Modeling cerebrovascular pathophysiology in amyloid-beta metabolism using neural-crest-derived smooth muscle cells

Christine Cheung, Yeek Teck Goh, Jingxian Zhang, Chenghan Wu, Ernesto Guccione

Research output: Contribution to journalArticleOther

17 Citations (Scopus)

Abstract

There is growing recognition of cerebrovascular contributions to neurodegenerative diseases. In the walls of cerebral arteries, amyloid-beta (A?) 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? metabolism. We confirm that the lipoprotein receptor, LRP1, functions in our neural-crest-derived SMCs to mediate A? uptake and intracellular lysosomal degradation. Hypoxia significantly compromises the contribution of SMCs to A? clearance by suppressing LRP1 expression. This enabled us to develop an assay of A? 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.
Original languageEnglish
Pages (from-to)391 - 401
Number of pages11
JournalCell Reports
Volume9
Issue number1
DOIs
Publication statusPublished - 2014

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