Download MendeleyCrystal structure of a conformational antibody that binds tau oligomers and inhibits pathological seeding by extracts from donors with Alzheimer's disease.
Abskharon, R., Seidler, P.M., Sawaya, M.R., Cascio, D., Yang, T.P., Philipp, S., Williams, C.K., Newell, K.L., Ghetti, B., DeTure, M.A., Dickson, D.W., Vinters, H.V., Felgner, P.L., Nakajima, R., Glabe, C.G., Eisenberg, D.S.(2020) J Biol Chem 295: 10662-10676
- PubMed: 32493775
- DOI: https://doi.org/10.1074/jbc.RA120.013638
- Primary Citation of Related Structures:
6PIL, 6PK8, 6PSC - PubMed Abstract:
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.
Organizational Affiliation:
Departments of Chemistry and Biochemistry and Biological Chemistry, UCLA-DOE Institute UCLA, Los Angeles, California, USA.
