Differential Clearance of Aβ Species from the Brain by Brain Lymphatic Endothelial Cells in Zebrafish.

Yun-Mi Jeong,Wang Sik Lee,Hyun-Ju Cho,Jinyoung Jeong,Jeong-Soo Lee,Jae-Geun Lee

doi:10.3390/ijms222111883

Abstract

The failure of amyloid beta (Aβ) clearance is a major cause of Alzheimer’s disease, and the brain lymphatic systems play a crucial role in clearing toxic proteins. Recently, brain lymphatic endothelial cells (BLECs), a non-lumenized lymphatic cell in the vertebrate brain, was identified, but Aβ clearance via this novel cell is not fully understood. We established an in vivo zebrafish model using fluorescently labeled Aβ42 to investigate the role of BLECs in Aβ clearance. We discovered the efficient clearance of monomeric Aβ42 (mAβ42) compared to oligomeric Aβ42 (oAβ42), which was illustrated by the selective uptake of mAβ42 by BLECs and peripheral transport. The genetic depletion, pharmacological inhibition via the blocking of the mannose receptor, or the laser ablation of BLECs resulted in the defective clearance of mAβ42. The treatment with an Aβ disaggregating agent facilitated the internalization of oAβ42 into BLECs and improved the peripheral transport. Our findings reveal a new role of BLECs in the differential clearance of mAβ42 from the brain and provide a novel therapeutic strategy based on promoting Aβ clearance.

Highlights

Alzheimer’s disease (AD), the most prevalent form of dementia, is a devastating neurodegenerative disease characterized by cognitive function impairment and memory loss
The monomeric Aβ42 (mAβ42) or oligomeric Aβ42 (oAβ42) peptides were introduced by a microinjection into the brain ventricle between the optic tectum and the hindbrain of zebrafish larvae at 3 days post-fertilization, and the clearance of the peptides from the brain was followed at 5 and 24 h post-injection for a quantification based on the fluorescence area (Figure 1A)
We visualized and monitored the real-time, in vivo localization and clearance of Aβ42 in the brain, by injecting fluorescently labeled Aβ42 peptides into the ventricle of the zebrafish larval brain, revealing the differential clearance dynamics of Aβ42 from the brain depending on its aggregation status

Summary

Introduction

Alzheimer’s disease (AD), the most prevalent form of dementia, is a devastating neurodegenerative disease characterized by cognitive function impairment and memory loss. The steady level of Aβ is balanced between production and clearance with the dynamic aggregation and disassembly of Aβ under normal conditions, an imbalance of the Aβ level via perturbed clearance is considered to be a major initiating factor of late onset AD [2,3]. Such an imbalance results in the accumulation of monomeric Aβ (mAβ) peptides in the brain, which generate oligomers, fibrils, and plaques of Aβ. It is of great importance to elucidate how different forms of Aβ are cleared under normal and pathological conditions to understand the pathogenesis of AD and to develop an effective therapeutic strategy for AD by reducing the excessive deposition of toxic Aβ species

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Results

Conclusion