Loss of LR11/SORLA Enhances Early Pathology in a Mouse Model of Amyloidosis: Evidence for a Proximal Role in Alzheimer’s Disease

• Type of Material: Article
• Authors: Sara E. Dodson, Emory University; Olav M. Andersen, Aarhus University; Vinit Karmali, Emory University; Jason Jon Fritz, Emory University; Dongmei Cheng, Emory University; Junmin Peng, Emory University; Allan I Levey, Emory University; Thomas E. Willnow, Max-Delbrueck-Center for Molecular Medicine; James J Lah, Emory University
• Language: English
• Date: 2008-11-26
• Publisher: Society for Neuroscience
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2008 Society for Neuroscience
• Final Published Version (URL): http://dx.doi.org/10.1523%2FJNEUROSCI.4582-08.2008
• Title of Journal or Parent Work: Journal of Neuroscience Nursing
• ISSN: 0270-6474
• Volume: 28
• Issue: 48
• Start Page: 12877
• End Page: 12886
• Grant/Funding Information: This work was supported by National Institutes of Health Grants AG05136 (J.J.L.) and F31 NS055881 (S.E.D.), and by the Deutsche Forschungsgemeinschaft (T.E.W.).; National Institute on Aging : NIA; National Institute of Neurological Disorders and Stroke : NINDS
• Keywords: Alzheimer’s disease; SORLA; β-amyloid; transgenic mouse; SORL1; LR11; APOE
• Research Categories: Biology, Neuroscience; Biology, Molecular

Abstract

Alzheimer’s disease (AD) is the most prevalent form of dementia, resulting in progressive neuronal death and debilitating damage to brain loci that mediate memory and higher cognitive function. While pathogenic genetic mutations have been implicated in ~2% of AD cases, the proximal events that underlie the common, sporadic form of the disease are incompletely understood. Converging lines of evidence from human neuropathology, basic biology, and genetics have implicated loss of the multifunctional receptor LR11 (also known as SORLA and SORL1) in AD pathogenesis. Cell-based studies suggest that LR11 reduces the formation of β-amyloid (Aβ), the molecule believed to be a primary toxic species in AD. Recently, mutant mice deficient in LR11 were shown to upregulate murine Aβ in mouse brain. In the current study, LR11-deficient mice were crossed with transgenic mice expressing autosomal-dominant human AD genes, presenilin-1 (PS1ΔE9) and amyloid precursor protein (APPswe). Here, we show that LR11 deficiency in this AD mouse model significantly increases Aβ levels and exacerbates early amyloid pathology in brain, causing a forward shift in disease onset that is LR11 gene dose-dependent. Loss of LR11 increases the processing of the APP holo-molecule into α-, β-, and γ-secretase derived metabolites. We propose that LR11 regulates APP processing and Aβ accumulation in vivo and is of proximal importance to the cascade of pathological amyloidosis. The results of the current study support the hypothesis that control of LR11 expression may exert critical effects on Alzheimer’s disease susceptibility in humans.