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成像探针表现出足够的药理学特性，用于定量检测tau转基因小鼠（tau-Tg）中形成的神经元内tau包涵体（TI）。结合PET和尸检神经病理学测定老年tau-Tg表明，海马中相对不成熟的tau组件导致神经元毒性死亡之前，TI的形成，而丰富的积累TI似乎与逐渐的神经元死亡在脑干和脊髓。这种区域差异可能与生物活性分子与tau聚集体的相互作用机制有关，因为粘附元件玻连蛋白（Vn）与脑干中的神经元tau而不是海马中的神经元tau共定位。在这种情况下，Vn可能参与tau聚合物在未成熟神经毒性和成熟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.