Regulation of Transport and Processing of Amyloid Precursor Protein by the Sorting Receptor SORLA

Trafficking of the amyloid precursor protein (APP) through intracellular compartments where the various secretase activities reside is a regulatory step that determines APP processing fates and is likely to play a role ill pathological processes leading to Alzheimer's disease (AD). SORLA is a member of a novel class of intracellular sorting proteins and acts as a neuronal receptor for APP, controlling transport and proteolytic processing of the precursor protein into amyloidogenic and non-amyloidogenic products. Substantial experimental evidence from epidemiological, cell biological and animal studies points to a model whereby SORLA determines trafficking of APP into cellular compartments less favorable for processing. Consequently, high levels of SORLA expression are associated with reduced APP processing rates, whereas low levels of the protein, as in patients with sporadic AD. may predispose to accelerated APP breakdown and enhanced senile plaque formation. This article discusses the molecular mechanisms that govern SORLA-mediated APP transport and processing and their potential relevance for neurodegenerative processes.