The link between histopathological hallmarks of Alzheimer’s disease (AD), i.e. amyloid plaques, and neurofibrillary tangles, and AD-associated cognitive impairment, has long been established. However, the introduction of interactions between amyloid-beta (Aβ) as well as hyperphosphorylated tau, and the cholinergic system to the territory of descriptive neuropathology has drastically changed this field by adding the theory of synaptic neurotransmission to the toxic pas de deux in AD. Accumulating data show that a multitarget approach involving all amyloid, tau, and cholinergic hypotheses could better explain the evolution of events happening in AD. Various species of both Aβ and tau could be traced in cholinergic neurons of the basal forebrain system early in the course of the disease. These molecules induce degeneration in the neurons of this system. Reciprocally, aberrant cholinergic system modulation promotes changes in amyloid precursor protein (APP) metabolism and tau phosphorylation, resulting in neurotoxicity, neuroinflammation, and neuronal death. Altogether, these changes may better correlate with the clinical findings and cognitive impairment detected in AD patients. Failure of several of Aβ- and tau-related therapies further highlights the need for special attention to molecules that target all of these mentioned pathologic changes. Another noteworthy fact here is that none of the popular hypotheses of AD such as amyloidopathy or tauopathy seem to be responsible for the changes observed in AD alone. Thus, the main culprit should be sought higher in the stream somewhere in APP metabolism or Wnt signaling in the cholinergic system of the basal forebrain. Future studies should target these pathological events.

中文翻译：

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淀粉样蛋白-β、tau 和阿尔茨海默病中的胆碱能系统：在一堆线索中寻找方向。

早在阿尔茨海默病 (AD) 的组织病理学特征（即淀粉样斑块和神经原纤维缠结）与 AD 相关的认知障碍之间建立了联系。然而，将突触神经传递理论添加到 AD 中的毒性双人舞中，将淀粉样蛋白 β (Aβ) 以及过度磷酸化 tau 和胆碱能系统之间的相互作用引入描述性神经病理学领域，彻底改变了这一领域。越来越多的数据表明，涉及所有淀粉样蛋白、tau 和胆碱能假设的多目标方法可以更好地解释 AD 中发生的事件的演变。在疾病早期，可以在基底前脑系统的胆碱能神经元中追踪不同种类的 Aβ 和 tau。这些分子诱导该系统神经元的退化。相反，异常的胆碱能系统调节促进淀粉样前体蛋白 (APP) 代谢和 tau 磷酸化的变化，导致神经毒性、神经炎症和神经元死亡。总之，这些变化可能与 AD 患者中检测到的临床发现和认知障碍更相关。几种 Aβ 和 tau 相关疗法的失败进一步突出了对针对所有这些提到的病理变化的分子给予特别关注的必要性。另一个值得注意的事实是，AD 的流行假设（如淀粉样蛋白病或 tau 蛋白病）似乎都不是单独在 AD 中观察到的变化的原因。因此，主要的罪魁祸首应该在 APP 代谢或基底前脑胆碱能系统中的 Wnt 信号传导中的某处更高。未来的研究应该针对这些病理事件。