Article

Tau oligomers impair artificial membrane integrity and cellular viability.

Paul Flechsig Institute of Brain Research, Germany
Journal of Biological Chemistry (Impact Factor: 4.6). 11/2012; 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.

1 Follower
 · 
143 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent studies have demonstrated that human tau can be secreted by neurons and non-neuronal cells, an event linked to the propagation of tau pathology in the brain. In the present study, we confirmed that under physiological conditions, one tau-positive band was detected in the culture medium with an anti-tau antibody recognizing total tau and the Tau-1 antibody directed against unphosphorylated tau. We then examined whether tau secretion was modified upon insults. Tau secretion was increased by starvation [Earle's Balanced Salt Solution (EBSS)], inhibition of lysosomal function (leupeptin) and when both of these conditions were superimposed, this combined treatment having the most important effects on tau secretion. Interestingly, the pattern of tau secretion was distinct from that of control neurons when neurons were treated either with EBSS alone or EBSS + leupeptin. In these conditions, three tau-positive bands were detected in the culture medium. Two of these three bands were immunoreactive to Tau-1 antibody revealing that at least two tau species were released upon these treatments. Collectively, our results indicate that insults such as nutrient deprivation and lysosomal dysfunction observed in neurodegenerative diseases could result in an increase of tau secretion and propagation of tau pathology in the brain.
    Scientific Reports 07/2014; 4:5715. DOI:10.1038/srep05715 · 5.08 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by peptide and protein misfolding and aggregation, in part due to the presence of excess metal ions such as copper. Aggregation and cytotoxicity of amyloid-β (Aβ) peptide with copper ion have been investigated extensively; however, the effects of metalation on tau are less known. Here, we presented the effects of Cu(+) and Cu(2+) on aggregation and neurotoxicity of the second repeat unit of the microtubule-binding domain of tau (tau-R2). Tau-R2 was demonstrated to bind 0.44 Cu(2+) and 0.34 Cu(+) per monomer with dissociation constants of 1.1 nM and 0.2 pM, respectively. Copper in both oxidation states stimulated the aggregation, ROS production, and neuronal cytotoxicity of tau-R2. We showed that copper-associated tau-R2 aggregates, decreased protein levels of microtubule-associated protein 2 (MAP-2), and synaptophysin in the primarily cultured cortical neurons, reduced mitochondrial density and mobility in the axon and, as a consequence, impaired the growth and probably also the function of neurons. Previously, we reported that the His-rich domain of selenoprotein P (SelP-H) inhibited metal-induced aggregation and toxicity of Aβ, due to its metal chelation ability. Here we demonstrated that SelP-H not only inhibited copper-mediated tau aggregation but also interfered with the ongoing aggregation and reversed the already formed aggregates. More intriguing, SelP-H significantly attenuated Cu(2+)/Cu(+)-tau-R2-induced intracellular ROS production and the impairments of synapse and mitochondrial movement in neurons. This work implies that the surface-exposed His-rich domain of SelP makes it capable of modulating Cu(+)/Cu(2+)-mediated aggregation and neurotoxicity of both Aß and tau and may play important roles in the prevention of AD progression.
    Inorganic Chemistry 10/2014; 53(20). DOI:10.1021/ic501788v · 4.79 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pathological aggregation of the microtubule-associated protein tau and subsequent accumulation of neurofibrillary tangles (NFTs) or other tau-containing inclusions are defining histopathological features of many neurodegenerative diseases, which are collectively known as tauopathies. Due to conflicting results regarding a correlation between the presence of NFTs and disease progression, the mechanism linking pathological tau aggregation with cell death is poorly understood. An emerging view is that NFTs are not the toxic entity in tauopathies; rather, tau intermediates between monomers and NFTs are pathogenic.Several proteins associated with neurodegenerative diseases, such as beta-amyloid (Abeta) and alpha-synuclein, have the tendency to form pore-like amyloid structures (annular protofibrils, APFs) that mimic the membrane-disrupting properties of pore-forming protein toxins. The present study examined the similarities of tau APFs with other tau amyloid species and showed for the first time the presence of tau APFs in brain tissue from patients with progressive supranuclear palsy (PSP) and dementia with Lewy bodies (DLB), as well as in the P301L mouse model, which overexpresses mutated tau. Furthermore, we found that APFs are preceded by tau oligomers and do not go on to form NFTs, evading fibrillar fate. Collectively, our results demonstrate that in vivo APF formation depends on mutations in tau, phosphorylation levels, and cell type. These findings establish the pathological significance of tau APFs in vivo and highlight their suitability as therapeutic targets for several neurodegenerative tauopathies.
    05/2014; 2(1):56. DOI:10.1186/2051-5960-2-56

Full-text

Download
68 Downloads
Available from
May 22, 2014

Similar Publications