乙酰化tau蛋白阻碍KIBRA介导的突触可塑性信号传导并促进tau蛋白病相关的记忆丧失。
Acetylated Tau Obstructs KIBRA-Mediated Signaling in Synaptic Plasticity and Promotes Tauopathy-Related Memory Loss.
作者信息
Tracy Tara E, Sohn Peter Dongmin, Minami S Sakura, Wang Chao, Min Sang-Won, Li Yaqiao, Zhou Yungui, Le David, Lo Iris, Ponnusamy Ravikumar, Cong Xin, Schilling Birgit, Ellerby Lisa M, Huganir Richard L, Gan Li
机构信息
Gladstone Institute of Neurological Disease, San Francisco, CA 91458, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 91458, USA.
Gladstone Institute of Neurological Disease, San Francisco, CA 91458, USA; Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA 91458, USA.
出版信息
Neuron. 2016 Apr 20;90(2):245-60. doi: 10.1016/j.neuron.2016.03.005. Epub 2016 Mar 31.
Tau toxicity has been implicated in the emergence of synaptic dysfunction in Alzheimer's disease (AD), but the mechanism by which tau alters synapse physiology and leads to cognitive decline is unclear. Here we report abnormal acetylation of K274 and K281 on tau, identified in AD brains, promotes memory loss and disrupts synaptic plasticity by reducing postsynaptic KIdney/BRAin (KIBRA) protein, a memory-associated protein. Transgenic mice expressing human tau with lysine-to-glutamine mutations to mimic K274 and K281 acetylation (tauKQ) exhibit AD-related memory deficits and impaired hippocampal long-term potentiation (LTP). TauKQ reduces synaptic KIBRA levels and disrupts activity-induced postsynaptic actin remodeling and AMPA receptor insertion. The LTP deficit was rescued by promoting actin polymerization or by KIBRA expression. In AD patients with dementia, we found enhanced tau acetylation is linked to loss of KIBRA. These findings suggest a novel mechanism by which pathogenic tau causes synaptic dysfunction and cognitive decline in AD pathogenesis.
Tau蛋白毒性与阿尔茨海默病（AD）中突触功能障碍的出现有关，但tau蛋白改变突触生理学并导致认知能力下降的机制尚不清楚。在此，我们报告在AD大脑中鉴定出的tau蛋白上K274和K281位点的异常乙酰化，通过减少突触后肾脏/脑（KIBRA）蛋白（一种与记忆相关的蛋白），促进记忆丧失并破坏突触可塑性。表达人类tau蛋白赖氨酸突变为谷氨酰胺以模拟K274和K281乙酰化（tauKQ）的转基因小鼠表现出与AD相关的记忆缺陷和海马长时程增强（LTP）受损。TauKQ降低突触KIBRA水平，并破坏活动诱导的突触后肌动蛋白重塑和AMPA受体插入。通过促进肌动蛋白聚合或KIBRA表达可挽救LTP缺陷。在患有痴呆症的AD患者中，我们发现tau蛋白乙酰化增强与KIBRA缺失有关。这些发现提示了一种新机制，即致病性tau蛋白在AD发病机制中导致突触功能障碍和认知能力下降。
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