Affiliations: [a] Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, College Station, TX, USA | [b] Sanders-Brown Center on Aging, Department of Anatomy and Neurobiology, and Neurology, University of Kentucky, Lexington, KY, USA
Correspondence:
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Correspondence to: Gregory J. Bix, M.D., Ph.D., University of Kentucky, 430 Sanders-Brown Center on Aging, 800 S. Limestone St., Lexington, KY 40536, USA. Tel.: +1 859 257 1412 x238; Fax: +1 859 257 9479; E-mail: gregorybix@uky.edu.
Note: [1] Current address: Lynntech Inc., College Station, TX, USA.
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.
