Role of N-terminal residues in Aβ interactions with integrin receptor and cell surface

beta-Amyloid (A beta) is the primary protein component of senile plaques in Alzheimer's disease (AD) and is believed to play a role in its pathology. To date, the mechanism of action of A beta in AD is unclear. We and others have observed that A beta interacts either with or in the vicinity of the alpha 6 sub-unit of integrin, and believe this may be important in its interaction with neuronal cells. In this study, we used confocal microscopy and flow cytometry to explore the residue specific interactions of A beta 40 with the cell surface and the alpha 6 integrin receptor sub-unit We probed the importance of the RHD sequence in A beta 40 and found that removal of the residues or their mutation using the A beta 8-40 or the D7N early onset AD sequence, respectively, led to a greater interaction between A beta 40 and an antibody bound to the alpha 6-integrin sub-unit, as measured by fluorescence resonance energy transfer (FRET). These results suggest that the RHD sequence of A beta 40 does not mediate A beta-alpha 6 integrin interactions. However, the cyclic RGD mimicking peptide, Cilengitide, reduced the measured interaction between A beta 40 fibrils without the RHD sequence and an antibody bound to the alpha 6-integrin sub-unit. We further probed the role of electrostatic forces on A beta 40-cell interactions and observed that the A beta sequence that included the N-terminal segment of the peptide had reduced cellular binding at low salt concentrations, suggesting that its first 7 residues contribute to an electrostatic repulsion for the cell surface. These findings contribute to our understanding of A beta-cell surface interactions and may provide insight into development of novel strategies to block A beta-cell interactions that contribute to pathology in Alzheimer's disease. Published by Elsevier B.V.