Browsing by Author "Yang, Tianxiao P."

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    Crystal structure of a conformational antibody that binds tau oligomers and inhibits pathological seeding by extracts from donors with Alzheimer's disease
    (American Society for Biochemistry and Molecular Biology, 2020-07-31) Abskharon, Romany; Seidler, Paul M.; Sawaya, Michael R.; Cascio, Duilio; Yang, Tianxiao P.; Philipp, Stephan; Williams, Christopher Kazu; Newell, Kathy L.; Ghetti, Bernardino; DeTure, Michael A.; Dickson, Dennis W.; Vinters, Harry V.; Felgner, Philip L.; Nakajima, Rie; Glabe, Charles G.; Eisenberg, David S.; Pathology and Laboratory Medicine, School of Medicine
    Soluble oligomers of aggregated tau accompany the accumulation of insoluble amyloid fibrils, a histological hallmark of Alzheimer disease (AD) and two dozen related neurodegenerative diseases. Both oligomers and fibrils seed the spread of Tau pathology, and by virtue of their low molecular weight and relative solubility, oligomers may be particularly pernicious seeds. Here, we report the formation of in vitro tau oligomers formed by an ionic liquid (IL15). Using IL15-induced recombinant tau oligomers and a dot blot assay, we discovered a mAb (M204) that binds oligomeric tau, but not tau monomers or fibrils. M204 and an engineered single-chain variable fragment (scFv) inhibited seeding by IL15-induced tau oligomers and pathological extracts from donors with AD and chronic traumatic encephalopathy. This finding suggests that M204-scFv targets pathological structures that are formed by tau in neurodegenerative diseases. We found that M204-scFv itself partitions into oligomeric forms that inhibit seeding differently, and crystal structures of the M204-scFv monomer, dimer, and trimer revealed conformational differences that explain differences among these forms in binding and inhibition. The efficiency of M204-scFv antibodies to inhibit the seeding by brain tissue extracts from different donors with tauopathies varied among individuals, indicating the possible existence of distinct amyloid polymorphs. We propose that by binding to oligomers, which are hypothesized to be the earliest seeding-competent species, M204-scFv may have potential as an early-stage diagnostic for AD and tauopathies, and also could guide the development of promising therapeutic antibodies.
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    Structure-based inhibitors halt prion-like seeding by Alzheimer’s disease–and tauopathy–derived brain tissue samples
    (The American Society for Biochemistry and Molecular Biology, 2019-11) Seidler, Paul Matthew; Boyer, David R.; Murray, Kevin A.; Yang, Tianxiao P.; Bentzel, Megan; Sawaya, Michael R.; Rosenberg, Gregory; Cascio, Duilio; Williams, Christopher Kazu; Newell, Kathy L.; Ghetti, Bernardino; DeTure, Michael A.; Dickson, Dennis W.; Vinters, Harry V.; Eisenberg, David S.; Pathology and Laboratory Medicine, School of Medicine
    In Alzheimer's disease (AD) and tauopathies, tau aggregation accompanies progressive neurodegeneration. Aggregated tau appears to spread between adjacent neurons and adjacent brain regions by prion-like seeding. Hence, inhibitors of this seeding offer a possible route to managing tauopathies. Here, we report the 1.0 Å resolution micro-electron diffraction structure of an aggregation-prone segment of tau with the sequence SVQIVY, present in the cores of patient-derived fibrils from AD and tauopathies. This structure illuminates how distinct interfaces of the parent segment, containing the sequence VQIVYK, foster the formation of distinct structures. Peptide-based fibril-capping inhibitors designed to target the two VQIVYK interfaces blocked proteopathic seeding by patient-derived fibrils. These VQIVYK inhibitors add to a panel of tau-capping inhibitors that targets specific polymorphs of recombinant and patient-derived tau fibrils. Inhibition of seeding initiated by brain tissue extracts differed among donors with different tauopathies, suggesting that particular fibril polymorphs of tau are associated with certain tauopathies. Donors with progressive supranuclear palsy exhibited more variation in inhibitor sensitivity, suggesting that fibrils from these donors were more polymorphic and potentially vary within individual donor brains. Our results suggest that a subset of inhibitors from our panel could be specific for particular disease-associated polymorphs, whereas inhibitors that blocked seeding by extracts from all of the tauopathies tested could be used to broadly inhibit seeding by multiple disease-specific tau polymorphs. Moreover, we show that tau-capping inhibitors can be transiently expressed in HEK293 tau biosensor cells, indicating that nucleic acid–based vectors can be used for inhibitor delivery.