Nmnat1 protects neuronal function without altering phospho-tau pathology in a mouse model of tauopathy.
Nmnat1 protects neuronal function without altering phospho-tau pathology in a mouse model of tauopathy.
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DOI：
10.1002/acn3.308
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发表时间：
2016-06
影响因子：
5.3
通讯作者：
Holtzman DM
中科院分区：
文献类型：
--
作者：
Musiek ES;Xiong DD;Patel T;Sasaki Y;Wang Y;Bauer AQ;Singh R;Finn SL;Culver JP;Milbrandt J;Holtzman DM
在急性轴突损伤模型中，烟酰胺核苷酸腺苷基转移酶蛋白Nmnat1是一种有效的轴突变性抑制剂。微管相关蛋白Tau的过度磷酸化和聚集与阿尔茨海默病和其他疾病的神经退行性变有关。先前的研究表明，其他Nmnat亚型既可以作为轴索保护剂，又具有蛋白伴侣功能，在果蝇和小鼠的牛头病模型中发挥保护作用。Nmnat1靶向细胞质（cytNmnat1）在新生儿缺氧缺血小鼠模型中具有神经保护作用，但cytNmnat1对牛头病的影响尚不清楚。我们在P301S慢性tau病小鼠模型中检测了cytNmnat1过表达对tau病理、神经变性和脑功能连通性的影响。过表达cytNmnat1可维持P301S小鼠体内皮层神经元功能连接。然而，尽管Nmnat1过表达减少了大脑皮层中洗涤剂不溶性tau聚集体的积累，但它对P301S小鼠的病理性tau磷酸化和错误折叠、海马萎缩或炎症标志物的免疫组织化学证据没有影响。我们的研究结果表明，在慢性tau病小鼠模型中，cytNmnat1部分保留神经元功能并减少生化不溶性tau，但不阻止tau磷酸化、可溶性聚集体的形成或tau诱导的炎症和萎缩。因此，Nmnat1可能代表了牛头病变的治疗靶点。
The nicotinamide‐nucleotide adenylyltransferase protein Nmnat1 is a potent inhibitor of axonal degeneration in models of acute axonal injury. Hyperphosphorylation and aggregation of the microtubule‐associated protein Tau are associated with neurodegeneration in Alzheimer's Disease and other disorders. Previous studies have demonstrated that other Nmnat isoforms can act both as axonoprotective agents and have protein chaperone function, exerting protective effects in drosophila and mouse models of tauopathy. Nmnat1 targeted to the cytoplasm (cytNmnat1) is neuroprotective in a mouse model of neonatal hypoxia‐ischemia, but the effect of cytNmnat1 on tauopathy remains unknown. We examined the impact of overexpression of cytNmnat1 on tau pathology, neurodegeneration, and brain functional connectivity in the P301S mouse model of chronic tauopathy. Overexpression of cytNmnat1 preserved cortical neuron functional connectivity in P301S mice in vivo. However, whereas Nmnat1 overexpression decreased the accumulation of detergent‐insoluble tau aggregates in the cerebral cortex, it exerted no effect on immunohistochemical evidence of pathologic tau phosphorylation and misfolding, hippocampal atrophy, or inflammatory markers in P301S mice. Our results demonstrate that cytNmnat1 partially preserves neuronal function and decreases biochemically insoluble tau in a mouse model of chronic tauopathy without preventing tau phosphorylation, formation of soluble aggregates, or tau‐induced inflammation and atrophy. Nmnat1 might thus represent a therapeutic target for tauopathies.