It’s all about tau

Tapia-Rojas, Cheril; Cabezas-Opazo, Fabian; Deaton, Carol A.; Vergara, Erick H.; Johnson, Gail V.W.; Quintanilla, Rodrigo A.

doi:10.1016/j.pneurobio.2018.12.005

Cited by 148 publications

(136 citation statements)

References 332 publications

(453 reference statements)

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“…1,40 PD is characterised by α-synuclein phosphorylation and fibrillization. 37,39 The hyperphosphorylation of Tau may promote its aggregation in vitro. 9 However, whether Tau phosphorylation occurs in the MPTP model of PD remains unknown.…”

Section: Discussionmentioning

confidence: 99%

“…41 The phosphor Tau (p-Tau) shows its tendency of aggregation which occurs in Alzheimer disease (AD), Pick disease and frontotemporal dementia with parkinsonism-17. 37 The phosphorylation of Tau reduces its affinity for microtubules and accumulation in the brain and causing related Tauopathies, 17 and also impact on microtubule binding and induces microtubule instability. 4 Although p-Tau links to the pathogenesis of AD and other Tauopathies, recent studies have revealed that p-Tau has a relationship with PD.…”

Section: Introductionmentioning

confidence: 99%

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<p>Phosphorylation of Tau and α-Synuclein Induced Neurodegeneration in MPTP Mouse Model of Parkinson’s Disease</p>

Hu¹,

Hu²,

Liu³

et al. 2020

NDT

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Parkinson's disease (PD) is the second most common neurodegenerative disease. The α-Synuclein is a major component of Lewy bodies and Lewy neurites, the pathologic hallmark of PD. It is known that α-Synuclein is phosphorylated (p-α-Synuclein) in PD and tau-hyperphosphorylation (p-Tau) is also a pathologic feature of PD. However, the relationship between p-Synuclein and p-Tau in PD is not clear, in particular in the MPTP model of PD. The purpose of this study was to reveal their relationship in the mouse MPTP model. Methods: Firstly, the p-α-Synuclein, α-Synuclein, p-Tau and Tau protein levels were analyzed. Then, GSK3β activation was determined using immunoblot and immunohistochemical staining. Finally, the dopaminergic neurodegeneration was assessed using Tyrosine Hydroxylase (TH) staining and retrograde labeling and microglial marker were labeled. Microglial activation and nigrostriatal pathway degeneration were observed. Results: The results showed that p-α-Synuclein, α-Synuclein, p-Tau and Tau were upregulated in both hippocampus and substantia nigra of the PD mouse model. Furthermore, p-α-Synuclein and p-Tau were localized in the same regions of substantial nigra (SN) and dentate gyrus (DG) of hippocampus (Hippo). The activated form of GSK3β (phosphor GSK3β Y216) was increased in multiple brain areas. The GSK3β inhibitor AZD1080 injected in MPTP mice suppressed the expression of p-Tau and p-GSK3β and improved motor functions. Conclusion: These findings revealed that p-α-Synuclein and p-Tau proteins are key pathological events leading to neurodegeneration and motor dysfunctions in the mouse MPTP model of PD. Our data suggest that the interference with the GSK3β activity may be an effective approach for the treatment of PD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

<p>Phosphorylation of Tau and α-Synuclein Induced Neurodegeneration in MPTP Mouse Model of Parkinson’s Disease</p>

Hu¹,

Hu²,

Liu³

et al. 2020

NDT

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“…We will focus here on the disrupted inhibitory function of interneurons and consecutive hyperexcitability caused by Abeta -while we are aware of various other factors with potential roles for AD aetiology, such as vascular changes (19--21), neuroinflammation (22--25), genetics (26--28), environmental factors (29,30) and concomitant proteinopathies others than Abeta pathology (31,32). Beside Abeta there is a second molecular hallmark associated with the pathogenesis of AD: the phosphorylated Tau 'tubulin--associated unit' protein (8,33,34) which contributes to microtubule stability in the neural cytoskeleton (34). One major argument in favor of the more prominent involvement of Abeta in the pathogenesis of AD, in contrast to Tau, is its higher specificity to AD and its appearance in the early familial variants of AD, where the molecular pathway is better understood (14,18,35).…”

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confidence: 99%

Linking molecular pathways and large-scale computational modeling to assess candidate disease mechanisms and pharmacodynamics in Alzheimer’s disease

Stefanovski

Triebkorn

Spiegler

et al. 2019

Preprint

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Introduction. While the prevalence of neurodegenerative diseases associated with dementia such as Alzheimer's disease (AD) increases, our knowledge on the underlying mechanisms, outcome predictors, or therapeutic targets is limited. In this work, we demonstrate how computational multi--scale brain modelling links phenomena of different scales and therefore identifies potential disease mechanisms leading the way to improved diagnostics and treatment. Methods. The Virtual Brain (TVB; thevirtualbrain.org) neuroinformatics platform allows standardized large--scale structural connectivity--based simulations of whole brain dynamics. We provide proof of concept for a novel approach that quantitatively links the effects of altered molecular pathways onto neuronal population dynamics. As a novelty, we connect chemical compounds measured with positron emission tomography (PET) with neural function in TVB addressing the phenomenon of hyperexcitability in AD related to the protein amyloid beta (Abeta). We construct personalized virtual brains based on individual PET derived distributions of Abeta in patients with mild cognitive impairment (MCI, N=8) and Alzheimer's Disease (AD, N=10) and in age--matched healthy controls (HC, N=15) using data from ADNI--3 data base (http://adni.lni.usc.edu). In the personalized virtual brains, individual Abeta burden modulates regional inhibition, leading to disinhibition and hyperexcitation with high Abeta loads. We analyze simulated regional neural activity and electroencephalograms (EEG). Results. Known empirical alterations of EEG in patients with AD compared to HCs were reproduced by simulations. The virtual AD group showed slower frequencies in simulated local field potentials and EEG compared to MCI and HC groups. The heterogeneity of the Abeta load is crucial for the virtual EEG slowing which is absent for control models with homogeneous Abeta distributions. Slowing phenomena primarily affect the network hubs, independent of the spatial distribution of Abeta. Modeling the N--methyl--D--aspartate (NMDA) receptor antagonism of memantine in local population models, reveals potential functional reversibility of the observed large--scale alterations (reflected by EEG slowing) in virtual AD brains. Discussion. We demonstrate how TVB enables the simulation of systems effects caused by pathogenetic molecular candidate mechanisms in human virtual brains.

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“…Tau protein has multiple normal functions including the modulation of microtubule stability, axonal transport, modulation of signaling pathways, and adult neurogenesis [6]. Recent work has shown that toxicity is mediated by a gain of toxic function caused by tau that has become modified by conformational changes accompanied by oligomer formation and aggregation.…”

Section: Introductionmentioning

confidence: 99%

In Vivo Validation of a Small Molecule Inhibitor of Tau Self-Association in htau Mice

Davidowitz

Krishnamurthy

Lopez

et al. 2020

JAD

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Tau oligomers have been shown to transmit tau pathology from diseased neurons to healthy neurons through seeding, tau misfolding, and aggregation that is thought to play an influential role in the progression of Alzheimer's disease (AD) and related tauopathies. To develop a small molecule therapeutic for AD and related tauopathies, we have developed in vitro and cellular assays to select molecules inhibiting the first step in tau aggregation, the self-association of tau into oligomers. In vivo validation studies of an optimized lead compound were independently performed in the htau mouse model of tauopathy that expresses the human isoforms of tau without inherited tauopathy mutations that are irrelevant to AD. Treated mice did not show any adverse events related to the compound. The lead compound significantly reduced the level of self-associated tau and total and phosphorylated insoluble tau aggregates. The dose response was linear with respect to levels of compound in the brain. A confirmatory study was performed with male htau mice that gave consistent results. The results validated our screening approach by showing that targeting tau self-association can inhibit the entire tau aggregation pathway by using the selected and optimized lead compound whose activity translated from in vitro and cellular assays to an in vivo model of tau aggregation.

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It’s all about tau

Cited by 148 publications

References 332 publications

<p>Phosphorylation of Tau and α-Synuclein Induced Neurodegeneration in MPTP Mouse Model of Parkinson’s Disease</p>

<p>Phosphorylation of Tau and α-Synuclein Induced Neurodegeneration in MPTP Mouse Model of Parkinson’s Disease</p>

Linking molecular pathways and large-scale computational modeling to assess candidate disease mechanisms and pharmacodynamics in Alzheimer’s disease

In Vivo Validation of a Small Molecule Inhibitor of Tau Self-Association in htau Mice

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