The accumulation of amyloid-beta peptide (Aβ) and the failure of cholinergic transmission are key players in Alzheimer’s disease (AD). However, in the healthy brain, Aβ contributes to synaptic plasticity and memory acting through α7 subtype nicotinic acetylcholine receptors (α7nAChRs). Here, we hypothesized that the α7nAChR deletion blocks Aβ physiological function and promotes a compensatory increase in Aβ levels that, in turn, triggers an AD-like pathology.

To validate this hypothesis, we studied the age-dependent phenotype of α7 knock out mice. We found that α7nAChR deletion caused an impairment of hippocampal synaptic plasticity and memory at 12 months of age, paralleled by an increase of Amyloid Precursor Protein expression and Aβ levels. This was accompanied by other classical AD features such as a hyperphosphorylation of tau at residues Ser 199, Ser 396, Thr 205, a decrease of GSK-3β at Ser 9, the presence of paired helical filaments and neurofibrillary tangles, neuronal loss and an increase of GFAP-positive astrocytes.

Our findings suggest that α7nAChR malfunction might precede Aβ and tau pathology, offering a different perspective to interpret the failure of anti-Aβ therapies against AD and to find novel therapeutical approaches aimed at restoring α7nAChRs-mediated Aβ function at the synapse.

淀粉样蛋白-β 肽 (Aβ) 的积累和胆碱能传递的失败是阿尔茨海默病 (AD) 的关键因素。然而，在健康的大脑中，Aβ 通过 α7 亚型烟碱乙酰胆碱受体 (α7nAChRs) 有助于突触可塑性和记忆。在这里，我们假设 α7nAChR 缺失会阻断 Aβ 生理功能并促进 Aβ 水平的补偿性增加，进而引发 AD 样病理。

为了验证这一假设，我们研究了 α7 基因敲除小鼠的年龄依赖性表型。我们发现 α7nAChR 缺失导致 12 个月大时海马突触可塑性和记忆力受损，同时淀粉样前体蛋白表达和 Aβ 水平的增加。这伴随着其他经典的 AD 特征，例如 tau 在 Ser 199、Ser 396、Thr 205 残基处过度磷酸化，在 Ser 9 处 GSK-3β 减少，成对螺旋丝和神经原纤维缠结的存在，神经元丢失和增加GFAP 阳性星形胶质细胞。

我们的研究结果表明，α7nAChR 功能障碍可能先于 Aβ 和 tau 病理学，提供了不同的视角来解释抗 Aβ 疗法对 AD 的失败，并找到旨在恢复 α7nAChRs 介导的突触 Aβ 功能的新治疗方法。