Neurobiology Center, Nencki Institute of Experimental Biology, 02-093 Warsaw, Poland.
Department of Applied Physiology, Mossakowski Medical Research Center, 02-093 Warsaw, Poland.
Curr Alzheimer Res. 2020;17(3):224-237. doi: 10.2174/1567205017666200424134311.
The molecular processes underlying neurodegenerative diseases (such as Alzheimer's Disease - AD) remain poorly understood. There is also an imperative need for disease-modifying therapies in AD since the present treatments, acetylcholinesterase inhibitors and NMDA antagonists, do not halt its progression. AD and other dementias present unique pathological features such as that of microtubule associated protein tau metabolic regulation. Tau has numerous binding partners, including signaling molecules, cytoskeletal elements and lipids, which suggests that it is a multifunctional protein. AD has also been associated with severe loss of cholinergic markers in the brain and such loss may be due to the toxic interaction of tau with cholinergic muscarinic receptors. By using specific antagonists of muscarinic receptors it was found in vitro that extracellular tau binds to M1 and M3 receptors and which the increase of intracellular calcium found in neuronal cells upon tau-binding. However, so far, the significance of tau signaling through muscarinic receptor in vivo in tauopathic models remains uncertain. The data reviewed in the present paper highlight the significant effect of M1 receptor/tau interaction in exacerbating tauopathy related pathological features and suggest that selective M1 agonists may serve as a prototype for future therapeutic development toward modification of currently intractable neurodegenerative diseases, such as tauopathies.
神经退行性疾病（如阿尔茨海默病 - AD）的分子过程仍知之甚少。由于目前的治疗方法（乙酰胆碱酯酶抑制剂和 NMDA 拮抗剂）无法阻止其进展，因此迫切需要疾病修饰疗法。AD 和其他痴呆症具有独特的病理特征，例如微管相关蛋白 tau 的代谢调节。Tau 有许多结合伴侣，包括信号分子、细胞骨架元件和脂质，这表明它是一种多功能蛋白。AD 还与大脑中胆碱能标志物的严重丧失有关，这种丧失可能是由于 tau 与胆碱能毒蕈碱受体的毒性相互作用。通过使用毒蕈碱受体的特异性拮抗剂，在体外发现细胞外 tau 与 M1 和 M3 受体结合，并且在 tau 结合后在神经元细胞中发现细胞内钙增加。然而，到目前为止，tau 通过毒蕈碱受体在体内的信号转导在 tau 病模型中的意义仍然不确定。本文综述的资料强调了 M1 受体/tau 相互作用在加剧与 tau 病相关的病理特征方面的重要作用，并表明选择性 M1 激动剂可能成为未来治疗开发的原型，以修饰目前难以治疗的神经退行性疾病，如 tau 病。
