Neuronal LR11/SorLA Expression Is Reduced in Mild Cognitive Impairment

• Type of Material: Article
• Authors: Kristen L. Sager, Emory University; Joanne Wuu, Rush University; Susan E. Leurgans, Rush University; Howard D Rees III, Emory University; Marla Gearing, Emory University; Elliott J. Mufson, Rush University; Allan I Levey, Emory University; James J Lah, Emory University
• Language: English
• Date: 2007-12
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2007 American Neurological Association
• Final Published Version (URL): http://dx.doi.org/10.1002%2Fana.21190
• Title of Journal or Parent Work: Annals of Neurology
• ISSN: 0364-5134
• Volume: 62
• Issue: 6
• Start Page: 640
• End Page: 647
• Grant/Funding Information: This work was supported by the NIH (National Institute on Aging, R01AG024214 [J.J.L.], P50AG025688 [A.I.L.], P01AG14449 [E.J.M.]) and the Luttrell Foundation [A.I.L.].
• Research Categories: Health Sciences, Pathology; Biology, Neuroscience

Abstract

Objective LR11 (aka sorLA) is a multifunctional neuronal receptor that binds apolipoprotein E and interacts with amyloid precursor protein to regulate amyloidogenesis. Reduced expression of LR11, as occurs in the brains of individuals with Alzheimer’s disease (AD), increases amyloidogenesis, and variants in the gene that encodes LR11, SORL1, have recently been linked to risk for late-onset AD. In this study, we sought to determine whether reduced expression of LR11 occurs early in the disease process and whether protein levels in cortical neurons are associated with clinical and pathological changes in mild cognitive impairment (MCI), a condition that may represent prodromal AD. Methods A novel quantitative immunohistochemical approach was used to measure LR11 levels in brain tissue collected from subjects diagnosed antemortem with either no cognitive impairment, MCI, or AD from the Rush University Religious Orders Study. Results LR11 levels in MCI were intermediate between no cognitive impairment and AD. LR11 expression was heterogeneous in MCI, forming low- and high-level LR11 subgroups. MCI subjects with low LR11 were significantly more cognitively impaired than the high LR11 subjects. We also found a significant correlation between cognitive performance and LR11 levels across all clinical groups examined. There was no association between LR11 and plaque and tangle pathology. Interpretation Neuronal LR11 levels are reduced in prodomal AD. The correlation between LR11 expression and cognitive performance indicates that reduced LR11 levels reflect disease severity and may predict progression to AD in a subgroup of individuals with MCI.