Development of diagnostic and therapeutic agents targeting pre- fibrillary tau lesions in Tauopathies.

一系列新开发的适用于正电子发射断层扫描（PET）的tau成像探针显示出足以定量检测tau转基因小鼠（tau- tg）中形成的神经元内tau内含物（TI）的药理学特性。老年tau- tg的PET和死后神经病理学分析表明，海马中相对不成熟的tau组装导致神经元在TI形成之前毒性死亡，而TI的大量积累似乎与脑干和脊髓中神经元的逐渐死亡有关。这种区域差异可能与生物活性分子与tau聚集体的相互作用有机制联系，作为一种粘附元件，vitronectin （Vn）在脑干中与神经元tau蛋白很好地共定位，但在海马中却没有。考虑到这一点，Vn可能参与了tau聚合物在未成熟的神经毒性和成熟的无毒形式之间的转化，这将为低阶tau组装的病因学和诊断治疗方法提供见解。

A series of newly developed tau imaging probes applicable to positron emission tomography (PET) exhibited pharmacological properties sufficient for quantitative detection of intraneuronal tau inclusions (TI) formed in tau transgenic mice (tau-Tg). Combined PET and postmortem neuropathological assays of aged tau-Tg indicated that relatively immature tau assemblies in the hippocampus led neurons to toxic death prior to the formation of TI, while abundant accumulation of TI appeared to be associated with gradual neuronal death in the brainstem and spinal cord. This regional difference may be mechanistically linked to interaction of bioactive molecules with tau aggregates, as an adhesion element, vitronectin (Vn), was well colocalized with neuronal tau in the brainstem but not hippocampus. In this consideration, Vn is likely to be involved in conversion of tau polymers between immature neurotoxic and mature nontoxic forms, which would provide insights into etiological and diagnostic-therapeutic approaches to low-order tau assemblies.