BACKGROUND Tau hyper-phosphorylation has been considered a major contributor to neurodegeneration in Alzheimer's disease (AD) and related tauopathies, and has gained prominence in therapeutic development for AD. To elucidate the pathogenic mechanisms underlying AD and evaluate therapeutic approaches targeting tau, numerous transgenic mouse models that recapitulate critical AD-like pathology have been developed. Tau P301S transgenic mice is one of the most widely used mouse models in AD research. Extensive studies have demonstrated that sex significantly influences AD pathology, behavioral status, and therapeutic outcomes, suggesting that studies using mouse models of AD must consider sex- and age-related differences in neuropathology, behavior, and plasma content. METHOD We systematically investigated differences in tau P301S transgenic mice (PS19 line) and wildtype littermates of different sex behavioral performance, tau neuropathology, and biomarkers in plasma and brain. RESULTS Male P301S transgenic mice exhibited significant changes in weight loss, survival rate, clasping, kyphosis, composite phenotype assessment, nest building performance, tau phosphorylation at Ser202/Thr205, and astrocyte activation compared to that of wild-type littermates. In contrast, female P301S transgenic mice were only sensitive in the Morris water maze and open field test. In addition, we characterized the absence of macrophage-inflammatory protein (MIP-3α) and the upregulation of interferon (IFN)-γ, interleukin (IL)-5, and IL-6 in the plasma of P301S transgenic mice, which can be served as potential plasma biomarkers in P301S Tg mice. Male P301S transgenic mice expressed more monokine induced by IFN-γ (MIG), tumor necrosis factor-α (TNF-α), IL-10, and IL-13 than those of female P301S mice. CONCLUSION Our findings highlight sexual dimorphism in the behavior, neuropathology, and plasma proteins in tau P301S transgenic AD mice, indicating that the use of male P301S transgenic mice may be more suitable for assessing anti-phosphorylated tau therapeutic strategies for AD and related tauopathies, and the MIP-3α may be a new potential plasma biomarker.

中文翻译：

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阿尔茨海默氏病的tau P301S小鼠模型的行为和神经病理学性二态性以及MIP-3α的缺失。

背景技术Tau过度磷酸化已被认为是阿尔茨海默氏病（AD）和相关疾病的神经退行性变的主要因素，并在AD的治疗开发中占有重要地位。为了阐明AD的致病机制并评估针对tau的治疗方法，已经开发了许多概括关键AD样病理的转基因小鼠模型。Tau P301S转基因小鼠是AD研究中使用最广泛的小鼠模型之一。广泛的研究表明，性别显着影响AD病理，行为状态和治疗结果，这表明使用AD小鼠模型的研究必须考虑与性别和年龄相关的神经病理，行为和血浆含量差异。方法我们系统地研究了tau P301S转基因小鼠（PS19系）和野生型同窝动物在性别和行为上的差异，tau神经病理学以及血浆和脑中生物标志物的差异。结果与野生型同窝幼仔相比，雄性P301S转基因小鼠在体重减轻，存活率，扣环，驼背，复合表型评估，筑巢性能，tau 202 / Thr205的tau磷酸化以及星形胶质细胞活化方面表现出显着变化。相反，雌性P301S转基因小鼠仅在莫里斯水迷宫和野外试验中敏感。此外，我们表征了P301S转基因小鼠血浆中巨噬细胞炎症蛋白（MIP-3α）的缺失以及干扰素（IFN）-γ，白介素（IL）-5和IL-6的上调，可用作P301S Tg小鼠的潜在血浆生物标志物。雄性P301S转基因小鼠比雌性P301S小鼠表达更多的IFN-γ（MIG），肿瘤坏死因子-α（TNF-α），IL-10和IL-13诱导的单因子。结论我们的研究结果突显了tau P301S转基因AD小鼠的行为，神经病理学和血浆蛋白中的性二态性，表明使用雄性P301S转基因小鼠可能更适合评估tau对AD和相关tauopathies的治疗策略，以及MIP-3α可能是新的潜在血浆生物标志物。