title: Perlecan domain V inhibits amyloid-β induced brain endothelial cell toxicity and restores angiogenic function.
abstract: In Alzheimer's disease (AD), amyloid-β (Aβ) deposits in the cerebrovasculature can result in neurovascular dysfunction and/or cerebral amyloid angiopathy. The accumulation of Aβ in blood vessels can cause endothelial cell damage, resulting in impaired Aβ clearance by the blood-brain barrier. Additionally, impaired endothelial cell function can result in decreased angiogenesis in the brains of AD patients, affecting cognitive function. VEGF is a crucial mediator of angiogenesis and is deficient in AD brains thus promoting angiogenesis could be an important component of successful AD treatment. The C-terminal portion of the extracellular matrix proteoglycan perlecan, Domain V (DV), promotes brain-derived endothelial cell proliferation and is proangiogenic in that it increases VEGFR2 expression and production of VEGF. In this study, we show that Aβ25-35 reduces proliferation of a mouse brain microvascular endothelial cell line (MBEC) in vitro and that DV and mouse LG3 (C-terminal fragment of DV) block these effects of Aβ25-35. Additionally, we show that DV restores the ability of MBECs to form tube-like structures on Matrigel in the presence of Aβ25-35 and that this is α5β1 dependent. Interestingly, the reduction in tube-like structure formation by Aβ25-35 was not due to endothelial cell death, suggesting that Aβ25-35 induces the downregulation of a cell surface molecule required for adhesion events critical to the angiogenic process. We propose a model suggesting that DV works through both the α5β1 integrin receptor and VEGFR2 to increase VEGF production, causing competition with Aβ25-35 for VEGFR2 binding, thus ultimately increasing VEGF expression and restoring angiogenesis. This supports DV as a potential anti-amyloid therapy.
authors: Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, College Station, TX, USA.
authors: Christi
authors: C
authors: Parham
authors: Lisa
authors: L
authors: Auckland
authors: Jessica
authors: J
authors: Rachwal
authors: Douglas
authors: D
authors: Clarke
authors: Gregory
authors: G
authors: Bix
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000166:cytology*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004347:Drug Interactions; D042783:Endothelial Cells / Q000187:drug effects*; D019812:Heparan Sulfate Proteoglycans / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009844:Oligosaccharides / Q000494:pharmacology; D010446:Peptide Fragments / Q000633:toxicity*; D017434:Protein Structure, Tertiary / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology
chemical_list: C111988:4(3)-O-galactosyl maltotrionolactone; D016229:Amyloid beta-Peptides; D019812:Heparan Sulfate Proteoglycans; D009844:Oligosaccharides; D010446:Peptide Fragments; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C074636:amyloid beta-protein (25-35); C071927:perlecan
keywords: Alzheimer's disease; amyloid-$\beta _{25-35}$; blood-brain barrier; extracellular matrix; integrins; perlecan
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