The Lipoprotein Receptor LR11 Regulates Amyloid β Production and Amyloid Precursor Protein Traffic in Endosomal Compartments

Offe, Katrin; Dodson, Sara E.; Shoemaker, James T.; Fritz, Jason J.; Gearing, Marla; Levey, Aĺlan I.; Lah, James J.

doi:10.1523/jneurosci.4946-05.2006

Cited by 259 publications

(250 citation statements)

References 52 publications

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“…The observation of an alternative pathway for APP exit from the TGN also raises the possibility that some fraction of APP is always routed via the endosomal/lysosomal route (also see Ang et al, 2004 and related studies) and that it is the abundance and relative affinities of different binding partners that determines the percentage of APP that traffics between the different alternative paths, which in turn could have an important impact on processing and A␤ generation. For example, LR11/SorLa is a lipoprotein receptor with links to Alzheimer's disease (Andersen et al, 2005;Offe et al, 2006;Rogaeva et al, 2007) that binds directly to APP in their lumenal domains (Andersen et al, 2006). The cytosolic tail of LR11 binds to GGAs (Jacobsen et al, 2002) and is thus predicted to exit the TGN via endosomal/lysosomal routing and could provide the means for recruitment of APP into GGA carriers and direct traffic into the endosomal system.…”

Section: Discussionmentioning

confidence: 99%

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Mint3/X11γ Is an ADP-Ribosylation Factor-dependent Adaptor that Regulates the Traffic of the Alzheimer's Precursor Protein from theTrans-Golgi Network

Shrivastava-Ranjan

Faúndez

Fang

et al. 2008

MBoC

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␤-Amyloid peptides (A␤) are the major component of plaques in brains of Alzheimer's patients, and are they derived from the proteolytic processing of the ␤-amyloid precursor protein (APP). The movement of APP between organelles is highly regulated, and it is tightly connected to its processing by secretases. We proposed previously that transport of APP within the cell is mediated in part through its sorting into Mint/X11-containing carriers. To test our hypothesis, we purified APP-containing vesicles from human neuroblastoma SH-SY5Y cells, and we showed that Mint2/3 are specifically enriched and that Mint3 and APP are present in the same vesicles. Increasing cellular APP levels increased the amounts of both APP and Mint3 in purified vesicles. Additional evidence supporting an obligate role for Mint3 in traffic of APP from the trans-Golgi network to the plasma membrane include the observations that depletion of Mint3 by small interference RNA (siRNA) or mutation of the Mint binding domain of APP changes the export route of APP from the basolateral to the endosomal/lysosomal sorting route. Finally, we show that increased expression of Mint3 decreased and siRNA-mediated knockdowns increased the secretion of the neurotoxic ␤-amyloid peptide, A␤ 1-40 . Together, our data implicate Mint3 activity as a critical determinant of post-Golgi APP traffic. INTRODUCTIONThe hallmark of Alzheimer's disease is the presence in brain of plaques that contain A␤ peptides, formed by the result of proteolytic processing of the ␤-amyloid precursor protein (APP). APP is a ubiquitous, single-pass transmembrane protein of unknown function that is highly expressed in brain. Processing involves the sequential actions of ␣-or ␤-plus ␥-secretases, each of which are found in multiple cellular locations (Kuentzel et al., 1993;Selkoe, 1998;Yan et al., 2001). Although processing may occur at any step, the trans-Golgi network (TGN) is the earliest site at which APP processing is thought to commence, and APP is internalized from the cell surface to endosomal compartments where ␥-secretase also acts (Selkoe et al., 1996;Greenfield et al., 1999;Lah and Levey, 2000;Bagshaw et al., 2003).The C-terminal domain of APP contains the tyrosinebased sorting motif, YENPTY, which is conserved across species and a determinant of APP traffic (Perez et al., 1999;Bonifacino and Traub, 2003;King et al., 2004). Such sorting motifs function by binding specific adaptors to facilitate their selective import into budding carriers and ensure specificity in cargo selection and coat recruitment. The highly conserved phosphotyrosine binding (PTB) domains in all three Mint proteins have been shown previously to bind directly to the YENPXY motif of APP (Borg et al., 1996(Borg et al., , 1998Zhang et al., 1997;Sastre et al., 1998;Tanahashi and Tabira, 1999;Tomita et al., 1999;Ho et al., 2002;Araki et al., 2003). Other PTB domain containing proteins have similarly been shown to bind APP, including the Fe65 (Sabo et al., 1999) family, Dab2 (Howell et al., 1999), JIP1b (King et al....

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Section: Discussionmentioning

confidence: 99%

“…Overexpression of human Mints was achieved in HEK293 cells by transient transfection using the pBK vector, which drives expression off the cytomegalovirus promoter, and A␤ 1-40 levels were determined in conditioned media as described previously (Offe et al, 2006). Empty vector was used as a control.…”

Section: Determination Of Secreted A␤ Levelsmentioning

confidence: 99%

Mint3/X11γ Is an ADP-Ribosylation Factor-dependent Adaptor that Regulates the Traffic of the Alzheimer's Precursor Protein from theTrans-Golgi Network

Shrivastava-Ranjan

Faúndez

Fang

et al. 2008

MBoC

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“…Sortilin-related receptor 1 (also known as sorLA and LR11) is an excellent biological candidate gene due to its role in amyloid precursor protein (APP) processing and evidence that variation in SORL1 levels are associated with both APP [1,15] and LOAD [19]. Association between variation in SORL1 and LOAD has been reported in Northern Europeans, Caucasian Americans, Caribbean Hispanics and Israeli Arabs [18]; Caribbean Hispanics and Caucasian Americans [6]; Han Chinese [23]; and Caucasian Americans with Down syndrome [7].…”

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confidence: 99%

No association of SORL1 SNPs with Alzheimer's disease

Minster¹,

DeKosky²,

Kamboh³

2008

Neuroscience Letters

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SORL1 is an element of the amyloid precursor protein processing pathway and is therefore a good candidate for affecting Alzheimer's disease (AD) risk. Indeed, there have been reports of associations between variation in SORL1 and AD risk. We examined six statistically significant single-nucleotide polymorphisms from the initial observation in a large Caucasian American case-controls cohort (1000 late-onset AD [LOAD] cases and 1000 older controls). Analysis of allele, genotype and haplotype frequencies revealed no association with LOAD risk in our cohort. KeywordsAlzheimer's disease; SORL1; genetics It is estimated that up to 79% of the risk for late-onset Alzheimer's disease (LOAD) is attributable to genetics [4]. Thus far, only variation in APOE has been definitively associated with LOAD [2], but only 20%-29% of risk is attributable to this variation [20,22]. Association between variation in an excellent biological candidate gene, sortilin-related receptor 1 (SORL1), and the risk of LOAD has been reported [18]. We genotyped and analyzed six of the single nucleotide polymorphisms (SNPs), listed in Table 1, that were reported to be associated with LOAD in a multiple case-control cohort or family-based samples [18] to verify this report.Case subjects were Caucasian Americans with LOAD (n = 1009; mean age-at-onset [AAO] 72.8 ± 6.2 [SD] years; 67.7% female; 7.3% autopsy-confirmed) recruited by the University of Pittsburgh Alzheimer's Disease Research Center. All cases were evaluated clinically and met criteria for probable or possible AD [11] or by autopsy and met neuropathological criteria for definite AD [13,14]. Controls were Caucasian Americans of age 60 or above with no psychiatric or neurological disorders (n = 1009; mean age-at-baseline 74.1 ± 6.2 [SD] years; 59.9% female; 1.3% autopsy-confirmed). All experiments on human subjects were conducted in accordance with the Declaration of Helsinki, and all procedures were carried out with the adequate understanding and written consent of the subjects. The genetic study was approved by the University of Pittsburgh Institutional Review Board.Genotypes for the six SORL1 SNPs were ascertained from genomic DNA using TaqMan SNP genotyping assays (Applied Biosystems, Foster City, California). Case and control samples were present on each 384-well plate used in genotyping. To estimate genotyping error rates, *Corresponding Author: University of Pittsburgh, Department of Human Genetics, Pittsburgh PA 15261, 412-624-3066, Fax: 412-383-7844, ikamboh@hgen.pitt.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 10% of the s...

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“…According to current concepts, SORLA inhibits trafficking of APP into cellular compartments where secretases reside, thereby reducing the extent of proteolytic breakdown of this precursor into neurotoxic amyloid-β peptides. Based on cumulative evidence from studies in cultured cells [5,8,9] in animal models [2,10] and in humans [6], SORLA is now considered a major risk factor for the sporadic form of AD (reviewed in [11]). …”

Section: Introductionmentioning

confidence: 99%

SORLA regulates calpain‐dependent degradation of synapsin

Hartl

Nebrich

Klein

et al. 2016

Alzheimer's & Dementia

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IntroductionSorting‐related receptor with A‐type repeats (SORLA) is an intracellular sorting receptor in neurons and a major risk factor for Alzheimer disease.MethodsHere, we performed global proteome analyses in the brain of SORLA‐deficient mice followed by biochemical and histopathologic studies to identify novel neuronal pathways affected by receptor dysfunction.ResultsWe demonstrate that the lack of SORLA results in accumulation of phosphorylated synapsins in cortex and hippocampus. We propose an underlying molecular mechanism by demonstrating that SORLA interacts with phosphorylated synapsins through 14‐3‐3 adaptor proteins to deliver synapsins to calpain‐mediated proteolytic degradation.DiscussionOur results suggest a novel function for SORLA which is in control of synapsin degradation, potentially impacting on synaptic vesicle endocytosis and/or exocytosis.

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The Lipoprotein Receptor LR11 Regulates Amyloid β Production and Amyloid Precursor Protein Traffic in Endosomal Compartments

Cited by 259 publications

References 52 publications

Mint3/X11γ Is an ADP-Ribosylation Factor-dependent Adaptor that Regulates the Traffic of the Alzheimer's Precursor Protein from theTrans-Golgi Network

Mint3/X11γ Is an ADP-Ribosylation Factor-dependent Adaptor that Regulates the Traffic of the Alzheimer's Precursor Protein from theTrans-Golgi Network

No association of SORL1 SNPs with Alzheimer's disease

SORLA regulates calpain‐dependent degradation of synapsin

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