The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease.

Centre for Research in Neurodegenerative Diseases, Department of Medicine, Department, University of Toronto, Toronto, Ontario, Canada.
Nature Genetics (Impact Factor: 29.65). 03/2007; 39(2):168-77. DOI: 10.1038/ng1943
Source: PubMed

ABSTRACT 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.

  • JAMA Neurology 04/2007; 64(4):479. · 7.01 Impact Factor
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    ABSTRACT: Intracellular protein trafficking plays an important role in neuronal function and survival. Protein misfolding is a common theme found in many neurodegenerative diseases, and intracellular trafficking machinery contributes to the pathological accumulation and clearance of misfolded proteins. Although neurodegenerative diseases exhibit distinct pathological features, abnormal endocytic trafficking is apparent in several neurodegenerative diseases, such as Alzheimer's disease (AD), Down syndrome (DS) and Parkinson's disease (PD). In this review, we will focus on protein sorting defects in three major neurodegenerative diseases, including AD, DS and PD. An important pathological feature of AD is the presence of extracellular senile plaques in the brain. Senile plaques are composed of beta-amyloid (Abeta) peptide aggregates. Multiple lines of evidence demonstrate that over-production/aggregation of Abeta in the brain is a primary cause of AD and attenuation of Abeta generation has become a topic of extreme interest in AD research. Abeta is generated from beta-amyloid precursor protein (APP) through sequential cleavage by beta-secretase and the gamma-secretase complex. Alternatively, APP can be cleaved by alpha-secretase within the Abeta domain to release soluble APPalpha which precludes Abeta generation. DS patients display a strikingly similar pathology to AD patients, including the generation of neuronal amyloid plaques. Moreover, all DS patients develop an AD-like neuropathology by their 40s. Therefore, understanding the metabolism/processing of APP and how these underlying mechanisms may be pathologically compromised is crucial for future AD and DS therapeutic strategies. Evidence accumulated thus far reveals that synaptic vesicle regulation, endocytic trafficking, and lysosome-mediated autophagy are involved in increased susceptibility to PD. Here we review current knowledge of endosomal trafficking regulation in AD, DS and PD.
    Molecular Neurodegeneration 08/2014; 9(1):31. · 5.29 Impact Factor
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    ABSTRACT: Background Alzheimer¿s disease (AD) is characterized by cerebral deposition of ß-amyloid peptide (Aß). Aß is produced by sequential cleavage of the Amyloid Precursor Protein (APP) by ß- and ¿-secretases. Many studies have demonstrated that the internalization of APP from the cell surface can regulate Aß production, although the exact organelle in which Aß is produced remains contentious. A number of recent studies suggest that intracellular trafficking also plays a role in regulating Aß production, but these pathways are relatively under-studied. The goal of this study was to elucidate the intracellular trafficking of APP, and to examine the site of intracellular APP processing.ResultsWe have tagged APP on its C-terminal cytoplasmic tail with photoactivatable Green Fluorescent Protein (paGFP). By photoactivating APP-paGFP in the Golgi, using the Golgi marker Galactosyltranferase fused to Cyan Fluorescent Protein (GalT-CFP) as a target, we are able to follow a population of nascent APP molecules from the Golgi to downstream compartments identified with compartment markers tagged with red fluorescent protein (mRFP or mCherry); including rab5 (early endosomes) rab9 (late endosomes) and LAMP1 (lysosomes). Because ¿-cleavage of APP releases the cytoplasmic tail of APP including the photoactivated GFP, resulting in loss of fluorescence, we are able to visualize the cleavage of APP in these compartments. Using APP-paGFP, we show that APP is rapidly trafficked from the Golgi apparatus to the lysosome; where it is rapidly cleared. Chloroquine and the highly selective ¿-secretase inhibitor, L685, 458, cause the accumulation of APP in lysosomes implying that APP is being cleaved by secretases in the lysosome. The Swedish mutation dramatically increases the rate of lysosomal APP processing, which is also inhibited by chloroquine and L685, 458. By knocking down adaptor protein 3 (AP-3; a heterotetrameric protein complex required for trafficking many proteins to the lysosome) using siRNA, we are able to reduce this lysosomal transport. Blocking lysosomal transport of APP reduces Aß production by more than a third.Conclusion These data suggests that AP-3 mediates rapid delivery of APP to lysosomes, and that the lysosome is a likely site of Aß production.
    Molecular Brain 08/2014; 7(1):54. · 4.35 Impact Factor

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