Tau oligomers and tau toxicity in neurodegenerative disease

Abstract

AD (Alzheimer's disease) is a progressive neurodegenerative disorder characterized by the extracellular accumulation of amyloid β-peptide and the intracellular accumulation of tau. Although there is much evidence linking tau to neurodegeneration, the precise mechanism of tau-mediated neurotoxicity remains elusive. The presence of tau-positive pre-tangle neurons lacking neurofibrillary tangles has been reported in AD brain tissue. In order to study this non-fibrillar tau, we generated a novel monoclonal antibody, named TOC1 (tau oligomeric complex 1), which selectively labels tau dimers and oligomers, but does not label filaments. Time-course analysis and antibody labelling indicates that oligomers appear as an early event in AD pathogenesis. Using a squid axoplasm assay, we have demonstrated that aggregated tau inhibits anterograde FAT (fast axonal transport), whereas monomeric tau has no effect. This inhibition requires a small stretch of N-terminal amino acids termed the PAD (phosphatase-activation domain). Using a PAD-specific antibody, TNT1 (tau N-terminal 1), we demonstrate that PAD exposure is increased in diseased neurons and this leads to an increase in FAT inhibition. Antibody co-labelling with the early-AD marker AT8 indicates that, similar to TOC1, TNT1 expression represents an early event in AD pathogenesis. Finally, the effects of the molecular chaperone Hsp70 (heat-shock protein 70) were also investigated within the squid axoplasm assay. We illustrate that Hsp70 preferentially binds to tau oligomers over filaments and prevents anterograde FAT inhibition observed with a mixture of both forms of aggregated tau. Together, these findings support the hypothesis that tau oligomers are the toxic form of tau in neurodegenerative disease.

The fuzzy coat of pathological human Tau fibrils is a two-layered polyelectrolyte brush

“…Remarkably, at low ion concentrations (≤50 mM KCl) that soften the fuzzy coat, Tau fibrils on hydrophobic surfaces become unstable and spontaneously disassemble into smaller subunits (16). In vivo, the softening of the fuzzy coat could trigger fibril fragmentation and formation of the soluble Tau oligomers that are widely discussed as toxic (40,41) and transmissive (42,43) species in tauopathies. When bound to MTs, the terminal domains of Tau project from the MT surface (4) in a highly flexible manner (15,44), and may thus also expose polyelectrolyte brush-like behavior.…”

Cl-NQTrp Alleviates Tauopathy Symptoms in a Model Organism through the Inhibition of Tau Aggregation-Engendered Toxicity

“…In tauopathies, not only do intracellular toxic accumulations of tau protein appear, but the abnormal phosphorylation of tau also leads to MT disassembly due to its decreased tubulin-binding capacity [7,8]. Aggregation of tau is believed to cause neuronal toxicity in two main ways: (1) tau aggregation sequestrates monomers from their normal function of promoting MT stability, and (2) tau aggregates by themselves were shown to be neurotoxic [14,15]. Interestingly, recent data suggest that soluble prefilament forms of tau may be the most toxic forms of tau aggregates rather than the large NFTs themselves [16].…”

Behind the curtain of tauopathy: a show of multiple players orchestrating tau toxicity

“…These studies suggest that NFTs may be an accompanying phenomenon or a protective mechanism insulating the cell from tau toxicities. Indeed, the current body of data implies that oligomerized forms of tau might be the true source of tau toxicity [72]. As discussed previously, studies in Drosophila and rodent models indicate that soluble forms of tau may behave as the toxic species [37, 111], due to the observation that no NFTs were detected in these animals, yet severe phenotypes still developed.…”

“…Thus, toxicity can arise from either or both of the two events: loss of normal functions and/or gain of new functions. tau aggregation/oligomerization-related toxicities, which will be discussed later, are accepted by many researchers in the field as the cause of tauopathy [71,72]. We will start our discussion with the known early events of tauopathy.…”

“…In addition, in the P301L mouse model, NFT bearing neurons undergo synapse loss and synaptic functional impairment [103-108]. Nevertheless, neurons with NFTs can survive for 20-30 years [109,110], indicating that NFTs might not be the major toxic species in tauopathies [72]. Studies in animal models also argue against the possibility that NFTs are the major toxicity source.…”