The influence of sorLA CR-domains on binding to and processing of APP

Description

Background: SorLA is a neuronal receptor that interacts directly with APP. SorLA regulates APP intracellular sorting, affecting processing of the precursor and leading to decreased generation of Aß. The sorLA CR-cluster is important for this interaction, but the precise molecular determinants of the sorLA-APP interaction and the mechanism of how binding affects APP processing have not yet been elucidated. Methods: We produced expression constructs for sorLA devoid of the 11 CR-domains and sorLA mutants with substitutions of fingerprint residues in central CR-domains. We generated SH-SY5Y cell lines stably expressing these sorLA variants to study binding and processing of APP using co-immunoprecipitation, Western blotting and ELISA. Results: The sorLA CR-cluster is essential for interaction with APP, and deletion of the CR-cluster abolishes protection against APP processing. We identified a region in the CR-cluster comprising known mutations for early onset Alzheimer's disease, as particularly important for the binding to APP. Mutations of identified fingerprint residues in sorLA CR-domains influence the binding to APP and impact shedding of the ectodomain of sorLA. Interestingly, some mutations lead to increased affinity for APP with a specific effect on complex O-linked glycosylation of APP. Conclusions: Our results demonstrate that the sorLA CR-cluster is the only region within the receptor that binds APP, and we identify central CR5-8 domains important for the binding of APP. Finally, we provide evidence for a novel mechanism of how sorLA activity influences APP metabolism by control of post-translational glycosylation in the Golgi, suggesting new strategies against Amyloidogenesis in Alzheimer's disease.

Period	14 Jul 2014
Event title	Alzheimer`s Association International Conference
Event type	Conference
Location	Copenhagen, DenmarkShow on map