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

ABSTRACT 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 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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