Department II of Anatomy, University of Cologne, Cologne, Germany.
Department II of Anatomy, University of Cologne, Cologne, Germany.
Neurobiol Aging. 2020 Sep;93:109-123. doi: 10.1016/j.neurobiolaging.2020.03.007. Epub 2020 Mar 16.
The intracellular accumulation of hyperphosphorylated tau characterizes many neurodegenerative diseases such as Alzheimer's disease and frontotemporal dementia. A critical role for tau is supported by studies in transgenic mouse models expressing the P301L mutation with accumulation of hyperphosphorylated human tau in hippocampal pyramidal neurons of aged mice. Especially, the somatodendritic mislocalization of hyperphosphorylated tau seems to affect the neuronal network of the hippocampus. To show the consequences of aggregation of hyperphosphorylated tau within hippocampal neurons of aged mice, the CA1 pyramidal cells were analyzed morphologically and electrophysiologically. Here we demonstrate in the P301L pR5 mouse model that hyperphosphorylated tau leads to an increase in stubby spines and filopodia, as well as a decrease in total dendritic length of hippocampal pyramidal neurons due to a decrease in apical dendritic length and nodes. This atrophy is in line with the significant reduction in CA1 long-term potentiation. Furthermore, mutant tau induced a depolarized threshold for action potential initiation and an increased current of inward rectifying potassium channels, which should lead, together with the long-term potentiation decrease, to a decreased excitability of CA1 neurons.
细胞内过度磷酸化 tau 的积累是许多神经退行性疾病的特征，如阿尔茨海默病和额颞叶痴呆。在表达 P301L 突变并在老年小鼠海马锥体神经元中积累过度磷酸化人 tau 的转基因小鼠模型中的研究支持 tau 的关键作用。特别是，过度磷酸化 tau 的体树突定位错误似乎影响了海马的神经网络。为了显示老年小鼠海马神经元内过度磷酸化 tau 聚集的后果，对 CA1 锥体细胞进行了形态和电生理分析。在这里，我们在 P301L pR5 小鼠模型中证明，过度磷酸化的 tau 导致短棘和丝状伪足的增加，以及由于树突顶部长度和节点减少导致海马锥体神经元总树突长度的减少。这种萎缩与 CA1 长时程增强的显著减少相一致。此外，突变 tau 引起动作电位起始的去极化阈值和内向整流钾通道电流增加，这应该与长时程增强减少一起导致 CA1 神经元兴奋性降低。
