Journal
PLOS ONE
Volume 8, Issue 4, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0060972
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Funding
- Alzheimer Association Grant [NIRG-06-24448]
- NIH Grant [1P01 AG18357, R21NS052385, 5R21AG032579, 1P01HL095486, AHA 0835676N]
- Bolashak scholarship
- Ministry of Education and Science of the Republic of Kazakhstan [1029/GF2]
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Increased deposition of amyloid-beta peptide (A beta) at the cerebral endothelial cell (CEC) surface has been implicated in enhancement of transmigration of monocytes across the brain blood barrier (BBB) in Alzheimer's disease (AD). In this study, quantitative immunofluorescence microscopy (QIM) and atomic force microscopy (AFM) with cantilevers biofunctionalized by sialyl-Lewis(x) (sLe(x)) were employed to investigate A beta-altered mechanics of membrane tethers formed by bonding between sLe(x) and p-selectin at the CEC surface, the initial mechanical step governing the transmigration of monocytes. QIM results indicated the ability for A beta to increase p-selectin expression at the cell surface and promote actin polymerization in both bEND3 cells (immortalized mouse CECs) and human primary CECs. AFM data also showed the ability for A beta to increase cell stiffness and adhesion probability in bEND3 cells. On the contrary, A beta lowered the overall force of membrane tether formation (F-mtf), and produced a bimodal population of F-mtf, suggesting subcellular mechanical alterations in membrane tethering. The lower F-mtf population was similar to the results obtained from cells treated with an F-actin-disrupting drug, latrunculin A. Indeed, AFM results also showed that both A beta and latrunculin A decreased membrane stiffness, suggesting a lower membrane-cytoskeleton adhesion, a factor resulting in lower F-mtf. In addition, these cerebral endothelial alterations induced by A beta were abrogated by lovastatin, consistent with its anti-inflammatory effects. In sum, these results demonstrated the ability for A beta to enhance p-selectin expression at the CEC surface and induce cytoskeleton reorganization, which in turn, resulted in changes in membrane-cytoskeleton adhesion and membrane tethering, mechanical factors important in transmigration of monocytes through the BBB.
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