Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein

TLDR

sorLA is a neuronal type‑1 membrane protein homologous to sorting receptors, implying a role in trafficking between the plasma membrane, endosomes, and Golgi. The study examined whether sorLA regulates APP trafficking and its cleavage into amyloid β‑peptide in Alzheimer’s disease. sorLA binds APP, localizes with it in endosomes and Golgi, and its overexpression redirects APP to the Golgi and lowers Aβ production, whereas loss of sorLA increases brain Aβ, indicating that reduced sorLA expression may drive amyloid plaque formation in AD.

Abstract

sorLA (sorting protein-related receptor) is a type-1 membrane protein of unknown function that is expressed in neurons. Its homology to sorting receptors that shuttle between the plasma membrane, endosomes, and the Golgi suggests a related function in neuronal trafficking processes. Because expression of sorLA is reduced in the brain of patients with Alzheimer's disease (AD), we tested involvement of this receptor in intracellular transport and processing of the amyloid precursor protein (APP) to the amyloid β-peptide (Aβ), the principal component of senile plaques. We demonstrate that sorLA interacts with APP in vitro and in living cells and that both proteins colocalize in endosomal and Golgi compartments. Overexpression of sorLA in neurons causes redistribution of APP to the Golgi and decreased processing to Aβ, whereas ablation of sorLA expression in knockout mice results in increased levels of Aβ in the brain similar to the situation in AD patients. Thus, sorLA acts as a sorting receptor that protects APP from processing into Aβ and thereby reduces the burden of amyloidogenic peptide formation. Consequently, reduced receptor expression in the human brain may increase Aβ production and plaque formation and promote spontaneous AD.