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Loss of LR11/SORLA enhances early pathology in a mouse model of amyloidosis: Evidence for a proximal role in Alzheimer's disease

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Item Type:Article
Title:Loss of LR11/SORLA enhances early pathology in a mouse model of amyloidosis: Evidence for a proximal role in Alzheimer's disease
Creators Name:Dodson, S.E. and Andersen, O.M. and Karmali, V. and Fritz, J.J. and Cheng, D. and Peng, J. and Levey, A.I. and Willnow, T.E. and Lah, J.J.
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 approximately 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 beta-amyloid (Abeta), the molecule believed to be a primary toxic species in AD. Recently, mutant mice deficient in LR11 were shown to upregulate murine Abeta in mouse brain. In the current study, LR11-deficient mice were crossed with transgenic mice expressing autosomal-dominant human AD genes, presenilin-1 (PS1DeltaE9) and amyloid precursor protein (APPswe). Here, we show that LR11 deficiency in this AD mouse model significantly increases Abeta 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 alpha-, beta-, and gamma-secretase derived metabolites. We propose that LR11 regulates APP processing and Abeta 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.
Keywords:LR11, SORLA, SORL1, Transgenic Mouse, beta-Amyloid, Alzheimer's Disease, APOE, Animals, Mice
Source:Journal of Neuroscience
Publisher:Society for Neuroscience
Page Range:12877-12886
Date:26 November 2008
Additional Information:Copyright (c) 2008 by The Society for Neuroscience
Official Publication:https://doi.org/10.1523/JNEUROSCI.4582-08.2008
PubMed:View item in PubMed

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