Reduction of SorLA/LR11, a Sorting Protein Limiting β-Amyloid Production, in Alzheimer Disease Cerebrospinal Fluid

Abstract

The sortilin-related receptor SorLA/LR11 (LR11) is a transmembrane neuronal sorting protein that reduces beta-amyloid precursor protein trafficking to secretases, notably BACE1 that generates beta-amyloid, the principal component of senile plaques in Alzheimer disease (AD). LR11 protein is reduced in patients with late-onset AD, and LR11 polymorphisms have been associated with late-onset AD. T o detect soluble LR11 and APP in cerebrospinal fluid (CSF) from patients with AD and control subjects, as (like beta-amyloid precursor protein) LR11 is cleaved near the membrane to release a large N-terminal fragment that is secreted to media from cultured cells. Case-control study. Academic research. Patients with AD and control subjects. We evaluated CSF LR11, beta-amyloid precursor protein, and apolipoprotein E levels by Western blot in lumbar and postmortem CSF samples. LR11 levels were detectable and stable during 6 months in the CSF of patients with AD. LR11 levels were significantly reduced in lumbar samples from patients with mild to moderate probable AD, as well as in ventricular CSF from patients with autopsy-confirmed AD (predominantly Braak stage III-IV). Bivariate analysis with beta-amyloid 42 and LR11 levels improved diagnostic specificity for AD. Reduced LR11 levels are significantly correlated with soluble beta-amyloid precursor protein but not apolipoprotein E levels. Reduced LR11 levels in CSF of patients with AD may have potential as a diagnostic biomarker for patients with LR11 deficits that promote beta-amyloid production or as an index of therapeutic response in late-onset AD.