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Reduction of SorLA/LR11, a Sorting Protein Limiting β-Amyloid Production, in Alzheimer Disease Cerebrospinal Fluid
Qiu-Lan Ma, MD, PhD;
Douglas R. Galasko, MD;
John M. Ringman, MD;
Harry V. Vinters, MD;
Steven D. Edland, PhD;
Justine Pomakian, MPH;
Oliver J. Ubeda, BS;
Emily R. Rosario, PhD;
Bruce Teter, PhD;
Sally A. Frautschy, PhD;
Greg M. Cole, PhD
Arch Neurol. 2009;66(4):448-457.
Background The sortilin-related receptor SorLA/LR11 (LR11) is a transmembrane neuronal sorting protein that reduces β-amyloid precursor protein trafficking to secretases, notably BACE1 that generates β-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.
Objective T o detect soluble LR11 and APP in cerebrospinal fluid (CSF) from patients with AD and control subjects, as (like β-amyloid precursor protein) LR11 is cleaved near the membrane to release a large N-terminal fragment that is secreted to media from cultured cells.
Design Case-control study.
Setting Academic research.
Participants Patients with AD and control subjects.
Main Outcome Measures We evaluated CSF LR11, β-amyloid precursor protein, and apolipoprotein E levels by Western blot in lumbar and postmortem CSF samples.
Results 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 β-amyloid 42 and LR11 levels improved diagnostic specificity for AD. Reduced LR11 levels are significantly correlated with soluble β-amyloid precursor protein but not apolipoprotein E levels.
Conclusion Reduced LR11 levels in CSF of patients with AD may have potential as a diagnostic biomarker for patients with LR11 deficits that promote β-amyloid production or as an index of therapeutic response in late-onset AD.
Author Affiliations: Departments of Medicine (Drs Ma, Rosario, Teter, Frautschy, and Cole and Mr Ubeda), Neurology (Drs Ringman, Vinters, Pomakian, Frautschy, and Cole), and Pathology and Laboratory Medicine (Drs Vinters and Pomakian), University of California, Los Angeles, Department of Neuroscience, University of California, San Diego (Drs Galasko and Edland), and Geriatric Research and Clinical Center, Greater Los Angeles Veterans Affairs (VA) Healthcare System, VA Medical Center, North Hills, California (Drs Ma, Rosario, Teter, Frautschy, and Cole and Mr Ubeda).
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