Tau Oligomers: Cytotoxicity, Propagation, and Mitochondrial Damage - PubMed (original) (raw)

Review

Tau Oligomers: Cytotoxicity, Propagation, and Mitochondrial Damage

Scott S Shafiei et al. Front Aging Neurosci. 2017.

Abstract

Aging has long been considered as the main risk factor for several neurodegenerative disorders including a large group of diseases known as tauopathies. Even though neurofibrillary tangles (NFTs) have been examined as the main histopathological hallmark, they do not seem to play a role as the toxic entities leading to disease. Recent studies suggest that an intermediate form of tau, prior to NFT formation, the tau oligomer, is the true toxic species. However, the mechanisms by which tau oligomers trigger neurodegeneration remain unknown. This review summarizes recent findings regarding the role of tau oligomers in disease, including release from cells, propagation from affected to unaffected brain regions, uptake into cells, and toxicity via mitochondrial dysfunction. A greater understanding of tauopathies may lead to future advancements in regards to prevention and treatment.

Keywords: mitochondrial dysfunction; propagation; tau oligomers; tau secretion; tauopathy.

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Figures

Figure 1

Figure 1

Propagation of tau oligomers. Schematic representation of free or exosomal tau oligomers release, local or trans-synaptic. In local transmission, tau oligomers are released from one neuron and taken up by another neuron in the vicinity. In trans-synaptic transmission, tau oligomers and/or exosomes containing tau oligomers are passed across the synapse of two neighboring neurons.

Figure 2

Figure 2

Mechanisms of tau oligomer internalization and mitochondrial damage. Schematic representation of the proposed mechanisms contributing to tau oligomer internalization that may lead to mitochondrial dysfunction and cell death. Methods of tau oligomer internalization include (1) dynamin-driven endocytosis; (2) muscarinic (M1 and M3) receptor-mediated endocytosis; (3) proteoglycan-mediated macropinocytosis (HSPGs); (4) exosomes; and (5) annular protofibrils. Internalized tau oligomers interfere with the mitochondrial respiratory chain, inducing cytochrome c release and stimulating reactive oxygen species (ROS) production. Tau oligomers induce mitochondrial fusion/fission imbalance by binding with dynamin-related protein 1 (DRP1). Tau oligomers interact with the outer membrane porin protein.

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