Tau alteration and neuronal degeneration in tauopathies: mechanisms and models

Abstract

Tau becomes characteristically altered both functionally and structurally in several neurodegenerative diseases now collectively called tauopathies. Although increasing evidence supports that alterations of tau may directly cause neuronal degeneration and cell death, the mechanisms, which render tau to become a toxic agent are still unclear. In addition, it is obscure, whether neurodegeneration in tauopathies occurs via a common mechanism or specific differences exist. The aim of this review is to provide an overview about the different experimental models that currently exist, how they are used to determine the role of tau during degeneration and what has been learnt from them concerning the mechanistic role of tau in the disease process. The review begins with a discussion about similarities and differences in tau alteration in paradigmatic tauopathies such as frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and Alzheimer's disease (AD). The second part concentrates on major experimental models that have been used to address the mechanistic role of tau during degeneration. This will include a discussion of cell-free assays, culture models using cell lines or dissociated neurons, and animal models. How these models aid to understand (i) alterations in the function of tau as a microtubule-associated protein (MAP), (ii) direct cytotoxicity of altered tau protein, and (iii) the potential role of tau aggregation in neurodegenerative processes will be the central theme of this part. The review ends with concluding remarks about a general mechanistic model of the role of tau alteration and neuronal degeneration in tauopathies and future perspectives.

Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration

“…Direct interactions include the binding, stabilization, and promotion of MT assembly that can be modulated by Tau and its phosphorylation (Brandt et al 2005;Dolan and Johnson 2010). This function requires the MT-binding domain (repeats þ flanking domains), but not necessarily the projection domain.…”

SR protein 9G8 modulates splicing of tau exon 10 via its proximal downstream intron, a clustering region for frontotemporal dementia mutations

“…Given the strong effects of mutants in positions +14 to +29 (reviewed in Andreadis, 2005), this must be at least one region where regulation of this exon differs among species. This crucial difference in the behavior of exon 10 in rodents may well correlate with the repeated failure to find neurofibrillary tangles in aged rodents as well as the difficulty of inducing them artificially in transgenic models (Brandt et al, 2005).…”

The Thioredoxin-like Protein Rod-derived Cone Viability Factor (RdCVFL) Interacts with TAU and Inhibits Its Phosphorylation in the Retina

“…In the brains of patients with Alzheimer disease (AD) TAU was found to be hyperphosphorylated (22), leading to aggregation of the protein and to a decrease in TAU binding to microtubules (23) resulting in cell death. Phosphorylated TAU is also toxic to neuronal cells (24). The interaction between RdCVFL and TAU is the first description of the participation of RdCVFL in the protection of photoreceptors and of a novel redox signaling pathway involved in regulating neuronal cell death.…”