title: Alzheimer's disease-related overexpression of the cation-dependent mannose 6-phosphate receptor increases Abeta secretion: role for altered lysosomal hydrolase distribution in beta-amyloidogenesis.
abstract: Prominent endosomal and lysosomal changes are an invariant feature of neurons in sporadic Alzheimer's disease (AD). These changes include increased levels of lysosomal hydrolases in early endosomes and increased expression of the cation-dependent mannose 6-phosphate receptor (CD-MPR), which is partially localized to early endosomes. To determine whether AD-associated redistribution of lysosomal hydrolases resulting from changes in CD-MPR expression affects amyloid precursor protein (APP) processing, we stably transfected APP-overexpressing murine L cells with human CD-MPR. As controls for these cells, we also expressed CD-MPR trafficking mutants that either localize to the plasma membrane (CD-MPRpm) or to early endosomes (CD-MPRendo). Expression of CD-MPR resulted in a partial redistribution of a representative lysosomal hydrolase, cathepsin D, to early endosomal compartments. Turnover of APP and secretion of sAPPalpha and sAPPbeta were not altered by overexpression of any of the CD-MPR constructs. However, secretion of both human Abeta40 and Abeta42 into the growth media nearly tripled in CD-MPR- and CD-MPRendo-expressing cells when compared with parental or CD-MPRpm-expressing cells. Comparable increases were confirmed for endogenous mouse Abeta40 in L cells expressing these CD-MPR constructs but not overexpressing human APP. These data suggest that redistribution of lysosomal hydrolases to early endocytic compartments mediated by increased expression of the CD-MPR may represent a potentially pathogenic mechanism for accelerating Abeta generation in sporadic AD, where the mechanism of amyloidogenesis is unknown.
authors.affiliation: Nathan Kline Institute and New York University School of Medicine, Orangeburg, New York 10962, USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Mathews
authors.forename: Carolyn B
authors.initials: CB
authors.lastname: Guerra
authors.forename: Ying
authors.initials: Y
authors.lastname: Jiang
authors.forename: Olivera M
authors.initials: OM
authors.lastname: Grbovic
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Kao
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Schmidt
authors.forename: Ravi
authors.initials: R
authors.lastname: Dinakar
authors.forename: Marc
authors.initials: M
authors.lastname: Mercken
authors.forename: Annette
authors.initials: A
authors.lastname: Hille-Rehfeld
authors.forename: Jack
authors.initials: J
authors.lastname: Rohrer
authors.forename: Pankaj
authors.initials: P
authors.lastname: Mehta
authors.forename: Anne M
authors.initials: AM
authors.lastname: Cataldo
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Nixon
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002402:Cathepsin D / Q000096:biosynthesis / Q000378:metabolism; D002412:Cations; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009154:Mutation; D017527:Receptor, IGF Type 2 / Q000096:biosynthesis*; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D002412:Cations; D018076:DNA, Complementary; D017527:Receptor, IGF Type 2; D002402:Cathepsin D