Methods and compositions comprising tau oligomers

摘要

Tau protein has a causative role in Alzheimer's disease and multiple other neurodegenerative disorders exhibiting tau histopathology collectively termed tauopathies. The primary function of tau protein is to facilitate assembly and maintenance of microtubules in neuronal axons. In the disease process tau protein becomes modified, loses its affinity to microtubules and accumulates in the cell body where it forms aggregates. The large neurofibrillary tangles formed from tau protein assembled into filaments were thought to be the pathological structure of tau. However, more recent work indicates that smaller, soluble oligomeric forms of tau are best associated with neuron loss and memory impairment. Here, novel compositions of tau oligomers and novel mechanisms for tau oligomer nucleation, extension and termination are taught. Methods for producing and purifying these structures for the development of small molecule and immunotherapeutics as well as antibodies for biomarkers of neurodegenerative diseases are taught.

主权项

1. A composition comprising a non-naturally occurring purified and/or isolated and stabilized tau oligomer and a buffer, wherein the tau oligomer comprises human recombinant tau protein produced recombinantly from bacteria in a buffer having a neutral pH, the tau oligomer being in a trimeric form having a first tau monomer containing a first cysteine, a second tau monomer containing a second cysteine, and a third tau monomer containing a third cysteine, wherein the first tau monomer is covalently attached to the second tau monomer and the second tau monomer is covalently attached to the third tau monomer by an intermolecular disulfide linkage between at least the first cysteine, the second cysteine and the third cysteine, and each monomer has an N-terminal and a C-terminal in a parallel orientation relative to each other in the trimeric form, and the tau oligomer is at least 90% purified, wherein the tau oligomer is formed without the addition of heparin or other polyanions.