Rogaeva, E. et al. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nature Genet. 39, 168-177

University of Florence, Florens, Tuscany, Italy
Nature Genetics (Impact Factor: 29.35). 03/2007; 39(2):168-77. DOI: 10.1038/ng1943
Source: PubMed


The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid beta peptide (Abeta) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease. These variants, which occur in at least two different clusters of intronic sequences within the SORL1 gene (also known as LR11 or SORLA) may regulate tissue-specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into Abeta-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.

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    • "However , similar genes have not been identified for LOAD that accounts for >95% of AD cases. A few low penetrance genes and risk factor genes have been identified such as: APOE4 [2], SOLR1 [3], and those on the Alz- Gene data base ( for LOAD. "
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    ABSTRACT: Currently available diagnostic tests have moved the field closer to early diagnosis of Alzheimer's disease (AD); however, a definitive diagnosis is made only with the development of clinical dementia and the presence of amyloid plaques and neurofibrillary tangles at autopsy. An ideal antemortem AD biomarker should satisfy the following criteria: the ability to diagnose AD with high sensitivity and specificity as confirmed by the gold standard of autopsy validation; the ability to detect early-stage disease and track the progression of AD; and monitor therapeutic efficacy. Several AD biomarker technologies are currently under development, including in vivo brain imaging with PET and MRI (i.e., imaging of amyloid plaques) and biochemical assays of various factors in cerebrospinal fluid (CSF) and peripheral tissues. CSF biomarkers have received increased attention in the past decade. However, it is unclear whether these biomarkers are capable of early diagnosis of AD, prior to Aβ accumulation, or whether they can differentiate between AD and non-AD dementias. In addition, CSF biomarkers may not lend themselves to diagnostic screening of elderly patients, given the invasiveness of the required lumbar puncture procedure, inter-laboratory variability in techniques and sample handling, and the circadian fluctuation of CSF components. Although commonly viewed as an abnormality of the brain, AD is a systemic disease with associated dysfunction in metabolic, oxidative, inflammatory, and biochemical pathways in peripheral tissues, such as the skin and blood cells. This has led researchers to investigate and develop assays of peripheral AD biomarkers that require minimally invasive skin or blood samples.
    Full-text · Article · Nov 2014 · Journal of Alzheimer's disease: JAD
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    • "Genome wide association studies (GWAS) continuously provide new risk genes for AD, a growing number of which are SEALE components (Source: One such protein is the neuronal sortilin-related receptor, SORL1, which has been shown to reduce the amyloidogenic processing of APP by redirecting internalised APP away from endosomal organelles containing b-secretase [66]. SorL1 also mediates the cellular uptake of Ab bound to ApoE [67], adding further weight to its neuroprotective function. "
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    ABSTRACT: For over a century, researchers have observed similar neurodegenerative hallmarks in brains of people affected by rare early-onset lysosomal storage diseases and late-onset neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Increasing evidence suggests these apparently disparate diseases share a common underlying feature, namely, a dysfunctional clearance of cellular cargo through the secretory-endosomal-autophagic-lysosomal-exocytic (SEALE) network. By providing examples of rare and common neurodegenerative diseases known to have pathologically altered cargo flux through the SEALE network, we explore the unifying hypothesis that impaired catabolism or exocytosis of SEALE cargo, places a burden of stress on neurons that initiates pathogenesis. We also describe how a growing understanding of genetic, epigenetic and age-related modifications of the SEALE network, has inspired a number of novel disease-modifying therapeutic approaches aimed at alleviating SEALE storage and providing therapeutic benefit to people affected by these devastating diseases across the age spectrum. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Full-text · Article · Sep 2014 · Best Practice & Research: Clinical Endocrinology & Metabolism
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    • "M, major allele; m, minor allele; MM, major allele homozygote; Mm, heterozygote; mm, minor allele homozygote; ref, reference; * p < 0.05; * * p < 0.01; * * * p < 0.001. a Rogaeva's SNP ID [2]. "

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