Department of Neurology, Technical University Munich, Munich, Germany; Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Neuropathol Appl Neurobiol. 2014 Dec;40(7):833-43. doi: 10.1111/nan.12160.
P301S MAPT transgenic mice (P301S mice) are a widely used model of frontotemporal dementia and parkinsonism linked to chromosome 17 with tau pathology (FTDP-17-tau). However, a systematic correlation between cognitive deficits and cellular tau pathology at different ages is still missing. Therefore, our study investigated memory deficits of P301S mice in relation to pathological tau species and dendritic spine pathology throughout adulthood.
We analysed P301S mice behaviourally with the novel open field, rotarod, and Morris water maze tests to measure deficits in locomotion, balance and cognition, respectively; immunohistochemically with different tau antibodies for specific tau species; and with Golgi staining for dendritic spine pathology.
We confirmed the occurrence of locomotor deficits at an age of 5 months and newly report memory deficits from 2.5 months of age onwards. At this early age, MC1 and CP13, but not AT180 immunoreactivity, was prominent in the hippocampus of P301S mice. Neuronal cell loss in the hippocampus of P301S mice was not observed to occur till 6 months of age. However, there was a significant reduction in the density of dendritic spines from young adulthood onwards in hippocampal pyramidal neurones.
In P301S mice, memory deficits precede the onset of locomotor dysfunction and coincide with the appearance of conformationally changed, S202-phosphorylated tau and reduced spine density in the absence of neuronal cell loss in the hippocampus. Our finding provides insights into the toxic effects of different tau species in vivo and may facilitate the development of new therapies against neurodegenerative tauopathies.
P301S MAPT 转基因小鼠（P301S 小鼠）是一种广泛用于研究与 17 号染色体相关的额颞叶痴呆和帕金森病伴 tau 病理学（FTDP-17-tau）的模型。然而，不同年龄认知缺陷与细胞 tau 病理学之间的系统相关性仍然缺失。因此，我们的研究调查了 P301S 小鼠在整个成年期与病理 tau 物种和树突棘病理相关的记忆缺陷。
我们使用新的旷场、转棒和 Morris 水迷宫测试对 P301S 小鼠进行行为分析，以分别测量运动、平衡和认知缺陷；使用不同的 tau 抗体进行免疫组织化学分析，以检测特定的 tau 物种；并用 Golgi 染色检测树突棘病理。
我们证实了 P301S 小鼠在 5 月龄时出现运动缺陷，并新报告了从 2.5 月龄开始的记忆缺陷。在这个早期年龄，MC1 和 CP13，但不是 AT180 免疫反应性，在 P301S 小鼠的海马体中明显存在。直到 6 月龄，P301S 小鼠的海马体神经元丢失才被观察到。然而，从年轻成年开始，海马体锥体神经元的树突棘密度显著降低。
在 P301S 小鼠中，记忆缺陷先于运动功能障碍的发生，并与构象改变的 tau 以及 S202 磷酸化 tau 的出现以及海马体神经元丢失同时发生。我们的发现提供了关于体内不同 tau 物种的毒性作用的见解，并可能有助于开发针对神经退行性 tau 病的新疗法。
