Tau Oligomers Impair Artificial Membrane Integrity and Cellular Viability

Paul Flechsig Institute of Brain Research, Germany
Journal of Biological Chemistry (Impact Factor: 4.57). 11/2012; 287(52). DOI: 10.1074/jbc.M112.396176
Source: PubMed


The microtubule-associated protein tau is mainly expressed in neurons, where it binds and stabilises microtubules. In Alzheimers disease and other tauopathies tau protein has a reduced affinity towards microtubules. As a consequence, tau protein detaches from microtubules and eventually aggregates into β-sheet containing filaments. The fibrillization of monomeric tau to filaments is a multistep process which involves the formation of various aggregates including spherical and protofibrillar oligomers. Previous concepts, primarily developed for Aβ and alpha-synuclein, propose these oligomeric intermediates as the primary cytotoxic species mediating their deleterious effects through membrane permeabilization. In the present study, we, thus, analysed whether this concept can also be applied to tau protein. To this end, viability and membrane integrity were assessed on SH-SY5Y neuroblastoma cells and artificial phospholipid vesicles, treated with tau monomers, tau aggregation intermediates or tau fibrils. Our findings suggest that oligomeric tau aggregation intermediates are the most toxic compounds of tau fibrillogenesis which effectively decrease cell viability and increase phospholipid vesicle leakage. Our data integrate tau protein into the class of amyloidogenic proteins and enforce the hypothesis of a common toxicity-mediating mechanism for amyloidogenic proteins.

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    • "The percentage of neurons taking up trypan blue was evaluated to be less than 1% for both control and treated neurons and was not significantly different between these two groups (p = 0.083) indicating that tau was not released by dying neurons in the medium of E + L treated neurons. To eliminate the possibility that the increase of tau in the culture medium was caused by cell damage induced by the treatments, we measured the amount of lactate dehydrogenase (LDH) activity, a marker of cell membrane integrity, in the culture medium38. The LDH was increased ~1.22 (p = 0.0124), 1.08 (p = 0.0172) and 1.19 (p = 0.0095) times in the medium of EBSS, leupeptin and E + L treated neurons, respectively, compared to the amount in the medium of control neurons revealing that cell membrane integrity was changed by our treatments (Figure 1c). "
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    Scientific Reports 07/2014; 4:5715. DOI:10.1038/srep05715 · 5.58 Impact Factor
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    • "The mechanism of lipid bilayer disruption by aggregate species may involve insertion of distinct pore-like structures, formation of large " defects " in the membrane , or a combination of both [19] [20] [21] [22] [23] [24]. Moreover, the first study has been recently published demonstrating increased phospholipid vesicle leakage, in association with decreased cell viability, induced by tau aggregation intermediates [25]. Membranes of organelles are potential targets of oligomeric complexes ; this applies particularly to mitochondria which are abundant in synapses and neurons. "
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    Biochimica et Biophysica Acta 06/2013; 1828(11). DOI:10.1016/j.bbamem.2013.06.026 · 4.66 Impact Factor
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    ABSTRACT: Prion diseases and prion-like protein misfolding diseases involve the accumulation of abnormally aggregated forms of the normal host proteins, such as prion protein and Tau protein. These proteins are special because of their self-duplicating and transmissible characteristics. Such abnormally aggregated proteins mainly formed in neurons, cause the neurons dysfunction, and finally lead to invariably fatal neurodegenerative diseases. Prion diseases appear not only in animals, such as bovine spongiform encephalopathy in cattle and scrapie in sheep, but also in humans, such as Creutzfeldt-Jacob disease, and even the same prion or prion-like proteins can have many different phenotypes. A lot of biological evidence has suggested that the molecular basis for different strains of prions could be hidden in protein conformations, and the misfolded proteins with conformations different from the normal proteins have been proved to be the main cause for protein aggregation. Crowded physiological environments can be imitated in vitro to study how the misfolding of these proteins leads to the diseases in vivo. In this review, we provide an overview of the existing structural information for prion and prion-like proteins, and discuss the post-translational modifications of prion proteins and the difference between prion and other infectious pathogens. We also discuss what makes a misfolded protein become an infectious agent, and show some examples of prion-like protein aggregation, such as Tau protein aggregation and superoxide dismutase 1 aggregation, as well as some cases of prion-like protein aggregation in crowded physiological environments.
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