title: Evidence that the rab5 effector APPL1 mediates APP-βCTF-induced dysfunction of endosomes in Down syndrome and Alzheimer's disease.
abstract: β-Amyloid precursor protein (APP) and its cleaved products are strongly implicated in Alzheimer's disease (AD). Endosomes are highly active APP processing sites, and endosome anomalies associated with upregulated expression of early endosomal regulator, rab5, are the earliest known disease-specific neuronal response in AD. Here, we show that the rab5 effector APPL1 (adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain and leucine zipper motif) mediates rab5 overactivation in Down syndrome (DS) and AD, which is caused by elevated levels of the β-cleaved carboxy-terminal fragment of APP (βCTF). βCTF recruits APPL1 to rab5 endosomes, where it stabilizes active GTP-rab5, leading to pathologically accelerated endocytosis, endosome swelling and selectively impaired axonal transport of rab5 endosomes. In DS fibroblasts, APPL1 knockdown corrects these endosomal anomalies. βCTF levels are also elevated in AD brain, which is accompanied by abnormally high recruitment of APPL1 to rab5 endosomes as seen in DS fibroblasts. These studies indicate that persistent rab5 overactivation through βCTF-APPL1 interactions constitutes a novel APP-dependent pathogenic pathway in AD.
authors.affiliation: Cellular and Molecular Biology Training Program, New York University School of Medicine, New York, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kim
authors.affiliation: Center for Dementia Research, Nathan S Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Center for Dementia Research, Nathan S Kline Institute for Psychiatric Research, Orangeburg, NY, USA.|Department of Psychiatry, New York University School of Medicine, New York, NY, USA.
authors.forename: P S
authors.initials: PS
authors.lastname: Mohan
authors.affiliation: Center for Dementia Research, Nathan S Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
authors.forename: C
authors.initials: C
authors.lastname: Peterhoff
authors.affiliation: Center for Dementia Research, Nathan S Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Pensalfini
authors.affiliation: Department of Cell Biology, New York University School of Medicine, New York, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Rigoglioso
authors.affiliation: Center for Dementia Research, Nathan S Kline Institute for Psychiatric Research, Orangeburg, NY, USA.|Department of Psychiatry, New York University School of Medicine, New York, NY, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Center for Dementia Research, Nathan S Kline Institute for Psychiatric Research, Orangeburg, NY, USA.|Department of Psychiatry, New York University School of Medicine, New York, NY, USA.|Department of Cell Biology, New York University School of Medicine, New York, NY, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Nixon
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004314:Down Syndrome / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006160:Guanosine Triphosphate / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism*
chemical_list: C545487:APP protein, human; C464801:APPL1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; D006160:Guanosine Triphosphate; C427755:RAB5C protein, human; D020696:rab5 GTP-Binding Proteins