Affiliations: [a] Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA | [b] Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA | [c] Centers for Molecular Neuroscience and Molecular Toxicology, Vanderbilt University Medical Center, Nashville, TN, USA | [d] Department of Pathology and Neurology and the Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA
Correspondence:
[*]
Department of Pathology, Vanderbilt University Medical Center, C-3321A Medical Center North, Nashville, TN 37232, USA. Tel.: +1 615 343 5841; Fax: +1 615 343 7023; E-mail: tom.montine@mcmail.vanderbilt.edu.
Abstract: Recent studies of cerebrospinal fluid (CSF) have shown increased oxidation of CSF lipoproteins in Alzheimer's disease (AD) patients, and neurotoxicity from oxidized CSF lipoproteins in culture. Since inheritance of different alleles of the apolipoprotein (apo) E gene is a risk factor for AD and apoE is the major lipoprotein trafficking molecule in brain, we hypothesized that apoE may modify the pathogenesis of AD by directing the delivery of oxidized CSF lipoproteins to neurons. To test this hypothesis, we adapted a method previously used with isolated plasma lipoproteins to specifically label lipid particles in situ in native CSF and quantified their delivery to human SK-N-BE(2)C neuroblastoma cells. CSF lipoproteins were delivered to neuronal cells largely through apoE-dependent processes. Importantly, CSF lipoproteins from AD patients were delivered more efficiently than CSF lipoproteins from age-matched controls; this effect was not associated with apoE genotype or degree of CSF lipoprotein oxidation but was associated with apoE monomer concentration that tended to be lower in AD patients. The inverse relationship between apoE monomer concentration and CSF lipoprotein delivery was duplicated in SK-N-BE(2)C cells, but not human astrocytoma cells, using artificial lipid particles and purified human apoE. These results suggest that lipoproteins in CSF from AD patients are delivered more efficiently to neurons than are CSF lipoproteins from controls, and that this abnormality may be explained largely by variations in CSF apoE concentration.
