Multi-model in vivo imaging of neuroimmune modulation in a mouse model of tauopathy

tau蛋白病小鼠模型中神经免疫调节的多模型体内成像

• 批准号: 21K15815
• 负责人: Zhou Xiaoyun
• 金额: $ 3万
• 依托单位: National Institutes for Quantum Science and Technology
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Early-Career Scientists
• 财政年份: 2021
• 资助国家: 日本
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-21K15815/
• 关键词: Neuroinflammation; PET; Tau; MAGL; rTg4510; multi-model imaging; neurodegeneration; tau; tauopathy; P2X7R

Monoacylglycerol lipase (MAGL) plays an important role in terminating endocannabinoid signaling by catalyzing endocannabinoid 2-acylglycerol to form arachidonic acid, an important mediator of inflammatory responses. To explore whether MAGL inhibition could limit pathological Tau-induced neuroinflammatory changes, rTg4510 mice with overexpressing pathological Tau protein have been treated with JZL-184, an inhibitor of monoacylglycerol lipase (MAGL). PET and MRI were carried out before, during, and after the treatment. The in vivo imaging studies revealed that chronic inhibition of the function of MAGL at an early but not late stage of tauopathy decelerated neurodegeneration. Furthermore, the effect of the treatment on constraining neuroinflammation occurred at five months, early than halting the rate of tau accumulation and rescuing neurons (at 7 months), indicating that MAGL inhibition may exert anti-tau and neuroprotective functions via its anti-inflammatory effects.

单酰基甘油脂肪酶（MAGL）通过催化内源性大麻素2-酰基甘油形成花生四烯酸（一种重要的炎症反应介质）在终止内源性大麻素信号传导中起重要作用。为了探索MAGL抑制是否可以限制病理性Tau诱导的神经炎症变化，用单酰基甘油脂肪酶（MAGL）抑制剂JZL-184处理过表达病理性Tau蛋白的rTg 4510小鼠。在治疗前、治疗中和治疗后进行PET和MRI检查。体内成像研究表明，在tau蛋白病的早期而非晚期阶段长期抑制MAGL的功能可减缓神经变性。此外，治疗对抑制神经炎症的作用发生在5个月时，早于停止tau积累速率和拯救神经元（在7个月时），表明MAGL抑制可以通过其抗炎作用发挥抗tau和神经保护功能。