Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.
Sci Rep. 2017 Jun 20;7(1):3914. doi: 10.1038/s41598-017-04305-4.
Intracellular accumulation of abnormally phosphorylated tau in different types of neurons is a pathological characteristic of Alzheimer's disease (AD). While tau modification and associated neuronal loss and hypometabolism start in the entorhinal cortex (EC) in early AD patients, the mechanism by which mutant P301L hTau leads to dementia is not fully elucidated. Here, we studied the effects of P301L hTau transduction in the medial EC (MEC) of mice on tau phosphorylation and accumulation, and cognitive deficit. We found that the exogenous mutant tau protein was restricted in MEC without spreading to other brain regions at one month after transduction. Interestingly, expression of the mutant tau in MEC induces endogenous tau hyperphosphorylation and accumulation in hippocampus and cortex, and inhibits neuronal activity with attenuated PP-DG synapse plasticity, leading to hippocampus-dependent memory deficit with intact olfactory function. These findings suggest a novel neuropathological mechanism of early AD, which is initiated by tau accumulation in MEC, and demonstrate a tau pathological model of early stage AD.
细胞内异常磷酸化 tau 的积累是阿尔茨海默病 (AD) 的病理学特征。虽然在早期 AD 患者中，tau 修饰以及相关的神经元丢失和低代谢首先发生在内嗅皮层 (EC)，但突变 P301L hTau 导致痴呆的机制尚未完全阐明。在这里，我们研究了 P301L hTau 在小鼠内侧 EC (MEC) 的转导对 tau 磷酸化和积累以及认知缺陷的影响。我们发现，转导一个月后，外源性突变 tau 蛋白局限于 MEC，不会扩散到其他脑区。有趣的是，MEC 中突变 tau 的表达会诱导内源性 tau 过度磷酸化和在海马体和皮质中的积累，并抑制神经元活动，减弱 PP-DG 突触可塑性，导致海马体依赖性记忆缺陷而嗅觉功能完好。这些发现表明了 AD 早期的一种新的神经病理学机制，该机制由 MEC 中的 tau 积累引发，并展示了 AD 早期阶段的 tau 病理学模型。
