Age-dependent impairment of cognitive and synaptic function in the htau mouse model of tau pathology.
Age-dependent impairment of cognitive and synaptic function in the htau mouse model of tau pathology.
复制标题
tau 病理学 htau 小鼠模型中认知和突触功能的年龄依赖性损害。
DOI：
10.1523/jneurosci.1065-09.2009
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发表时间：
2009-08-26
影响因子：
5.3
通讯作者：
Davies, Peter
中科院分区：
文献类型：
--
作者：
Polydoro, Manuela;Acker, Christopher M.;Duff, Karen;Castillo, Pablo E.;Davies, Peter
阿尔茨海默病病理学的一个标志性特征是神经原纤维缠结 (NFT) 的存在，它是构象异常和过度磷酸化的 tau 蛋白的细胞内聚集体。前脑中 NFT 的存在与认知功能损伤相关，这支持了 tau 在痴呆症中的核心作用。 NFT 积累对神经元和认知功能的意义仍不清楚。 NFT 有可能破坏突触传递和可塑性，导致记忆缺陷和认知功能障碍。为了阐明 tau 病理学发展与突触和认知功能之间的关系，我们在 tau 小鼠中进行了行为测试和电生理学实验。在这里，我们报告了 htau 小鼠在神经变性之前出现的年龄依赖性认知和生理损伤。具有中度 tau 病理学的 12 个月大的 htau 小鼠，而不是具有早期 tau 病理学的 4 个月大的小鼠，在物体识别记忆任务中表现出认知缺陷，其中新物体的视觉识别记忆被破坏。此外，只有 12 个月大的 htau 小鼠表现出空间记忆缺陷，如莫里斯水迷宫中表现受损所示。此外，我们报告称，老年 htau 小鼠的海马 CA1 区的基础突触传递和高频刺激（而非 θ 爆发刺激）诱导的长期增强受到干扰，而年轻的 htau 小鼠则没有。我们的结果表明，tau 蛋白病理学可能通过破坏突触功能而导致年龄依赖性学习障碍。
A hallmark feature of Alzheimer’s disease pathology is the presence of neurofibrillary tangles (NFTs), which are intracellular aggregates of conformationally abnormal and hyperphosphorylated tau. The presence of NFTs in the forebrain is associated with impairments of cognitive function, supporting a central role for tau in dementia. The significance of the accumulation of NFTs for neuronal and cognitive function is still obscure. It is possible that NFTs disrupt synaptic transmission and plasticity, leading to memory deficits and cognitive malfunction. To elucidate the relationship between the development of tau pathology and synaptic and cognitive functions, we performed behavioral tests and electrophysiological experiments in the htau mouse. Here we report age-dependent cognitive and physiological impairments in htau mice which preceded neurodegeneration. 12-month-old htau mice with moderate tau pathology, but not 4-month-old mice with early stage tau pathology, presented cognitive deficits in an object recognition memory task in which the visual recognition memory of a novel object was disrupted. Moreover, only 12-month-old htau mice exhibit spatial memory deficits, as indicated by the impaired performance in the Morris water maze. In addition, we report that basal synaptic transmission and induction of long-term potentiation with high frequency stimulation, but not theta burst stimulation, is perturbed in hippocampal CA1 region of old but not young htau mice. Our results suggest that tau pathology may underlie an age-dependent learning impairment through disruption of synaptic function.