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Evidence that the rab5 effector APPL1 mediates APP-ßCTF-induced dysfunction of endosomes in Down syndrome and Alzheimer's disease.
Kim, S; Sato, Y; Mohan, P S; Peterhoff, C; Pensalfini, A; Rigoglioso, A; Jiang, Y; Nixon, R A.
Afiliación
  • Kim S; Cellular and Molecular Biology Training Program, New York University School of Medicine, New York, NY, USA.
  • Sato Y; Center for Dementia Research, Nathan S Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
  • Mohan PS; Center for Dementia Research, Nathan S Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
  • Peterhoff C; Department of Psychiatry, New York University School of Medicine, New York, NY, USA.
  • Pensalfini A; Center for Dementia Research, Nathan S Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
  • Rigoglioso A; Center for Dementia Research, Nathan S Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
  • Jiang Y; Department of Cell Biology, New York University School of Medicine, New York, NY, USA.
  • Nixon RA; Center for Dementia Research, Nathan S Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
Mol Psychiatry ; 21(5): 707-16, 2016 May.
Article en En | MEDLINE | ID: mdl-26194181
ß-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 ß-cleaved carboxy-terminal fragment of APP (ßCTF). ßCTF 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. ßCTF 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 ßCTF-APPL1 interactions constitutes a novel APP-dependent pathogenic pathway in AD.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Endosomas / Precursor de Proteína beta-Amiloide / Síndrome de Down / Proteínas de Unión al GTP rab5 / Proteínas Adaptadoras Transductoras de Señales / Enfermedad de Alzheimer Límite: Aged / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: Mol Psychiatry Asunto de la revista: BIOLOGIA MOLECULAR / PSIQUIATRIA Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Endosomas / Precursor de Proteína beta-Amiloide / Síndrome de Down / Proteínas de Unión al GTP rab5 / Proteínas Adaptadoras Transductoras de Señales / Enfermedad de Alzheimer Límite: Aged / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: Mol Psychiatry Asunto de la revista: BIOLOGIA MOLECULAR / PSIQUIATRIA Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido