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.