Requirement of aggregation propensity of Alzheimer amyloid peptides for neuronal cell surface binding.
BACKGROUND
Aggregation of the amyloid peptides, Abeta40 and Abeta42, 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 Abeta (Abeta40, Abeta42, and an Abeta mutant).


RESULTS
Using confocal microscopy and flow cytometry with fluorescently labelled Abeta, 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 Abeta42 associates with the surface of neuronal cells within one hour, while the less aggregation prone Abeta40 associates over 24 hours. We show that a double mutation in Abeta42 that reduces its aggregation propensity also reduces its association with the cell surface. Furthermore, we find that a cell line that is resistant to Abeta cytotoxicity, the non-neuronal human lymphoma cell line U937, does not bind either Abeta40 or Abeta42.


CONCLUSIONS
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 Abeta imaging in live cells, will be highly useful for evaluating the efficacy of therapeutic drugs that prevent toxic Abeta association with neuronal cells.
Bateman
David A
DA
Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada. dbateman@uhnres.utoronto.ca <dbateman@uhnres.utoronto.ca>
McLaurin
JoAnne
J
Chakrabartty
Avijit
A
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D020298:U937 Cells
D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)