内嗅皮层中的 Tau 乙酰化诱导其在小鼠中的慢性海马传播和认知缺陷。

Tau Acetylation in Entorhinal Cortex Induces its Chronic Hippocampal Propagation and Cognitive Deficits in Mice.

机构信息

Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

出版信息

J Alzheimers Dis. 2020;77(1):241-255. doi: 10.3233/JAD-200529.

DOI:10.3233/JAD-200529

PMID:32804150

Abstract

BACKGROUND

Increased tau acetylation at K174, K274, K280, and K281 has been observed in the brains of Alzheimer's disease (AD) patients or in transgenic mice, but the role of acetylation in tau propagation is elusive.

OBJECTIVE

To study the effect of tau acetylation in entorhinal cortex on tau transmission and learning and memory.

METHODS

Stereotactic brain injection, behavioral test, electrophysiological recording, immunohistochemistry, and immunofluorescence were used.

RESULTS

We constructed the hyperacetylation mimics of tau (AAV-Tau-4Q), the non-acetylation tau mutant (AAV-Tau-4R), and the wild-type tau (AAV-Tau-WT). By overexpressing these different tau proteins in the entorhinal cortex (EC) of 2-month-old mice, we found that overexpressing Tau-4Q in EC for 3 or 6 months (to 5 or 8 months of age) neither induces tau propagation to dentate gyrus (DG) nor glial activation in DG, nor spatial memory deficit. However, overexpressing Tau-WT and Tau-4Q in EC for 13.5 months (15.5 months of age) at 2 months promoted tau propagation respectively to granulosa and hilus of DG with glial activation, synaptic dysfunction, and memory deficit, while overexpressing Tau-4R abolished tau propagation with improved cellular pathologies and cognitive functions. Furthermore, overexpressing Tau-4Q in unilateral DG of 2-month-old mice for 8 weeks also promoted its contralateral transmission with glial activation, and mice with tau (Tau-WT, Tau-4Q, and Tau-4R) overexpression in DG showed cognitive deficits compared with the empty vector controls.

CONCLUSION

Tau acetylation induces a time-dependent propagation from EC to DG, and only hippocampus but not EC tau accumulation induces cognitive deficits.

摘要

背景

阿尔茨海默病（AD）患者或转基因小鼠的大脑中观察到 tau 在 K174、K274、K280 和 K281 处的乙酰化增加，但乙酰化在 tau 传播中的作用尚不清楚。

目的

研究内嗅皮层 tau 乙酰化对 tau 传播及学习记忆的影响。

方法

立体定向脑内注射、行为学测试、电生理记录、免疫组化和免疫荧光。

结果

我们构建了 tau 的高乙酰化模拟物（AAV-Tau-4Q）、非乙酰化 tau 突变体（AAV-Tau-4R）和野生型 tau（AAV-Tau-WT）。通过在 2 个月大的小鼠内嗅皮层（EC）过表达这些不同的 tau 蛋白，我们发现，在 EC 中过表达 Tau-4Q 3 或 6 个月（至 5 或 8 个月大）既不会诱导 tau 向齿状回（DG）传播，也不会在 DG 中引起神经胶质激活，也不会导致空间记忆缺陷。然而，在 2 个月大时，在 EC 中过表达 Tau-WT 和 Tau-4Q 13.5 个月（15.5 个月大）分别促进了 tau 向 DG 的颗粒细胞层和门区传播，同时伴有神经胶质激活、突触功能障碍和记忆缺陷，而过表达 Tau-4R 则消除了 tau 传播，改善了细胞病理和认知功能。此外，在 2 个月大的小鼠单侧 DG 中过表达 Tau-4Q 8 周也促进了 tau 的对侧传播，同时在 DG 中过表达 tau（Tau-WT、Tau-4Q 和 Tau-4R）的小鼠与空载体对照相比表现出认知缺陷。