Department of Biochemistry and Molecular Biomedicine and IBUB (Institute of Biomedicine of the University of Barcelona), University of Barcelona, Barcelona, Spain; Centro de investigación en Red: Enfermedades Neurodegenerativas, CIBERNED, Madrid, Spain.
Instituto de Neurociencias del Principado de Asturias (INEUROPA), Departamento de Morfología y Biología Celular, Facultad de Medicina, Universidad de Oviedo, Asturias, Spain.
Prog Neurobiol. 2017 Feb-Mar;149-150:21-38. doi: 10.1016/j.pneurobio.2017.01.004. Epub 2017 Feb 9.
Despite efforts to understand the mechanism of neuronal cell death, finding effective therapies for neurodegenerative diseases is still a challenge. Cognitive deficits are often associated with neurodegenerative diseases. Remarkably, in the absence of consensus biomarkers, diagnosis of diseases such as Alzheimer's still relies on cognitive tests. Unfortunately, all efforts to translate findings in animal models to the patients have been unsuccessful. Alzheimer's disease may be addressed from two different points of view, neuroprotection or cognitive enhancement. Based on recent data, the mammalian target of rapamycin (mTOR) pathway arises as a versatile player whose modulation may impact on mechanisms of both neuroprotection and cognition. Whereas direct targeting of mTOR does not seem to constitute a convenient approach in drug discovery, its indirect modulation by other signaling pathways seems promising. In fact, G-protein-coupled receptors (GPCRs) remain the most common 'druggable' targets and as such pharmacological manipulation of GPCRs with selective ligands may modulate phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), mitogen-activated protein (MAP) kinase and mTOR signaling pathways. Thus, GPCRs become important targets for potential drug treatments in different neurodegenerative disorders including, but not limited to, Alzheimer's disease. GPCR-mediated modulation of mTOR may take advantage of different GPCRs coupled to different G-dependent and G-independent signal transduction routes, of functional selectivity and/or of biased agonism. Signals mediated by GPCRs may act as coincidence detectors to achieve different benefits in different stages of the neurodegenerative disease.
尽管人们努力了解神经元细胞死亡的机制，但找到治疗神经退行性疾病的有效疗法仍然是一个挑战。认知缺陷通常与神经退行性疾病有关。值得注意的是，在缺乏共识生物标志物的情况下，阿尔茨海默病等疾病的诊断仍然依赖于认知测试。不幸的是，将动物模型中的发现转化为患者的所有努力都没有成功。阿尔茨海默病可以从两个不同的角度来治疗，即神经保护或认知增强。基于最近的数据，雷帕霉素靶蛋白（mTOR）途径作为一个多功能的参与者出现，其调节可能会影响神经保护和认知的机制。虽然直接靶向 mTOR 似乎不是药物发现的一种方便方法，但通过其他信号通路间接调节 mTOR 似乎很有前途。事实上，G 蛋白偶联受体（GPCR）仍然是最常见的“可成药”靶点，因此，用选择性配体对 GPCR 进行药理学操作可能会调节磷脂酰肌醇-4,5-二磷酸 3-激酶（PI3K）、丝裂原激活蛋白（MAP）激酶和 mTOR 信号通路。因此，GPCR 成为不同神经退行性疾病（包括但不限于阿尔茨海默病）潜在药物治疗的重要靶点。GPCR 介导的 mTOR 调节可以利用与不同 G 依赖性和 G 非依赖性信号转导途径、功能选择性和/或偏向激动剂偶联的不同 GPCR。GPCR 介导的信号可以作为巧合探测器，在神经退行性疾病的不同阶段实现不同的益处。
