背景:转运蛋白(TSPO)已被确定为正电子发射断层扫描(PET)可见的炎症生物标志物和有希望的免疫治疗靶标,用于治疗阿尔茨海默病(AD)。虽然TSPO配体已被证明可以减少毒性阿尔茨海默症β-淀粉样蛋白肽的积累,它们对tau病理学的影响尚未得到调查。为了解决这个问题,我们分析了TSPO配体的作用,Ro5-4864,关于rTg4510tau转基因小鼠(TauTg)的神经病理学进展。
方法:脑萎缩,tau积累,使用体积磁共振成像纵向评估神经炎症,tau-PET,和TSPO-PET,分别。体内神经影像学结果通过免疫组织化学证实了神经元存活标志物(NeuN),tau病变(AT8),和炎症(TSPO,来自扫描小鼠的脑切片中的离子化钙结合衔接分子1或IBA-1和补体成分1q或C1q)。
结果:TSPO配体治疗减轻了脑萎缩和海马神经元丢失,但没有检测到对tau沉积的任何影响。萎缩和神经元丢失与TSPO-PET测量的体内炎症信号密切相关,IBA-1和C1q的水平,补体级联的调节剂。体外研究证实,TSPO配体Ro5-4864在小胶质细胞系中减少了对炎症反应的C1q表达,在先前的研究中已显示减少了在tau蛋白病模型中保护突触和神经元。
结论:这些发现支持TSPO配体在tau病变中的保护作用,减少神经炎症,神经变性,和脑萎缩.
BACKGROUND: The translocator protein (TSPO) has been identified as a positron emission tomography (PET)-visible biomarker of inflammation and promising immunotherapeutic target for the treatment of Alzheimer\'s disease (AD). While TSPO ligands have been shown to reduce the accumulation of the toxic Alzheimer\'s beta-amyloid peptide, their effect on tau pathology has not yet been investigated. To address this, we analyzed the effects of TSPO ligand, Ro5-4864, on the progression of neuropathology in rTg4510 tau transgenic mice (TauTg).
METHODS: Brain atrophy, tau accumulation, and neuroinflammation were assessed longitudinally using volumetric magnetic resonance imaging, tau-PET, and TSPO-PET, respectively. In vivo neuroimaging results were confirmed by immunohistochemistry for markers of neuronal survival (NeuN), tauopathy (AT8), and inflammation (TSPO, ionized calcium-binding adaptor molecule 1 or IBA-1, and complement component 1q or C1q) in brain sections from scanned mice.
RESULTS: TSPO ligand treatment attenuated brain atrophy and hippocampal neuronal loss in the absence of any detected effect on tau depositions. Atrophy and neuronal loss were strongly associated with in vivo inflammatory signals measured by TSPO-PET, IBA-1, and levels of C1q, a regulator of the complement cascade. In vitro studies confirmed that the TSPO ligand Ro5-4864 reduces C1q expression in a microglial cell line in response to inflammation, reduction of which has been shown in previous studies to protect synapses and neurons in models of tauopathy.
CONCLUSIONS: These findings support a protective role for TSPO ligands in tauopathy, reducing neuroinflammation, neurodegeneration, and brain atrophy.