A fragment of the scaffolding protein RanBP9 is increased in Alzheimer's disease brains and strongly potentiates amyloid-β peptide generation

Increasing biochemical and genetic evidence indicates that the amyloid-beta ( A beta)peptide derived from amyloid precursor protein (APP) plays a central role in Alzheimer's disease ( AD) pathogenesis. We previously reported that RanBP9 promotes A beta generation by scaffolding APP/BACE1/LRP complexes together. Interestingly, the RanBP9-Delta 1/N60 ( residues 1-392) deletion mutant interacted much more strongly with APP/BACE1/LRP than full-length RanBP9. In this study, we found that RanBP9-N60, a processed form of RanBP9 virtually identical to the RanBP9-Delta 1/N60 mutant, was strongly increased in AD brains compared with controls. To evaluate the potential pathogenic consequences of this phenotype, we studied the differential biological properties of full-length RanBP9 vs. RanBP9-Delta 1/N60 in HEK293T and Neuro-2A cells. The RanBP9-Delta 1/N60 fragment, which lacks a nuclear localization signal, displayed enhanced cytoplasmic vs. nuclear localization and >3-fold enhanced stability than full-length RanBP9. Importantly, RanBP9-Delta 1/N60, which contains the LisH dimerization domain, retained the capacity to form self-interacting multimeric complexes and increased A beta generation by similar to 5-fold over vector controls, more potent than the similar to 3-fold increase seen by full-length RanBP9. Taken together, these data indicate that RanBP9-N60 may further drive the amyloid cascade in AD and that the proteolytic processing of RanBP9 may be an attractive therapeutic target.-Lakshmana, M. K., Chung, J. Y., Wickramarachchi, S., Tak, E., Bianchi, E., Koo, E. H., Kang, D. E. A fragment of the scaffolding protein RanBP9 is increased in Alzheimer's disease brains and strongly potentiates amyloid beta peptide generation. FASEB J. 24,119-127 ( 2010). www.fasebj.org