Ruiz de Martín Esteban Samuel, Benito-Cuesta Irene, Terradillos Itziar, Martínez-Relimpio Ana M, Arnanz M Andrea, Ruiz-Pérez Gonzalo, Korn Claudia, Raposo Catarina, Sarott Roman C, Westphal Matthias V, Elezgarai Izaskun, Carreira Erick M, Hillard Cecilia J, Grether Uwe, Grandes Pedro, Grande M Teresa, Romero Julián
Faculty of Experimental Sciences, Universidad Francisco de Vitoria, Pozuelo de Alarcón, Spain.
Department of Neurosciences, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain.
Front Pharmacol. 2022 Apr 27;13:841766. doi: 10.3389/fphar.2022.841766. eCollection 2022.
The distribution and roles of the cannabinoid CB receptor in the CNS are still a matter of debate. Recent data suggest that, in addition to its presence in microglial cells, the CB receptor may be also expressed at low levels, yet biologically relevant, in other cell types such as neurons. It is accepted that the expression of CB receptors in the CNS is low under physiological conditions and is significantly elevated in chronic neuroinflammatory states associated with neurodegenerative diseases such as Alzheimer's disease. By using a novel mouse model (CB ), we studied the distribution of cannabinoid CB receptors in the 5xFAD mouse model of Alzheimer's disease (by generating 5xFAD/CB mice) and explored the roles of CB receptors in microglial function. We used a novel selective and brain penetrant CB receptor agonist (RO6866945) as well as mice lacking the CB receptor (5xFAD/CB ) for these studies. We found that CB receptors are expressed in dystrophic neurite-associated microglia and that their modulation modifies the number and activity of microglial cells as well as the metabolism of the insoluble form of the amyloid peptide. These results support microglial CB receptors as potential targets for the development of amyloid-modulating therapies.
大麻素CB受体在中枢神经系统中的分布和作用仍存在争议。最近的数据表明，除了在小胶质细胞中存在外，CB受体在其他细胞类型（如神经元）中也可能以低水平表达，但具有生物学相关性。人们普遍认为，CB受体在中枢神经系统中的表达在生理条件下较低，而在与神经退行性疾病（如阿尔茨海默病）相关的慢性神经炎症状态下会显著升高。通过使用一种新型小鼠模型（CB），我们研究了大麻素CB受体在阿尔茨海默病的5xFAD小鼠模型中的分布（通过培育5xFAD/CB小鼠），并探讨了CB受体在小胶质细胞功能中的作用。我们使用了一种新型的选择性且能穿透血脑屏障的CB受体激动剂（RO6866945）以及缺乏CB受体的小鼠（5xFAD/CB）进行这些研究。我们发现CB受体在营养不良性神经突相关的小胶质细胞中表达，并且对其进行调节会改变小胶质细胞的数量和活性以及淀粉样肽不溶性形式的代谢。这些结果支持将小胶质细胞CB受体作为开发淀粉样蛋白调节疗法的潜在靶点。
