Department of Pathophysiology, School of Basic Medicine, Ministry of Education Key Laboratory for Neurological Disorders, Hubei Key Laboratory for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Co-innovation Center of Neuroregeneration, Nantong University, Nantong 226000, China.
Biosci Rep. 2020 Feb 28;40(2). doi: 10.1042/BSR20193629.
Abnormal aggregation of pathological tau protein is a neuropathological feature of Alzheimer's disease (AD). In the AD patients, the abnormal tau accumulation first appeared in entorhinal cortex (EC) and then propagated to the hippocampus with microglia activation and inflammation, but the mechanism is elusive. Here, we studied the role and mechanisms underlying periphery inflammation on brain tau transmission. By intraperitoneal injection of lipopolysaccharide (LPS) with brain medial entorhinal cortex (MEC)-specific overexpressing P301L human tau (P301L-hTau), we found that both acute and chronic administration of LPS remarkably promoted P301L-hTau transmission from MEC to the hippocampal subsets. Interestingly, the chronic LPS-induced P301L-hTau transmission was still apparent after blocking microglia activation. Further studies demonstrated that LPS disrupted the integrity of blood-brain barrier (BBB) and simultaneous intraperitoneal administration of glucocorticoid (GC) attenuated LPS-promoted P301L-hTau transmission. These data together suggest that a non-microglia-dependent BBB disruption contributes to peripheral LPS-promoted brain P301L-hTau transmission, therefore, maintaining the integrity of BBB can be a novel strategy for preventing pathological tau propagation in AD and other tauopathies.
病理性 tau 蛋白的异常聚集是阿尔茨海默病（AD）的神经病理学特征。在 AD 患者中，tau 蛋白的异常积累首先出现在内嗅皮层（EC），然后随着小胶质细胞的激活和炎症传播到海马体，但具体机制尚不清楚。在这里，我们研究了外周炎症对大脑 tau 传播的作用和机制。通过腹腔注射脂多糖（LPS），并在大脑内侧内嗅皮层（MEC）中特异性过表达 P301L 人 tau（P301L-hTau），我们发现 LPS 的急性和慢性给药均可显著促进 P301L-hTau 从 MEC 向海马亚区的传递。有趣的是，在阻断小胶质细胞激活后，慢性 LPS 诱导的 P301L-hTau 传递仍然明显。进一步的研究表明，LPS 破坏了血脑屏障（BBB）的完整性，同时腹腔内给予糖皮质激素（GC）可减弱 LPS 促进的 P301L-hTau 传递。这些数据共同表明，非小胶质细胞依赖性 BBB 破坏有助于外周 LPS 促进大脑 P301L-hTau 传递，因此，维持 BBB 的完整性可能是预防 AD 和其他 tau 病中病理性 tau 传播的一种新策略。
