Peripheral inflammation promotes brain tau transmission via disrupting blood-brain barrier.

Yanchao Liu,Xin Wang,Xiaoguang Li,Jian-Zhi Wang,Jinwang Ye,Qiuzhi Zhou,Shujuan Zhang,Enjie Liu

doi:10.1042/bsr20193629

Abstract

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.

Highlights

Alzheimer’s disease (AD) is the most common neurodegenerative disease characterized by two major pathological features: senile plaques formed by amyloid β (Aβ) and neurofibrillary tangles formed by pathological tau aggregation [1]
The neurofibrillary tangle formed by the aggregated tau proteins is an important pathological features of AD, and the degree was positively correlated to cognitive decline [19]
Many researchers had focused on the mechanism of tau transmission

Summary

Introduction

Alzheimer’s disease (AD) is the most common neurodegenerative disease characterized by two major pathological features: senile plaques formed by amyloid β (Aβ) and neurofibrillary tangles formed by pathological tau aggregation [1]. The onset of the disease is concealed, and it can progressively develop into learning and memory dysfunction and even lead to comprehensive dementia. In AD, the irreversibility of the progress and the harmfulness of the results bring a heavy burden to the individual and whole society [2]. Without clear secondary or tertiary structure, is prone to misfolding to form fibrous aggregates under pathological conditions. Studies have shown that pathological tau protein aggregation can spread in different brain regions, which is closely associated with cognitive impairments in AD [4,5]. In the early stage of AD, tau protein first appears in the entorhinal cortex (EC) and spreads to the hippocampus [6,7]. A recent study has tried to block tau transmission in the P301L mouse model by eliminating microglia and inhibiting the secretion of exosomes [8], but the mechanism for AD-like tau transmission is still unclear

Methods

Results

Conclusion