Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), B° Sarriena s/n, 48940 Leioa, Spain; Neurodegenerative Diseases, BioBizkaia Health Research Institute, Bizkaia, Spain, 48903 Barakaldo, Spain.
Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), B° Sarriena s/n, 48940 Leioa, Spain.
Neurobiol Dis. 2024 Nov;202:106713. doi: 10.1016/j.nbd.2024.106713. Epub 2024 Oct 22.
Some specific lipid molecules in the brain act as signaling molecules, neurotransmitters, or neuromodulators, by binding to specific G protein-coupled receptors (GPCR) for neurolipids. One such receptor, sphingosine 1-phosphate receptor subtype 1 (S1P), is coupled to G proteins and is involved in cell proliferation, growth, and neuroprotection. S1P constitutes an interesting target for neurodegenerative diseases like multiple sclerosis and Alzheimer's disease (AD), in which changes in the sphingolipid metabolism have been observed. This study analyzes S1P receptor-mediated activity in healthy brains and during AD progression using postmortem samples from controls and patients at different Braak's stages. Additionally, the distribution of S1P receptor activity in human brains is compared to that in commonly used rodent models, rats and mice, through functional autoradiography, measuring [S]GTPγS binding stimulated by the S1P receptor selective agonist CYM-5442 to obtain the distribution of functional activity of S1P receptors. S1P receptor-mediated activity, along with that of the cannabinoid CB receptor, is one of the highest recorded for any GPCR in many gray matter areas of the brain, reaching maximum values in the cerebellar cortex, specific areas of the hippocampus and the basal forebrain. S1P signaling is crucial in areas that regulate learning, memory, motor control, and nociception, such as the basal forebrain and basal ganglia. In AD, S1P receptor activity is increased in the inner layers of the frontal cortex and underlying cortical white matter at early stages, but decreases in the hippocampus in advanced stages, indicating ongoing brain impairment. Importantly, we identified significant correlations between S1P receptor activity and Braak stages, suggesting that S1P receptor dysfunction is associated to disease progression, particularly in memory-related regions. The S1P signaling via S1P receptor is a promising neurological target due to its role in key neurophysiological functions and its potential to modify the progression of neurodegenerative diseases. Finally, rats are suggested as a preferred experimental model for studying S1P receptor-mediated responses in the human brain.
脑内某些特定的脂质分子作为神经脂类的信号分子、神经递质或神经调质，通过与特定的 G 蛋白偶联受体（GPCR）结合发挥作用。神经脂类的一种这样的受体是鞘氨醇 1-磷酸受体亚型 1（S1P），它与 G 蛋白偶联，参与细胞增殖、生长和神经保护。S1P 构成了多发性硬化症和阿尔茨海默病（AD）等神经退行性疾病的一个有趣的靶点，在这些疾病中，鞘脂代谢发生了变化。本研究使用来自不同 Braak 阶段的对照和患者的死后样本，分析了 S1P 受体介导的健康大脑中的活性以及 AD 进展过程中的活性。此外，通过功能性放射自显影术比较了 S1P 受体活性在人类大脑中的分布与在常用的啮齿动物模型（大鼠和小鼠）中的分布，通过测量 S1P 受体选择性激动剂 CYM-5442 刺激的[S]GTPγS 结合来获得 S1P 受体功能活性的分布。S1P 受体介导的活性与大麻素 CB 受体的活性一样，是大脑许多灰质区域中记录到的任何 GPCR 中最高的之一，在小脑皮层、海马体特定区域和基底前脑达到最大值。S1P 信号在调节学习、记忆、运动控制和痛觉的区域（如基底前脑和基底神经节）中至关重要。在 AD 中，S1P 受体活性在早期阶段在前额皮质内层和皮质下白质中增加，但在晚期阶段在海马体中减少，表明大脑持续受损。重要的是，我们发现 S1P 受体活性与 Braak 阶段之间存在显著相关性，表明 S1P 受体功能障碍与疾病进展有关，特别是在与记忆相关的区域。S1P 信号通过 S1P 受体是一个有前途的神经学靶点，因为它在关键的神经生理功能中发挥作用，并且有可能改变神经退行性疾病的进展。最后，建议大鼠作为研究人类大脑中 S1P 受体介导反应的首选实验模型。
