title: Numb endocytic adapter proteins regulate the transport and processing of the amyloid precursor protein in an isoform-dependent manner: implications for Alzheimer disease pathogenesis.
abstract: Central to the pathogenesis of Alzheimer disease is the aberrant processing of the amyloid precursor protein (APP) to generate amyloid beta-peptide (Abeta), the principle component of amyloid plaques. The cell fate determinant Numb is a phosphotyrosine binding domain (PTB)-containing endocytic adapter protein that interacts with the carboxyl-terminal domain of APP. The physiological relevance of this interaction is unknown. Mammals produce four alternatively spliced variants of Numb that differ in the length of their PTB and proline-rich region. In the current study, we determined the influence of the four human Numb isoforms on the intracellular trafficking and processing of APP. Stable expression of Numb isoforms that differ in the PTB but not in the proline-rich region results in marked differences in the sorting of APP to the recycling and degradative pathways. Neural cells expressing Numb isoforms that lack the insert in the PTB (short PTB (SPTB)) exhibited marked accumulation of APP in Rab5A-labeled early endosomal and recycling compartments, whereas those expressing isoforms with the insertion in the PTB (long PTB (LPTB)) exhibited reduced amounts of cellular APP and its proteolytic derivatives relative to parental control cells. Neither the activities of the beta- and gamma-secretases nor the expression of APP mRNA were significantly different in the stably transfected cells, suggesting that the differential effects of the Numb proteins on APP metabolism is likely to be secondary to altered APP trafficking. In addition, the expression of SPTB-Numb increases at the expense of LPTB-Numb in neuronal cultures subjected to stress, suggesting a role for Numb in stress-induced Abeta production. Taken together, these results suggest distinct roles for the human Numb isoforms in APP metabolism and may provide a novel potential link between altered Numb isoform expression and increased Abeta generation.
authors.affiliation: Biomolecular Science Center, University of Central Florida, Orlando, Florida 32816.
authors.forename: George A
authors.initials: GA
authors.lastname: Kyriazis
authors.affiliation: Biomolecular Science Center, University of Central Florida, Orlando, Florida 32816.
authors.forename: Zelan
authors.initials: Z
authors.lastname: Wei
authors.affiliation: Biomolecular Science Center, University of Central Florida, Orlando, Florida 32816.
authors.forename: Miriam
authors.initials: M
authors.lastname: Vandermey
authors.affiliation: College of Pharmacy, Sungkyunkwan University, Suwon 440-746, Korea.
authors.forename: Dong-Gyu
authors.initials: DG
authors.lastname: Jo
authors.affiliation: Laboratory of Neurosciences, NIA, National Institutes of Health, Intramural Research Program, Baltimore, Maryland 21224.
authors.forename: Ouyang
authors.initials: O
authors.lastname: Xin
authors.affiliation: Laboratory of Neurosciences, NIA, National Institutes of Health, Intramural Research Program, Baltimore, Maryland 21224.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
authors.affiliation: Biomolecular Science Center, University of Central Florida, Orlando, Florida 32816. Electronic address: schan@mail.ucf.edu.
authors.forename: Sic L
authors.initials: SL
authors.lastname: Chan
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D004705:Endocytosis; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D016716:PC12 Cells; D058255:Protease Nexins; D020033:Protein Isoforms; D051381:Rats; D011956:Receptors, Cell Surface / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C113026:NUMB protein, human; D058255:Protease Nexins; D020033:Protein Isoforms; D011956:Receptors, Cell Surface; D020691:rab GTP-Binding Proteins