title: Cell surface binding and internalization of aβ modulated by degree of aggregation.
abstract: The amyloid peptides, Aβ40 and Aβ42, are generated through endoproteolytic cleavage of the amyloid precursor protein. Here we have developed a model to investigate the interaction of living cells with various forms of aggregated Aβ40/42. After incubation at endosomal pH 6, we observed a variety of Aβ conformations after 3 (Aβ(3)), 24 (Aβ(24)), and 90 hours (Aβ(90)). Both Aβ42(24) and Aβ40(24) were observed to rapidly bind and internalize into differentiated PC12 cells, leading to accumulation in the lysosome. In contrast, Aβ40/42(90) were both found to only weakly associate with cells, but were observed as the most aggregated using dynamic light scattering and thioflavin-T. Internalization of Aβ40/42(24) was inhibited with treatment of monodansylcadaverine, an endocytosis inhibitor. These studies indicate that the ability of Aβ40/42 to bind and internalize into living cells increases with degree of aggregation until it reaches a maximum beyond which its ability to interact with cells diminishes drastically.
authors.affiliation: Laboratory of Biochemistry and Genetics, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0830, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Bateman
authors.forename: Avijit
authors.initials: A
authors.lastname: Chakrabartty