Journal
CELL REPORTS
Volume 9, Issue 1, Pages 391-401Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2014.08.065
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- Institute of Molecular and Cell Biology, Singapore
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There is growing recognition of cerebrovascular contributions to neurodegenerative diseases. In the walls of cerebral arteries, amyloid-beta (A beta) accumulation is evident in a majority of aged people and patients with cerebral amyloid angiopathy. Here, we leverage human pluripotent stem cells to generate vascular smooth muscle cells (SMCs) from neural crest progenitors, recapitulating brain-vasculature-specific attributes of A beta metabolism. We confirm that the lipoprotein receptor, LRP1, functions in our neural-crest-derived SMCs to mediate A beta uptake and intracellular lysosomal degradation. Hypoxia significantly compromises the contribution of SMCs to A beta clearance by suppressing LRP1 expression. This enabled us to develop an assay of A beta uptake by using the neural crest-derived SMCs with hypoxia as a stress paradigm. We then tested several vascular protective compounds in a high-throughput format, demonstrating the value of stem-cell-based phenotypic screening for novel therapeutics and drug repurposing, aimed at alleviating amyloid burden.
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