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.