Human P301L-mutant tau expression in mouse entorhinal-hippocampal network causes tau aggregation and presynaptic pathology but no cognitive deficits.
Human P301L-mutant tau expression in mouse entorhinal-hippocampal network causes tau aggregation and presynaptic pathology but no cognitive deficits.
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DOI：
10.1371/journal.pone.0045881
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Mucke L
中科院分区：
文献类型：
--
作者：
Harris JA;Koyama A;Maeda S;Ho K;Devidze N;Dubal DB;Yu GQ;Masliah E;Mucke L
内嗅皮层（EC）中过度磷酸化tau蛋白的积累是阿尔茨海默病（AD）患者最早的病理标志之一。它可以发生在显著的Aβ沉积之前，并且似乎“扩散”到解剖学上连接的脑区域。为了确定这种早期病理是否足以在实验模型中引起疾病进展和认知能力下降，我们主要在小鼠EC的II/III层神经元中过表达突变型人tau（hTauP 301 L）。认知功能在4、8、12和16个月大的小鼠中保持正常，尽管在EC中有早期和广泛的tau积累。即使在年轻的EC-hTau小鼠中，齿状回（DG）内的穿孔通路（PP）轴突终末也含有异常的tau构象，并且磷酸化tau在EC和PP中均随年龄增加。在老年小鼠中，突触前末梢的超微结构的改变，观察到PP颗粒细胞突触。磷酸化tau蛋白在突触前比突触后成分中更丰富。在该小鼠模型的海马神经元内也检测到人类和病理性tau。因此，hTauP 301 L主要在EC中的积累和海马回路中的相关突触前病理不足以在此处分析的年龄范围内引起稳健的认知缺陷。
Accumulation of hyperphosphorylated tau in the entorhinal cortex (EC) is one of the earliest pathological hallmarks in patients with Alzheimer’s disease (AD). It can occur before significant Aβ deposition and appears to “spread” into anatomically connected brain regions. To determine whether this early-stage pathology is sufficient to cause disease progression and cognitive decline in experimental models, we overexpressed mutant human tau (hTauP301L) predominantly in layer II/III neurons of the mouse EC. Cognitive functions remained normal in mice at 4, 8, 12 and 16 months of age, despite early and extensive tau accumulation in the EC. Perforant path (PP) axon terminals within the dentate gyrus (DG) contained abnormal conformations of tau even in young EC-hTau mice, and phosphorylated tau increased with age in both the EC and PP. In old mice, ultrastructural alterations in presynaptic terminals were observed at PP-to-granule cell synapses. Phosphorylated tau was more abundant in presynaptic than postsynaptic elements. Human and pathological tau was also detected within hippocampal neurons of this mouse model. Thus, hTauP301L accumulation predominantly in the EC and related presynaptic pathology in hippocampal circuits was not sufficient to cause robust cognitive deficits within the age range analyzed here.
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影响因子：
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