First Author | Yáñez MJ | Year | 2016 |
Journal | Biochim Biophys Acta | Volume | 1862 |
Issue | 11 | Pages | 2158-2167 |
PubMed ID | 27565738 | Mgi Jnum | J:255892 |
Mgi Id | MGI:6105029 | Doi | 10.1016/j.bbadis.2016.08.016 |
Citation | Yanez MJ, et al. (2016) c-Abl links APP-BACE1 interaction promoting APP amyloidogenic processing in Niemann-Pick type C disease. Biochim Biophys Acta 1862(11):2158-2167 |
abstractText | BACKGROUND: Niemann-Pick type C (NPC) disease is characterized by lysosomal accumulation of cholesterol. Interestingly, NPC patients'' brains also show increased levels of amyloid-beta (Abeta) peptide, a key protein in Alzheimer''s disease pathogenesis. We previously reported that the c-Abl tyrosine kinase is active in NPC neurons and in AD animal models and that Imatinib, a specific c-Abl inhibitor, decreased the amyloid burden in brains of the AD mouse model. Active c-Abl was shown to interact with the APP cytosolic domain, but the relevance of this interaction to APP processing has yet to be defined. RESULTS: In this work we show that c-Abl inhibition reduces APP amyloidogenic cleavage in NPC cells overexpressing APP. Indeed, we found that levels of the Abeta oligomers and the carboxy-terminal fragment betaCTF were decreased when the cells were treated with Imatinib and upon shRNA-mediated c-Abl knockdown. Moreover, Imatinib decreased APP amyloidogenic processing in the brain of an NPC mouse model. In addition, we found decreased levels of betaCTF in neuronal cultures from c-Abl null mice. We demonstrate that c-Abl directly interacts with APP, that c-Abl inhibition prevents this interaction, and that Tyr682 in the APP cytoplasmic tail is essential for this interaction. More importantly, we found that c-Abl inhibition by Imatinib significantly inhibits the interaction between APP and BACE1. CONCLUSION: We conclude that c-Abl activity facilitates the APP-BACE1 interaction, thereby promoting amyloidogenic processing of APP. Thus, inhibition of c-Abl could be a pharmacological target for preventing the injurious effects of increased Abeta levels in NPC disease. |