期刊
MABS
卷 11, 期 3, 页码 477-488出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/19420862.2019.1574530
关键词
Monoclonal antibody; Alzheimer's disease; tau protein; antibody-antigen complex; phospho-epitope
资金
- National Institute of Neurological Disorders and Stroke [NS077239, AG032611]
- National Institute on Aging [AG032611]
Targeting tau with immunotherapies is currently the most common approach taken in clinical trials of patients with Alzheimer's disease. The most prominent pathological feature of tau is its hyperphosphorylation, which may cause the protein to aggregate into toxic assemblies that collectively lead to neurodegeneration. Of the phospho-epitopes, the region around Ser(396)/Ser(404) has received particular attention for therapeutic targeting because of its prominence and stability in diseased tissue. Herein, we present the antigen-binding fragment (Fab)/epitope complex structures of three different monoclonal antibodies (mAbs) that target the pSer(404) tau epitope region. Most notably, these structures reveal an antigen conformation similar to a previously described pathogenic tau epitope, pSer(422), which was shown to have a beta-strand structure that may be linked to the seeding core in tau oligomers. In addition, we have previously reported on the similarly ordered conformation observed in a pSer(396) epitope, which is in tandem with pSer(404). Our data are the first Fab structures of mAbs bound to this epitope region of the tau protein and support the existence of proteopathic tau conformations stabilized by specific phosphorylation events that are viable targets for immune modulation.
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