Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz 51368, Iran.
Department of Clinical Pharmacy, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz 51368, Iran.
Rev Neurosci. 2020 May 26;31(4):391-413. doi: 10.1515/revneuro-2019-0089.
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.
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 相关认知障碍之间的联系早已确立。然而，将淀粉样β（Aβ）和过度磷酸化的 tau 与胆碱能系统之间的相互作用引入描述性神经病理学领域，通过将突触神经传递理论添加到 AD 的毒性双人舞中，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 和胆碱能假说的多靶点方法可以更好地解释 AD 中发生的事件的演变。在疾病早期，各种 Aβ和 tau 都可以在基底前脑系统的胆碱能神经元中追踪到。这些分子诱导该系统神经元变性。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 患者的临床发现和认知障碍更好地相关。几种与 Aβ和 tau 相关的治疗方法的失败进一步强调了需要特别关注针对所有这些病理变化的分子。另一个值得注意的事实是，AD 中没有一个流行的假说，如淀粉样变性或 tau 病，似乎单独负责观察到的变化。因此，应该在 APP 代谢或基底前脑胆碱能系统中的 Wnt 信号转导的某个地方，在更高的地方寻找主要的罪魁祸首。未来的研究应该针对这些病理事件。
