title: App gene dosage modulates endosomal abnormalities of Alzheimer's disease in a segmental trisomy 16 mouse model of down syndrome.
abstract: Altered neuronal endocytosis is the earliest known pathology in sporadic Alzheimer's disease (AD) and Down syndrome (DS) brain and has been linked to increased Abeta production. Here, we show that a genetic model of DS (trisomy 21), the segmental trisomy 16 mouse Ts65Dn, develops enlarged neuronal early endosomes, increased immunoreactivity for markers of endosome fusion (rab5, early endosomal antigen 1, and rabaptin5), and endosome recycling (rab4) similar to those in AD and DS individuals. These abnormalities are most prominent in neurons of the basal forebrain, which later develop aging-related atrophy and degenerative changes, as in AD and DS. We also show that App, one of the triplicated genes in Ts65Dn mice and human DS, is critical to the development of these endocytic abnormalities. Selectively deleting one copy of App or a small portion of the chromosome 16 segment containing App from Ts65Dn mice eliminated the endosomal phenotype. Overexpressing App at high levels in mice did not alter early endosomes, implying that one or more additional genes on the triplicated segment of chromosome 16 are also required for the Ts65Dn endosomal phenotype. These results identify an essential role for App gene triplication in causing AD-related endosomal abnormalities and further establish the pathogenic significance of endosomal dysfunction in AD.
authors.affiliation: Mailman Research Center, McLean Hospital, Belmont, Massachusetts 02478, USA. acataldo@mclean.harvard.edu
authors.forename: Anne M
authors.initials: AM
authors.lastname: Cataldo
authors.forename: Suzana
authors.initials: S
authors.lastname: Petanceska
authors.forename: Corrinne M
authors.initials: CM
authors.lastname: Peterhoff
authors.forename: Nicole B
authors.initials: NB
authors.lastname: Terio
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Epstein
authors.forename: Angela
authors.initials: A
authors.lastname: Villar
authors.forename: Elaine J
authors.initials: EJ
authors.lastname: Carlson
authors.forename: Matthias
authors.initials: M
authors.lastname: Staufenbiel
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Nixon
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D001923:Brain Chemistry; D004195:Disease Models, Animal; D018450:Disease Progression; D004314:Down Syndrome / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D004705:Endocytosis / Q000235:genetics; D011992:Endosomes / Q000378:metabolism / Q000473:pathology*; D018628:Gene Dosage; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D009474:Neurons / Q000473:pathology; D010641:Phenotype; D053764:Presenilin-1; D016548:Prosencephalon / Q000473:pathology; D017384:Sequence Deletion; D014314:Trisomy / Q000235:genetics / Q000503:physiopathology*; D020696:rab5 GTP-Binding Proteins / Q000096:biosynthesis
chemical_list: D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D020696:rab5 GTP-Binding Proteins