Inhibition of Abeta aggregation and neurotoxicity by the 39-kDa receptor-associated protein

Megan L Kerr, Robert Gasperini, Marie Elizabeth Gibbs, Xu Hou, Claire E Shepherd, Dudley K Strickland, Lisa Foa, Alfons Lawen, David Henry Small

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Abstract

Aggregation of beta -amyloid protein (AI?) to form oligomers is considered to be a key step in generating neurotoxicity in the Alzheimera??s disease (AD) brain. Agents that bind to A beta and inhibit oligomerization have been proposed as AD therapeutics. In this study, we investigated the binding of fluorescein-labelled A beta 1-42 (FluoA beta 1-42) to SH-SY5Y neuroblastoma cells and examined the effect of the 39 kDa receptor-associated protein (RAP), on the A beta -cell interaction. FluoA beta 1-42 bound to the cells in a punctate pattern. Surprisingly, when RAP was added to the incubations, FluoA beta 1-42 and RAP were found to be co-localized on the cell surface, suggesting that RAP and A beta may bind to each other. Experiments using the purified proteins confirmed that a RAP-A beta complex was stable and resistant to sodium dodecyl sulfate. RAP also inhibited A beta oligomerization. We next examined whether RAP could inhibit the neurotoxic effects of A beta . Addition of A beta 1-42 to SH-SY5Y cells caused an increase in intracellular Ca2+ that was inhibited by treatment of the AI? peptide with RAP. RAP also blocked an AI?-induced inhibition of long-term memory consolidation in one-day-old chicks. This study demonstrates that RAP binds to A beta and is an inhibitor of the neurotoxic effects of A beta .
Original languageEnglish
Pages (from-to)1199 - 1209
Number of pages10
JournalJournal of Neurochemistry
Volume112
DOIs
Publication statusPublished - 2010

Cite this

Kerr, M. L., Gasperini, R., Gibbs, M. E., Hou, X., Shepherd, C. E., Strickland, D. K., Foa, L., Lawen, A., & Small, D. H. (2010). Inhibition of Abeta aggregation and neurotoxicity by the 39-kDa receptor-associated protein. Journal of Neurochemistry, 112, 1199 - 1209. https://doi.org/10.1111/j.1471-4159.2009.06540.x