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Author Notes:

Correspondence should be addressed to either of the following: James J. Lah, Center for Neurodegenerative Disease, 615 Michael Street, Suite 505 S, Atlanta, GA 30322, E-mail: jlah@emory.edu; or Thomas E. Willnow, Max-Delbrueck-Center for Molecular Medicine, R. Roessle Strasse 10, D-13125 Berlin, Germany, E-mail: willnow@mdc-berlin.de

We gratefully acknowledge Stephanie Carter for excellent technical assistance and Joanne Wuu for providing expert statistical advice.


Research Funding:

National Institute on Aging : NIA

National Institute of Neurological Disorders and Stroke : NINDS

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.).


  • LR11
  • SORL1
  • transgenic mouse
  • β-amyloid
  • Alzheimer’s disease
  • APOE

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


Journal Title:

Journal of Neuroscience Nursing


Volume 28, Number 48


, Pages 12877-12886

Type of Work:

Article | Post-print: After Peer Review


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.

Copyright information:

© 2008 Society for Neuroscience

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