背景:Tau在各种神经退行性疾病中异常乙酰化,包括老年痴呆症,额颞叶变性(FTLD),和创伤性脑损伤(TBI)。以前,我们报道,在动物模型中,通过抑制赖氨酸174处的p300介导的tau乙酰化来减少乙酰化tau,从而减少tau病理并改善认知功能.
方法:我们研究了两种不同抗体的治疗功效,这些抗体特异性靶向tau上的乙酰化赖氨酸174(ac-tauK174)。我们处理了PS19小鼠,其中包含导致FTLD的P301Stau蛋白病突变,使用抗ac-tauK174并测量对tau病理学的影响,神经变性,和神经行为结果。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,以建立创伤与乙酰化tau水平之间的联系。来自治疗小鼠的TBI后脑组织的单核RNA测序提供了对观察到的治疗效果的潜在分子机制的见解。
结果:抗ac-tauK174治疗减轻了PS19小鼠的神经行为障碍并降低了tau病理学。Ac-tauK174在TBI后24小时在人血浆中显著增加,和抗ac-tauK174治疗PS19小鼠阻断TBI诱导的神经变性并保留记忆功能。抗ac-tauK174治疗挽救了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。
结论:抗ac-tauK174治疗挽救神经行为障碍的能力,减少tau病理学,和挽救神经胶质反应表明,靶向K174的tau乙酰化是一种有前途的神经保护性治疗方法,可治疗由TBI或遗传疾病引起的人类tau蛋白病。
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.