicity in brain slices and mice. Moreover, its chronic intracerebroventricular administration improves memory in AD-model animals. Our results point to unique mToxin neuroprotective properties, which might be tailored for the treatment of AD. Our methodology bridges the gaps in understanding Aβ-α7AChR interaction and represents a promising direction for further investigations and clinical development.

阿尔茨海默病 (AD) 是老年痴呆症的最常见原因，也是最大的医疗、社会和经济挑战之一。根据主流理论，β淀粉样蛋白（Aβ）肽是AD的关键致病因素。Aβ 可溶性物质会干扰突触功能，逐渐聚集，形成斑块，并引发神经变性。AD 相关的病理学影响许多系统，尽管胆碱能神经元和 α7 烟碱受体 (α7AChR) 的大量丧失对于认知能力逐渐下降至关重要。在各种实验设置下，Aβ 与 α7AChR 结合；然而，这种相互作用的功能意义并不明确。虽然低 Aβ 浓度激活 α7AChR 的能力在功能上是有益的，但大脑广泛暴露于高 Aβ 浓度会降低 α7AChR 活性，导致 AD 特有的胆碱能缺陷。Aβ 和蛇 α-神经毒素竞争性结合 α7AChR。因此，我们设计了一种化学修饰的α-眼镜蛇毒素（mToxin）来抑制Aβ和α7AChR之间的相互作用。随后，我们在一组原始的计算机、体外、离体实验和小鼠 AD 模型中检查了 mToxin。我们报告说，mToxin 可逆地抑制 α7AChR，但它会减弱 Aβ 诱导的突触传递异常，并上调支持长期增强和减少细胞凋亡的途径。值得注意的是，mToxin 在脑切片和小鼠中没有显示出毒性。此外，其长期脑室内给药可改善 AD 模型动物的记忆力。我们的结果表明 mToxin 具有独特的神经保护特性，可能适合治疗 AD。我们的方法弥合了理解 Aβ-α7AChR 相互作用的差距，并为进一步研究和临床开发提供了一个有希望的方向。