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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.

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.

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  • Authors+Show Affiliations

    ,

    Center for Neurodegenerative Disease, Emory University, Atlanta, Georgia 30322, USA.

    , , , , , , ,

    Source

    MeSH

    Alzheimer Disease
    Amyloid beta-Peptides
    Amyloid beta-Protein Precursor
    Amyloidosis
    Animals
    Brain
    Disease Models, Animal
    Gene Dosage
    Gene Expression Regulation
    Genetic Predisposition to Disease
    Humans
    Membrane Transport Proteins
    Mice
    Mice, Knockout
    Mice, Transgenic
    Neurons
    Plaque, Amyloid
    Receptors, LDL
    Up-Regulation

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    19036982

    Citation

    Dodson, Sara E., et al. "Loss of LR11/SORLA Enhances Early Pathology in a Mouse Model of Amyloidosis: Evidence for a Proximal Role in Alzheimer's Disease." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 28, no. 48, 2008, pp. 12877-86.
    Dodson SE, Andersen OM, Karmali V, et al. Loss of LR11/SORLA enhances early pathology in a mouse model of amyloidosis: evidence for a proximal role in Alzheimer's disease. J Neurosci. 2008;28(48):12877-86.
    Dodson, S. E., Andersen, O. M., Karmali, V., Fritz, J. J., Cheng, D., Peng, J., ... Lah, J. J. (2008). Loss of LR11/SORLA enhances early pathology in a mouse model of amyloidosis: evidence for a proximal role in Alzheimer's disease. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 28(48), pp. 12877-86. doi:10.1523/JNEUROSCI.4582-08.2008.
    Dodson SE, et al. Loss of LR11/SORLA Enhances Early Pathology in a Mouse Model of Amyloidosis: Evidence for a Proximal Role in Alzheimer's Disease. J Neurosci. 2008 Nov 26;28(48):12877-86. PubMed PMID: 19036982.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Loss of LR11/SORLA enhances early pathology in a mouse model of amyloidosis: evidence for a proximal role in Alzheimer's disease. AU - Dodson,Sara E, AU - Andersen,Olav M, AU - Karmali,Vinit, AU - Fritz,Jason J, AU - Cheng,Dongmei, AU - Peng,Junmin, AU - Levey,Allan I, AU - Willnow,Thomas E, AU - Lah,James J, PY - 2008/11/28/pubmed PY - 2009/1/27/medline PY - 2008/11/28/entrez SP - 12877 EP - 86 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J. Neurosci. VL - 28 IS - 48 N2 - 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. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/19036982/Loss_of_LR11/SORLA_enhances_early_pathology_in_a_mouse_model_of_amyloidosis:_evidence_for_a_proximal_role_in_Alzheimer's_disease_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=19036982 DB - PRIME DP - Unbound Medicine ER -