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

一系列新开发的可用于正电子发射断层扫描(PET)的tau成像探针具有足够的药理学特性，足以定量检测tau转基因小鼠(tau-TG)中形成的神经元内tau包涵体(TI)。对老年tau-TG的PET结合死后神经病理分析表明，在TI形成之前，海马区相对不成熟的tau集合体导致神经元中毒死亡，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关，作为一种黏附元件，Vitronectin(VN)与神经元tau在脑干中很好地共存，而不是在海马区。考虑到这一点，VN可能参与了未成熟的神经毒性形式和成熟的无毒形式之间的tau聚合物的转换，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.