Title: Alzheimer's disease-related overexpression of the cation-dependent mannose 6-phosphate receptor increases Aβ secretion : role for altered lysosomal hydrolase distribution in β-amyloidogenesis
Authors : Mathews, Paul M.
Guerra, Carolyn B.
Jiang, Ying
Grbovic, Olivera M.
Kao, Benjamin H.
Schmidt, Stephen D.
Dinakar, Ravi
Mercken, Marc
Hille-Rehfeld, Annette
Rohrer, Jack
Mehta, Pankaj
Cataldo, Anne M.
Nixon, Ralph A.
Published in : Journal of Biological Chemistry
Volume(Issue) : 277
Issue : 7
Pages : 5299
Pages to: 5307
Publisher / Ed. Institution : American Society for Biochemistry and Molecular Biology
Issue Date: 10-Sep-2002
License (according to publishing contract) : Licence according to publishing contract
Type of review: Peer review (Publication)
Language : English
Subject (DDC) : 571: Physiology and related subjects
572: Biochemistry
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.
Departement: Life Sciences und Facility Management
Organisational Unit: Institute of Chemistry and Biotechnology (ICBT)
Publication type: Article in scientific Journal
DOI : 10.1074/jbc.M108161200
ISSN: 1083-351X
URI: https://digitalcollection.zhaw.ch/handle/11475/6807
Appears in Collections:Publikationen Life Sciences und Facility Management

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