Requirement of aggregation propensity of Alzheimer amyloid peptides for neuronal cell surface binding

Background: Aggregation of the amyloid peptides, A beta 40 and A beta 42, is known to be involved in the pathology of Alzheimer's disease ( AD). Here we investigate the relationship between peptide aggregation and cell surface binding of three forms of A beta ( A beta 40, A beta 42, and an A beta mutant). Results: Using confocal microscopy and flow cytometry with fluorescently labelled A beta, we demonstrate a correlation between the aggregation propensity of the Alzheimer amyloid peptides and their neuronal cell surface association. We find that the highly aggregation prone A beta 42 associates with the surface of neuronal cells within one hour, while the less aggregation prone A beta 40 associates over 24 hours. We show that a double mutation in A beta 42 that reduces its aggregation propensity also reduces its association with the cell surface. Furthermore, we find that a cell line that is resistant to A beta cytotoxicity, the non-neuronal human lymphoma cell line U937, does not bind either A beta 40 or A beta 42. Conclusion: Taken together, our findings reveal that amyloid peptide aggregation propensity is an essential determinant of neuronal cell surface association. We anticipate that our approach, involving A beta imaging in live cells, will be highly useful for evaluating the efficacy of therapeutic drugs that prevent toxic A beta association with neuronal cells.