Your browser doesn't support javascript.
loading
ß-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3ß/tau cascade.
Zhang, Fang; Gannon, Mary; Chen, Yunjia; Yan, Shun; Zhang, Sixue; Feng, Wendy; Tao, Jiahui; Sha, Bingdong; Liu, Zhenghui; Saito, Takashi; Saido, Takaomi; Keene, C Dirk; Jiao, Kai; Roberson, Erik D; Xu, Huaxi; Wang, Qin.
Afiliación
  • Zhang F; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • Gannon M; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • Chen Y; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • Yan S; Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • Zhang S; Department of Chemistry, Southern Research Institute, Birmingham, AL 35205, USA.
  • Feng W; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • Tao J; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • Sha B; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • Liu Z; Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • Saito T; Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Saitama 351-0198, Japan.
  • Saido T; Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Saitama 351-0198, Japan.
  • Keene CD; Department of Pathology, University of Washington, Seattle, WA 98104, USA.
  • Jiao K; Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • Roberson ED; Alzheimer's Disease Center, Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • Xu H; Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • Wang Q; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. qinwang@uab.edu.
Sci Transl Med ; 12(526)2020 01 15.
Article en En | MEDLINE | ID: mdl-31941827
The brain noradrenergic system is critical for normal cognition and is affected at early stages in Alzheimer's disease (AD). Here, we reveal a previously unappreciated direct role of norepinephrine signaling in connecting ß-amyloid (Aß) and tau, two key pathological components of AD pathogenesis. Our results show that Aß oligomers bind to an allosteric site on α2A adrenergic receptor (α2AAR) to redirect norepinephrine-elicited signaling to glycogen synthase kinase 3ß (GSK3ß) activation and tau hyperphosphorylation. This norepinephrine-dependent mechanism sensitizes pathological GSK3ß/tau activation in response to nanomolar accumulations of extracellular Aß, which is 50- to 100-fold lower than the amount required to activate GSK3ß by Aß alone. The significance of our findings is supported by in vivo evidence in two mouse models, human tissue sample analysis, and longitudinal clinical data. Our study provides translational insights into mechanisms underlying Aß proteotoxicity, which might have strong implications for the interpretation of Aß clearance trial results and future drug design and for understanding the selective vulnerability of noradrenergic neurons in AD.
Asunto(s)
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Norepinefrina / Péptidos beta-Amiloides / Proteínas tau / Glucógeno Sintasa Quinasa 3 beta Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Norepinefrina / Péptidos beta-Amiloides / Proteínas tau / Glucógeno Sintasa Quinasa 3 beta Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos