title: Modeling cerebrovascular pathophysiology in amyloid-β metabolism using neural-crest-derived smooth muscle cells.
abstract: There is growing recognition of cerebrovascular contributions to neurodegenerative diseases. In the walls of cerebral arteries, amyloid-beta (Aβ) 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 Aβ metabolism. We confirm that the lipoprotein receptor, LRP1, functions in our neural-crest-derived SMCs to mediate Aβ uptake and intracellular lysosomal degradation. Hypoxia significantly compromises the contribution of SMCs to Aβ clearance by suppressing LRP1 expression. This enabled us to develop an assay of Aβ 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.
authors.affiliation: Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, NUHS Tower Block, Singapore 119228, Singapore. Electronic address: ccheung@imcb.a-star.edu.sg.
authors.forename: Christine
authors.initials: C
authors.lastname: Cheung
authors.affiliation: Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore.
authors.forename: Yeek Teck
authors.initials: YT
authors.lastname: Goh
authors.affiliation: Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore.
authors.forename: Jingxian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Faculty of Medicine, Nursing and Health Sciences, Monash University, 246 Clayton Road, VIC 3168, Australia.
authors.forename: Chenghan
authors.initials: C
authors.lastname: Wu
authors.affiliation: Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Guccione
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D005956:Glucose-6-Phosphate Isomerase; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D032389:Myocytes, Smooth Muscle; D009432:Neural Crest / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D005956:Glucose-6-Phosphate Isomerase