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PMID:17293612

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Citation

Tansley, GH, Burgess, BL, Bryan, MT, Su, Y, Hirsch-Reinshagen, V, Pearce, J, Chan, JY, Wilkinson, A, Evans, J, Naus, KE, McIsaac, S, Bromley, K, Song, W, Yang, HC, Wang, N, DeMattos, RB and Wellington, CL (2007) The cholesterol transporter ABCG1 modulates the subcellular distribution and proteolytic processing of beta-amyloid precursor protein. J. Lipid Res. 48:1022-34

Abstract

Although intracellular cholesterol levels are known to influence the proteolysis of beta-amyloid precursor protein (APP), the effect of specific genes that regulate cholesterol metabolism on APP processing remains poorly understood. The cholesterol transporter ABCG1 facilitates cholesterol efflux to HDL and is expressed in brain. Notably, the human ABCG1 gene maps to chromosome 21q22.3, and individuals with Down syndrome (DS) typically manifest with Alzheimer's disease (AD) neuropathology in their 30s. Here, we demonstrate that expression of ABCG1 enhances amyloid-beta protein (Abeta) production in transfected HEK cells in a manner that requires functional cholesterol transporter activity. ABCG1-expressing cells also exhibit increased secreted APP (sAPP)alpha and sAPPbeta secretion and display increased cell surface-associated APP. These results suggest that ABCG1 increases the availability of APP as a secretase substrate for both the amyloidogenic and nonamyloidogenic pathways. In vivo, ABCG1 mRNA levels are 2-fold more abundant in DS brain compared with age- and sex-matched normal controls. Finally, both Abeta and sAPPalpha levels are increased in DS cortex relative to normal controls. These findings suggest that altered cholesterol metabolism and APP trafficking mediated by ABCG1 may contribute to the accelerated onset of AD neuropathology in DS.

Links

PubMed Online version:10.1194/jlr.M600542-JLR200

Keywords

ATP-Binding Cassette Transporters/genetics; ATP-Binding Cassette Transporters/metabolism; Adult; Aged; Aged, 80 and over; Amyloid Precursor Protein Secretases/metabolism; Amyloid beta-Protein Precursor/metabolism; Amyloid beta-Protein Precursor/secretion; Animals; Brain/metabolism; Child; Cholesterol/metabolism; Down Syndrome/genetics; Down Syndrome/metabolism; Down Syndrome/pathology; Female; Gene Expression Regulation; Humans; Lipoproteins/deficiency; Lipoproteins/genetics; Lipoproteins/metabolism; Male; Mice; Mice, Knockout; Middle Aged; Neurons/metabolism; Protein Subunits/metabolism; Protein Subunits/secretion

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:ABCG1

involved_in

GO:0050714: positive regulation of protein secretion

ECO:0000314: direct assay evidence used in manual assertion

P

  • regulates_transport_of:(UniProtKB:P05067)

Seeded From UniProt

complete

HUMAN:ABCG1

involved_in

GO:1902004: positive regulation of amyloid-beta formation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ABCG1

involved_in

GO:0034436: glycoprotein transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ABCG1

enables

GO:0034437: glycoprotein transmembrane transporter activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:ABCG1

involved_in

GO:0042987: amyloid precursor protein catabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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