Reduction of advanced tau-mediated memory deficits by the MAP kinase p38γ
Reduction of advanced tau-mediated memory deficits by the MAP kinase p38γ
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DOI：
10.1007/s00401-020-02191-1
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发表时间：
2020-07-29
影响因子：
12.7
通讯作者：
Ittner, Lars M.
中科院分区：
文献类型：
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作者：
Ittner, Arne;Asih, Prita Riana;Ittner, Lars M.
神经元tau蛋白的过度磷酸化通过促进tau病理以及神经元和认知缺陷而导致阿尔茨海默病(AD)。相反，我们之前已经证明，在小鼠模型中，位点特异的tau磷酸化可以抑制淀粉样β蛋白(Aβ)诱导的毒性信号。突触后丝裂原活化蛋白(MAP)激活蛋白(MAP)激酶p38-γ介导了这种苏氨酸-205(T205)处tau的特异性磷酸化。使用基因治疗方法，我们利用这种神经保护机制来改善两个Aβ依赖的阿尔茨海默病小鼠模型的记忆，在出现高级记忆缺陷的阶段。在症状性Aβ诱导的AD模型中，靶向T205的突触后激酶p38伽马的活性增加减少了记忆缺陷。野生型人tau或磷酸化缺陷tauT205A的重组实验表明，T205修饰对于p38伽马的下游效应至关重要，p38伽马可以防止APP转基因小鼠的记忆损伤。此外，对小鼠MAPT基因中T205密码子的基因组编辑表明，内源性tau中的这个单侧链对APP转基因阿尔茨海默氏症小鼠的记忆缺陷起着关键的调节作用。在表达非致病tau的tau转基因小鼠模型中，通过基因p38伽马缺失来消除p38伽马活性的保护作用，导致tau中毒，并导致在缺乏人Aβ的情况下记忆功能受损。因此，我们认为，调节神经元p38伽马活性可以作为一种内在的tau依赖的治疗方法，以增强晚期痴呆患者的认知损害。
Hyperphosphorylation of the neuronal tau protein contributes to Alzheimer's disease (AD) by promoting tau pathology and neuronal and cognitive deficits. In contrast, we have previously shown that site-specific tau phosphorylation can inhibit toxic signals induced by amyloid-beta (A beta) in mouse models. The post-synaptic mitogen-activated protein (MAP) kinase p38 gamma mediates this site-specific phosphorylation on tau at Threonine-205 (T205). Using a gene therapeutic approach, we draw on this neuroprotective mechanism to improve memory in two A beta-dependent mouse models of AD at stages when advanced memory deficits are present. Increasing activity of post-synaptic kinase p38 gamma that targets T205 in tau reduced memory deficits in symptomatic A beta-induced AD models. Reconstitution experiments with wildtype human tau or phosphorylation-deficient tauT205A showed that T205 modification is critical for downstream effects of p38 gamma that prevent memory impairment in APP-transgenic mice. Furthermore, genome editing of the T205 codon in the murineMaptgene showed that this single side chain in endogenous tau critically modulates memory deficits in APP-transgenic Alzheimer's mice. Ablating the protective effect of p38 gamma activity by geneticp38 gamma deletion in a tau transgenic mouse model that expresses non-pathogenic tau rendered tau toxic and resulted in impaired memory function in the absence of human A beta. Thus, we propose that modulating neuronal p38 gamma activity serves as an intrinsic tau-dependent therapeutic approach to augment compromised cognition in advanced dementia.