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

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.

Lymphatic vasculature in the central nervous system

“…Real-time in vivo analysis in zebrafish allows the investigation of the clearance capacity of Amyloid-β isoform 42 (Aβ 1-42 ). Remarkably, Jeong et al (2021) demonstrated that the dynamic uptake of Aβ 42 depends on its aggregation status, where Aβ 1-42 monomers are selectively internalized and cleared by perivascular LECs but not Aβ 1-42 oligomers. The discovery of these isolated LECs in the surface of the brain involved in the homeostasis and uptake of Aβ peptides provides new therapeutic avenues in AD, where the enhancement of their function in combination with the reduction of Aβ aggregates might contribute to new approaches to prevent their accumulation.…”

Advances in brain barriers and brain fluids research in 2021: great progress in a time of adversity

“…The ability to visualize these lymphatics in vivo may make this a useful model for studying their function. Brain lymphatic endothelial cells that do not form a lumen have been described and Jeong et al [ 82 ] found that those cells take up monomeric β-amyloid42 and were involved in clearing it from the zebrafish brain.…”

Amyloid β and Alzheimer’s Disease: Molecular Updates from Physiology to Pathology

“…Baidya A TK et al [3] and Jeong YM et al [4] both investigated the activities of Aβ in physiology. In the first paper, the authors provide new insight into cholinergic dysfunction, which is known to be central to the pathology of Alzheimer's disease [5].…”