2. Academic Validation
  3. β-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3β/tau cascade

β-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3β/tau cascade

  • Sci Transl Med. 2020 Jan 15;12(526):eaay6931. doi: 10.1126/scitranslmed.aay6931.
Fang Zhang 1,  Mary Gannon 1,  Yunjia Chen 1,  Shun Yan 2,  Sixue Zhang 3,  Wendy Feng 1,  Jiahui Tao 1,  Bingdong Sha 1,  Zhenghui Liu 4,  Takashi Saito 5,  Takaomi Saido 5,  C Dirk Keene 6,  Kai Jiao 2,  Erik D Roberson 7,  Huaxi Xu 8,  Qin Wang 9
Affiliations

Affiliations

  • 1 Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • 2 Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • 3 Department of Chemistry, Southern Research Institute, Birmingham, AL 35205, USA.
  • 4 Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • 5 Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Saitama 351-0198, Japan.
  • 6 Department of Pathology, University of Washington, Seattle, WA 98104, USA.
  • 7 Alzheimer's Disease Center, Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • 8 Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • 9 Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. qinwang@uab.edu.
PMID: 31941827 DOI: 10.1126/scitranslmed.aay6931
Abstract

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 β-amyloid (Aβ) and tau, two key pathological components of AD pathogenesis. Our results show that Aβ oligomers bind to an allosteric site on α2A Adrenergic Receptor (α2AAR) to redirect norepinephrine-elicited signaling to glycogen synthase kinase 3β (GSK3β) activation and tau hyperphosphorylation. This norepinephrine-dependent mechanism sensitizes pathological GSK3β/tau activation in response to nanomolar accumulations of extracellular Aβ, which is 50- to 100-fold lower than the amount required to activate GSK3β by Aβ 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 Aβ proteotoxicity, which might have strong implications for the interpretation of Aβ clearance trial results and future drug design and for understanding the selective vulnerability of noradrenergic neurons in AD.

Figures