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

The failure of amyloid beta (A beta) 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 A beta clearance via this novel cell is not fully understood. We established an in vivo zebrafish model using fluorescently labeled A beta 42 to investigate the role of BLECs in A beta clearance. We discovered the efficient clearance of monomeric A beta 42 (mA beta 42) compared to oligomeric A beta 42 (oA beta 42), which was illustrated by the selective uptake of mA beta 42 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 mA beta 42. The treatment with an A beta disaggregating agent facilitated the internalization of oA beta 42 into BLECs and improved the peripheral transport. Our findings reveal a new role of BLECs in the differential clearance of mA beta 42 from the brain and provide a novel therapeutic strategy based on promoting A beta clearance.