Preparation and Characterization of Neurotoxic Tau Oligomers

Abstract

Tau aggregation is a pathological hallmark of Alzheimer's disease, Parkinson's disease, and many other neurodegenerative disorders known as tauopathies. Tau aggregates take on many forms, and their formation is a multistage process with intermediate stages. Recently, tau oligomers have emerged as the pathogenic species in tauopathies and a possible mediator of amyloid-β toxicity in Alzheimer's disease. Here, we use a novel, physiologically relevant method (oligomer cross-seeding) to prepare homogeneous populations of tau oligomers and characterize these oligomers in vitro. We show that both Aβ and α-synuclein oligomers induce tau aggregation and the formation of β-sheet-rich neurotoxic tau oligomers.

Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients

“…Seeding of amyloid fibrils with amyloid protein is often used to generate homogenous fibril species 35 or eliminate the nucleation step to form amyloid oligomers 36,37 . Recently, oligomer cross-seeding of Ab and asynuclein to induce toxic t-oligomers was demonstrated 38 . Here we examined Ab40 fibrillization by ThT assay in the absence and presence of TDP-43 oligomers, ranging from 0.4 to 4%.…”

Tau oligomers in cerebrospinal fluid in Alzheimer's disease

“…This recombinant tau was then oligomerized following our published protocol 34. In brief, tau protein was treated with 8M urea to obtain monomers.…”

Alzheimer disease

“…In the absence of any other proteins or peptides, Aβ can bind to tau 43 and tau monomers can be induced to oligomerize in vitro after exposure to low substoichiometric levels of Aβ oligomers. 44 These findings raise the obvious possibility that, in vivo, Aβ oligomers seed the initial formation of tau oligomers, which can then self-propagate in the absence of additional input from Aβ (Fig. 1).…”

“…A straightforward interpretation of these data suggests a model in which the specific folding patterns of oligomers formed early in the aggregation proteins whose misfolding into β-sheet-rich structures underlies other well-known neurodegenerative diseases. [26][27][28]30,32 Most intriguing in this regard is evidence for Aβ-tau interactions, both physically 43,44 and in cell signaling. 5,9,11,39,45-52 AD can thus be regarded as a disease that requires prion-like behavior of two distinct proteins.…”

“…72 Small oligomers, especially tau dimers, are intermediates in the filament assembly process. 44,73 Once filament polymerization has occurred, sonication can fracture the filaments into shorter, more numerous structures that can seed the assembly of additional tau monomers. 74 Tau filaments therefore have the ability to self-propagate.…”