Tau is aberrantly acetylated in various neurodegenerative conditions, including Alzheimer’s disease, frontotemporal lobar degeneration (FTLD), and traumatic brain injury (TBI). Previously, we reported that reducing acetylated tau by pharmacologically inhibiting p300-mediated tau acetylation at lysine 174 reduces tau pathology and improves cognitive function in animal models. We investigated the therapeutic efficacy of two different antibodies that specifically target acetylated lysine 174 on tau (ac-tauK174). We treated PS19 mice, which harbor the P301S tauopathy mutation that causes FTLD, with anti-ac-tauK174 and measured effects on tau pathology, neurodegeneration, and neurobehavioral outcomes. Furthermore, PS19 mice received treatment post-TBI to evaluate the ability of the immunotherapy to prevent TBI-induced exacerbation of tauopathy phenotypes. Ac-tauK174 measurements in human plasma following TBI were also collected to establish a link between trauma and acetylated tau levels, and single nuclei RNA-sequencing of post-TBI brain tissues from treated mice provided insights into the molecular mechanisms underlying the observed treatment effects. Anti-ac-tauK174 treatment mitigates neurobehavioral impairment and reduces tau pathology in PS19 mice. Ac-tauK174 increases significantly in human plasma 24 h after TBI, and anti-ac-tauK174 treatment of PS19 mice blocked TBI-induced neurodegeneration and preserved memory functions. Anti-ac-tauK174 treatment rescues alterations of microglial and oligodendrocyte transcriptomic states following TBI in PS19 mice. The ability of anti-ac-tauK174 treatment to rescue neurobehavioral impairment, reduce tau pathology, and rescue glial responses demonstrates that targeting tau acetylation at K174 is a promising neuroprotective therapeutic approach to human tauopathies resulting from TBI or genetic disease.

中文翻译：

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抗乙酰化 tau 免疫疗法对 tau 病和脑损伤具有神经保护作用


Tau 在多种神经退行性疾病中异常乙酰化，包括阿尔茨海默病、额颞叶变性 (FTLD) 和创伤性脑损伤 (TBI)。此前，我们报道了通过药理学抑制 p300 介导的赖氨酸 174 处的 tau 乙酰化来减少 tau 乙酰化，从而减少动物模型中的 tau 病理并改善认知功能。我们研究了两种特异性靶向 tau 上乙酰化赖氨酸 174 (ac-tauK174) 的不同抗体的治疗效果。我们用抗 ac-tauK174 治疗带有 P301S tau 蛋白病突变（导致 FTLD）的 PS19 小鼠，并测量了对 tau 蛋白病理学、神经变性和神经行为结果的影响。此外，PS19 小鼠在 TBI 后接受治疗，以评估免疫疗法预防 TBI 诱导的 tau 蛋白病表型恶化的能力。还收集了 TBI 后人血浆中的 Ac-tauK174 测量值，以建立创伤和乙酰化 tau 水平之间的联系，并对治疗小鼠的 TBI 后脑组织进行单核 RNA 测序，为观察到的治疗效果背后的分子机制提供了见解。抗 ac-tauK174 治疗可减轻 PS19 小鼠的神经行为损伤并减少 tau 病理。 TBI 后 24 小时，人血浆中的 Ac-tauK174 显着增加，PS19 小鼠的抗 ac-tauK174 治疗可阻断 TBI 诱导的神经退行性变并保留记忆功能。抗 ac-tauK174 治疗可挽救 PS19 小鼠 TBI 后小胶质细胞和少突胶质细胞转录组状态的改变。 抗 ac-tauK174 治疗能够挽救神经行为损伤、减少 tau 病理学并挽救神经胶质反应，这表明针对 K174 的 tau 乙酰化是治疗由 TBI 或遗传性疾病引起的人类 tau 病的一种有前途的神经保护治疗方法。