INTRODUCTIONProgressive supranuclear palsy (PSP) is a devastating 4R tauopathy affecting motor functions and is often misdiagnosed/underdiagnosed due to a lack of specific biomarkers. Synaptic loss is an eminent feature of tauopathies including PSP. Novel synaptic positron emission tomography tracer UCB‐J holds great potential for early diagnosis; however, there is a substantial knowledge gap in terms of the mechanism and the extent and nature of synaptic loss in PSP.METHODSHere, we report an in‐depth post mortem validation and mechanistic study of UCB‐J in PSP and control brains using radioligand/autoradiography binding studies, alongside biochemical correlation analyses of synaptic markers.RESULTS AND DISCUSSION3H‐UCB‐J targeted synaptic vesicle protein 2A protein with high specificity and demonstrated a distinct interrelation with synaptic markers in PSP patients’ brain regions. The loss of UCB‐J binding in the early and severely affected globus pallidus of PSP patients’ brains revealed deficits of glutamate/GABAergic synaptic terminals. Cortical and subcortical 4R tau load differentially impacted synaptic marker profiles across PSP patients, warranting further investigation.Highlights UCB‐J targeted synaptic vesicle protein 2A with high specificity in progressive supranuclear palsy (PSP) brains and demonstrated a conserved single nM binding site across different brain regions. UCB‐J depicted prominent synaptic loss at the synaptosome levels and revealed deficits of glutamate/GABAergic synaptic terminals in the early affected globus pallidus of PSP brains as compared to the control. Cortical and subcortical 4R tau load distinctly influenced synaptic markers profile across PSP patients and highlighted that presynaptic “ubiquitous” markers individually might not be able to represent the complete state of synaptic deficits/loss in PSP brains.

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进行性核上性麻痹患者大脑中 UCB-J 的尸检验证和机制研究


引言性核上性麻痹 （PSP） 是一种影响运动功能的破坏性 4R tau 蛋白病，由于缺乏特异性生物标志物，经常被误诊/漏诊。突触丢失是 tau 蛋白病（包括 PSP）的一个突出特征。新型突触正电子发射断层扫描示踪剂 UCB-J 具有巨大的早期诊断潜力;然而，在 PSP 突触丢失的机制、程度和性质方面存在很大的知识差距。方法我们报告了 PSP 和对照大脑中 UCB-J 的深入尸检验证和机制研究，使用放射配体/放射自显影结合研究，以及突触标志物的生化相关性分析。结果和 DISCUSSION3H‐UCB-J 靶向突触囊泡蛋白 2A 蛋白，特异性高，并与 PSP 患者脑区的突触标志物存在明显的相互关系。PSP 患者大脑早期和严重受影响的苍白球中 UCB-J 结合的缺失揭示了谷氨酸/GABA 能突触末梢的缺陷。皮质和皮质下 4R tau 负荷对 PSP 患者的突触标志物谱产生差异影响，值得进一步研究。亮点 UCB-J 在进行性核上性麻痹 （PSP） 脑中靶向突触囊泡蛋白 2A，具有高度特异性，并证明跨不同脑区存在保守的单个 nM 结合位点。UCB-J 描述了突触体水平的显着突触丢失，并揭示了与对照组相比，PSP 大脑早期受影响的苍白球中谷氨酸/GABA 能突触末梢的缺陷。 皮质和皮质下 4R tau 负荷明显影响了 PSP 患者的突触标志物谱，并强调突触前“普遍存在”标志物单独可能无法代表 PSP 大脑中突触缺陷/丢失的完整状态。