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bioRxiv · 10.1101/2022.11.17.516996

Amyloid-beta peptides 40 and 42 employ distinct molecular pathways for cell entry and intracellular transit at the BBB endothelium

Wang, Z.·Sharda, N.·Omtri, R.·Li, L.·Kandimalla, K. K.
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Abstract

Blood-brain barrier (BBB) is a critical portal regulating the bidirectional transport of amyloid beta (A{beta}) proteins between blood and brain. Disrupted trafficking at the BBB may not only promote the build-up of A{beta} plaques in the brain parenchyma, but also facilitate A{beta} accumulation within the BBB endothelium, which aggravates BBB dysfunction. Soluble A{beta}42:A{beta}40 ratios in plasma and cerebrospinal fluid have been reported to decrease during Alzheimers disease (AD) progression. Our previous publications demonstrated that trafficking of A{beta}42 and A{beta}40 at the BBB is distinct and is disrupted under various pathophysiological conditions. However, the intracellular mechanisms that allow BBB endothelium to differentially handle A{beta}40 and A{beta}42 have not been clearly elucidated. In this study, we identified mechanisms of fluorescently labeled A{beta} (F-A{beta}) endocytosis in polarized human cerebral microvascular endothelial (hCMEC/D3) cell monolayers using pharmacological inhibition and siRNA knock-down approaches. Further, intracellular transit of F-A{beta} following endocytosis was tracked using live cell imaging. Our studies demonstrated that both F-A{beta} peptides were internalized by BBB endothelial cells via energy, dynamin and actin dependent endocytosis. Interestingly, endocytosis of F-A{beta}40 is found to be clathrin-mediated, whereas F-A{beta}42 endocytosis is caveolae-mediated. Following endocytosis, both isoforms were sorted by the endo-lysosomal system. While A{beta}42 was shown to accumulate more in the lysosome which could lead to its higher degradation and/or aggregation at lower lysosomal pH, A{beta}40 demonstrated robust accumulation in recycling endosomes which may facilitate its transcytosis across the BBB. These results provide a mechanistic insight into the selective ability of BBB endothelium to transport A{beta}40 versus A{beta}42. This knowledge contributes to the understanding of molecular pathways underlying A{beta} accumulation in the BBB endothelium and associated cerebrovascular dysfunction as well as amyloid deposition in the brain parenchyma which are implicated in AD pathogenesis.

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Wang, Z., Sharda, N., Omtri, R., Li, L., Kandimalla, K. K.. 2022-11-18. Amyloid-beta peptides 40 and 42 employ distinct molecular pathways for cell entry and intracellular transit at the BBB endothelium. https://doi.org/10.1101/2022.11.17.516996

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