Myelin and axon losses are associated with cognitive decline in healthy ageing but are worse in people diagnosed with tauopathy. To determine whether tauopathy is also associated with enhanced myelin plasticity, we evaluated the behaviour of OPCs in mice that expressed a human pathological variant of microtubule-associated protein tau (MAPT^P301S). By 6 months of age (P180), MAPT^P301S mice overexpressed hyperphosphorylated tau and had developed reactive gliosis in the hippocampus but had not developed overt locomotor or memory impairment. By performing cre-lox lineage tracing of adult OPCs, we determined that the number of newborn oligodendrocytes added to the hippocampus, entorhinal cortex and fimbria was equivalent in control and MAPT^P301S mice prior to P150. However, between P150 and P180, significantly more new oligodendrocytes were added to these regions in the MAPT^P301S mouse brain. This large increase in new oligodendrocyte number was not the result of increased OPC proliferation, nor did it alter oligodendrocyte density in the hippocampus, entorhinal cortex or fimbria, which was equivalent in P180 wild-type and MAPT^P301S mice. Furthermore, the proportion of hippocampal and fimbria axons with myelin was unaffected by tauopathy. However, the proportion of myelinated axons that were ensheathed by immature myelin internodes was significantly increased in the hippocampus and fimbria of P180 MAPT^P301S mice, when compared with their wild-type littermates. These data suggest that MAPT^P301S transgenic mice experience significant oligodendrocyte turnover, with newborn oligodendrocytes compensating for myelin loss early in the development of tauopathy.

中文翻译：

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在成年 tau 蛋白病小鼠模型中，在运动或记忆障碍之前，海马灰质和白质的少突胶质细胞生成增加

髓磷脂和轴突的损失与健康衰老过程中的认知能力下降有关，但在诊断为 tau 蛋白病的人中情况更糟。为了确定 tau 蛋白病是否也与髓磷脂可塑性增强相关，我们评估了表达微管相关蛋白 tau的人类病理变体( MAPT ^P301S ) 的小鼠中 OPC 的行为。到 6 个月大时 (P180)，MAPT ^P301S小鼠过度表达过度磷酸化的 tau 蛋白，并在海马中出现反应性神经胶质增生，但没有出现明显的运动或记忆障碍。通过对成年 OPC 进行 cre-lox 谱系追踪，我们确定在 P150 之前，对照组和MAPT ^P301S小鼠的海马、内嗅皮层和菌毛中添加的新生少突胶质细胞数量相同。然而，在 P150 和 P180 之间， MAPT ^P301S小鼠大脑中的这些区域添加了明显更多的新少突胶质细胞。新少突胶质细胞数量的大量增加并不是OPC增殖增加的结果，也没有改变海马、内嗅皮层或菌毛中的少突胶质细胞密度，这在P180野生型和MAPT P301S小鼠中是相当^的。此外，海马和海马伞轴突与髓磷脂的比例不受 tau 蛋白病的影响。然而，与野生型同窝小鼠相比， P180 MAPT ^P301S小鼠的海马和菌伞中被未成熟髓磷脂节间包裹的有髓轴突的比例显着增加。这些数据表明，MAPT ^P301S转基因小鼠经历了显着的少突胶质细胞更新，新生少突胶质细胞在 tau 蛋白病发展的早期补偿了髓鞘质的损失。