Tau Oligomers Impair Artificial Membrane Integrity and Cellular Viability

Flach, Katharina; Hilbrich, Isabel; Schiffmann, Andrea; Gärtner, Ulrich; Krüger, Melanie; Leonhardt, Marion; Waschipky, Hanka; Wick, Lukas Y.; Arendt, Thomas; Holzer, Max

doi:10.1074/jbc.m112.396176

Cited by 170 publications

(168 citation statements)

References 69 publications

Supporting

Mentioning

156

Contrasting

Order By: Relevance

“…This stimulates macropinocytosis, a form of fluid phase endocytosis, to bring pathogenic "seeds" into the cell, and underlies transcellular propagation (10). Recent studies have suggested that uptake of exogenous Tau depends on aggregate size (11) and that smaller Tau assemblies could be disruptive to membranes (12). However, the minimum Tau assembly that can spontaneously bind the cell membrane, trigger cell uptake, and serve as a template for aggregation of Tau is not known.…”

mentioning

confidence: 99%

Tau Trimers Are the Minimal Propagation Unit Spontaneously Internalized to Seed Intracellular Aggregation

Mirbaha

Holmes

Sanders

et al. 2015

Journal of Biological Chemistry

193

180

View full text Add to dashboard Cite

Background:It is unknown what the minimum assembly of Tau is that can trigger cell uptake and seeding of intracellular aggregation. Results: Recombinant and AD-derived Tau assemblies were fractionated, and uptake and intracellular seeding activities were determined. Conclusion: Only Tau assemblies of n Ն 3 units trigger uptake and seeding. Significance: Definition of the minimal Tau propagation unit elucidates disease mechanisms for diagnosis and therapy.

show abstract

mentioning

confidence: 99%

Tau Trimers Are the Minimal Propagation Unit Spontaneously Internalized to Seed Intracellular Aggregation

Mirbaha

Holmes

Sanders

et al. 2015

Journal of Biological Chemistry

193

180

View full text Add to dashboard Cite

show abstract

“…Although the mechanism of tau toxicity is subject to some debate, increasing evidence suggests that a prefibrillar oligomeric state of tau is the primary toxic species responsible for neurodegeneration (6,7), similar to models proposed for many other amyloid-forming proteins. According to this model, tau dissociates from microtubules and forms oligomers with the potential to disrupt cellular membranes and impair synaptic and mitochondrial function before ultimately forming relatively inert amyloid fibrils in what may or may not be a protective mechanism to remove toxic oligomers (6)(7)(8). How cells control the relative populations of tau monomers, oligomers, and fibrils, and protect against associated toxicity, remains poorly understood.…”

mentioning

confidence: 99%

HspB1 and Hsc70 chaperones engage distinct tau species and have different inhibitory effects on amyloid formation

Baughman

Clouser

Klevit

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

The microtubule-associated protein tau forms insoluble, amyloid-type aggregates in various dementias, most notably Alzheimer's disease. Cellular chaperone proteins play important roles in maintaining protein solubility and preventing aggregation in the crowded cellular environment. While tau is known to interact with numerous chaperones, it remains unclear how these chaperones function mechanistically to prevent tau aggregation and how chaperones from different classes compare in terms of mechanism. Here, we focused on the small heat shock protein HspB1 and the constitutive chaperone Hsc70 (also known as HspA8), and report how each chaperone interacts with tau to prevent its fibril formation. Using fluorescence and NMR spectroscopy, we show that the two chaperones inhibit tau fibril formation by distinct mechanisms. HspB1 delayed tau fibril formation by weakly interacting with early species in the aggregation process, while Hsc70 was highly efficient at preventing tau fibril elongation possibly by capping the ends of tau fibrils. Both chaperones recognized aggregation-prone motifs within the microtubule-binding repeat region of tau. However, HspB1 binding remained transient in both aggregation-promoting and nonaggregating conditions, whereas Hsc70 binding was significantly tighter under aggregationpromoting conditions. These differences highlight the fact that chaperones from different families play distinct but complementary roles in the prevention of pathological protein aggregation.

show abstract

“…An interesting UV raman spectroscopy study showed that at early stages, within the first hour, fibrillar aggregates possess a mixture of β-sheet and disordered content. Afterward, the UVRR spectra shows a consolidation in fibril structure, augmenting the content of β sheet [15], interesting is to remark that toxicity apparently relies on β sheet content [16]. …”

mentioning

confidence: 99%

Secondary Metabolites of Lichens as Both Anti-aggregative and Antioxidant Agents in Tauopathies

Cornejo¹,

Areche²

2017

J Clin Cell Immunol

View full text Add to dashboard Cite

This commentary described our findings of parietin, an anthraquinone, isolated from Ramalina terebrata as inhibitor of tau protein. Moreover, we considered important to link tauopathies with reactive oxygen species since oligomers and fibril-forming elements are responsible for activating reactive oxygen species, which cause inflammatory response and neurodegeneration. Together, we considered important to find naturally occurring compounds that might be able to stop aggregation and reduce ROS cells damage.Keywords: Tauopathies; Secondary metabolites; Lichens; Reactive oxygen species; Inflammatory response; Neurodegeneration Tauopathies and NeurotoxicityTaoupathies are neurodegenerative disorders involving tau protein, such as progressive nuclear palsy (PSP), corticobasal degeneration (CBD), Pick´s disease among others. Tau is an unfolded protein which is found mainly in axons of mature and physiologically is involved in microtubule stability and axonal transport [1]. However, once tau becomes hyperphosphorylated it detaches from microtubule starting the aggregation process [2,3]. Pathological tau aggregates are able to activate glia cells that release cytotoxic factors, which cause pro inflammatory cytokines such as TNF-α, IL-1 and IL-6 and chemokines [4]. Tau phosphorylation is increased in both physiologically and pathological state [5], however phosphorylation is increased during development, suggesting that process is needed for neuronal plasticity [6]. Tau phosphorylation is an event highly regulated by kinases and phosphatases. Its balance is deregulated due to several stimuli such as oxidative stress [7]. Tau is able to form paired helical filaments closely related to neurofibrillary tangles [8,9]. Hyperphosphorylated tau protein is found in patients suffering with tauopathies in cerebrospinal fluid (CNS), which correlates well with hypocampal atrophy [10]. In addition, tauopathies have tau hyperphosphorylated as a hallmark; however, the degree of phosphorylation differs among them. In addition, it is important to notice that there is no single phosphorylation site associated to a particular tauopathy [5]. Moreover, tau has the propensity to form aggregates, since inside the full length protein (441 aminoacids) resides a region known as 4R (four microtubule binding domain) containing two hexapeptides 275 VQIINK 280 and 306 VQIVYK 311 both associated to β sheet formation [11]. Increased tau phosphorylation decreased its binding for microtubules. These species prone to form aggregates which are toxic in both cell and transgenic mouse model [12,13]. Despite that fact, there are evidences showing that soluble species and pre fibrils which are more related to toxicity [14]. An interesting UV raman spectroscopy study showed that at early stages, within the first hour, fibrillar aggregates possess a mixture of β-sheet and disordered content. Afterward, the UVRR spectra shows a consolidation in fibril structure, augmenting the content of β sheet [15], interesting is to remark that toxicity apparently reli...

show abstract

Tau Oligomers Impair Artificial Membrane Integrity and Cellular Viability

Cited by 170 publications

References 69 publications

Tau Trimers Are the Minimal Propagation Unit Spontaneously Internalized to Seed Intracellular Aggregation

Tau Trimers Are the Minimal Propagation Unit Spontaneously Internalized to Seed Intracellular Aggregation

HspB1 and Hsc70 chaperones engage distinct tau species and have different inhibitory effects on amyloid formation

Secondary Metabolites of Lichens as Both Anti-aggregative and Antioxidant Agents in Tauopathies

Contact Info

Product

Resources

About