title: GGA1-mediated endocytic traffic of LR11/SorLA alters APP intracellular distribution and amyloid-β production.
abstract: Proteolytic processing of the amyloid-β precursor protein (APP) and generation of amyloid-β peptide (Aβ) are key events in Alzheimer's disease (AD) pathogenesis. Cell biological and genetic evidence has implicated the low-density lipoprotein and sorting receptor LR11/SorLA in AD through mechanisms related to APP and Aβ production. Defining the cellular pathway(s) by which LR11 modulates Aβ production is critical to understanding how changes in LR11 expression affect the development of Aβ pathology in AD progression. We report that the LR11 ectodomain is required for LR11-mediated reduction of Aβ and that mutagenesis of the LR11 Golgi-localizing, γ-adaptin ear homology domain, ADP-ribosylation factor (GGA)-binding motif affects the endosomal distribution of LR11, as well as LR11's effects on APP traffic and Aβ production. Targeted small interfering RNA (siRNA) knockdown studies of GGA1, GGA2, and GGA3 indicate a surprising degree of specificity toward GGA1, suggesting that GGA1 is a candidate regulator of LR11 traffic. Additional siRNA knockdown experiments reveal that GGA1 is necessary for both LR11 and β-site APP-cleaving enzyme-1 (BACE1) modulation of APP processing to Aβ. Mutagenesis of BACE1 serine 498 to alanine enhances BACE1 targeting to LR11-positive compartments and nullifies LR11-mediated reduction of Aβ. On basis of these results, we propose that GGA1 facilitates LR11 endocytic traffic and that LR11 modulates Aβ levels by promoting APP traffic to the endocytic recycling compartment.
authors.affiliation: Center for Neurodegenerative Disease, Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Jeremy H
authors.initials: JH
authors.lastname: Herskowitz
authors.forename: Katrin
authors.initials: K
authors.lastname: Offe
authors.forename: Aniruddha
authors.initials: A
authors.lastname: Deshpande
authors.forename: Richard A
authors.initials: RA
authors.lastname: Kahn
authors.forename: Allan I
authors.initials: AI
authors.lastname: Levey
authors.forename: James J
authors.initials: JJ
authors.lastname: Lah
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D016296:Mutagenesis; D034622:RNA Interference; D034741:RNA, Small Interfering
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C407306:GGA adaptor proteins; D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; D034741:RNA, Small Interfering; C102582:SORL1 protein, human; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human