A Brief Overview of Tauopathy: Causes, Consequences, and Therapeutic Strategies

Orr, Miranda E.; Sullivan, Anna C.; Frost, Bess

doi:10.1016/j.tips.2017.03.011

Cited by 186 publications

(163 citation statements)

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“…To investigate whether the findings in human AD neurons and transgenic mice translated to human brains with pure tauopathy (i.e., NFT pathology without other protein aggregates such as Aβ), we acquired human brain tissue with histopathologically confirmed progressive supranuclear palsy (PSP; Table 1 for patient characteristics). PSP is an age‐associated tauopathy that clinically manifests as parkinsonism with additional motor abnormalities and cognitive dysfunction (Orr et al, 2017) and is neuropathologically defined by the accumulation of four‐repeat (4R) tau, NFTs, gliosis, and neurodegeneration (Flament, Delacourte, Verny, Hauw, & Javoy‐Agid, 1991). Consistent with the results from transgenic mice, CDKN2A was upregulated in PSP brains ( p = 0.0415, Figure 4g) and expression correlated with NFT deposition, specifically in the parietal lobe (ANOVA, p = 0.0008; Kendall's Tau rank correlation, p = 0.059, Figure 4h).…”

Section: Resultsmentioning

confidence: 99%

“…The accumulation of tau protein is the most common pathology among these diseases making tau an appealing molecular target for intervention (Orr, Sullivan, & Frost, 2017). Tau‐containing neurofibrillary tangles (NFTs) closely track with disease severity in human AD (Arriagada, Growdon, Hedley‐Whyte, & Hyman, 1992); however, NFT‐containing neurons are long‐lived and do not induce immediate cell death (de Calignon, Spires‐Jones, Pitstick, Carlson, & Hyman, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Tau protein aggregation is associated with cellular senescence in the brain

et al. 2018

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Tau protein accumulation is the most common pathology among degenerative brain diseases, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), traumatic brain injury (TBI), and over twenty others. Tau‐containing neurofibrillary tangle (NFT) accumulation is the closest correlate with cognitive decline and cell loss (Arriagada, Growdon, Hedley‐Whyte, & Hyman, 1992), yet mechanisms mediating tau toxicity are poorly understood. NFT formation does not induce apoptosis (de Calignon, Spires‐Jones, Pitstick, Carlson, & Hyman, 2009), which suggests that secondary mechanisms are driving toxicity. Transcriptomic analyses of NFT‐containing neurons microdissected from postmortem AD brain revealed an expression profile consistent with cellular senescence. This complex stress response induces aberrant cell cycle activity, adaptations to maintain survival, cellular remodeling, and metabolic dysfunction. Using four AD transgenic mouse models, we found that NFTs, but not Aβ plaques, display a senescence‐like phenotype. Cdkn2a transcript level, a hallmark measure of senescence, directly correlated with brain atrophy and NFT burden in mice. This relationship extended to postmortem brain tissue from humans with PSP to indicate a phenomenon common to tau toxicity. Tau transgenic mice with late‐stage pathology were treated with senolytics to remove senescent cells. Despite the advanced age and disease progression, MRI brain imaging and histopathological analyses indicated a reduction in total NFT density, neuron loss, and ventricular enlargement. Collectively, these findings indicate a strong association between the presence of NFTs and cellular senescence in the brain, which contributes to neurodegeneration. Given the prevalence of tau protein deposition among neurodegenerative diseases, these findings have broad implications for understanding, and potentially treating, dozens of brain diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Tau protein aggregation is associated with cellular senescence in the brain

et al. 2018

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“…In contrast to AD, numerous pathogenic mutations in MAPT gene have been found in the autosomal dominantly inherited dementia FTDP‐17, proving that Tau pathology alone is sufficient to cause neurodegeneration . There are over 50 identified mutations in MAPT that are responsible for FTDP‐17, and most of them occur in the microtubule binding domain of Tau . It has been demonstrated that mutations in MAPT can stimulate fibrillization of Tau even in the absence of polyanionic inducers .…”

Section: Molecular Bases Of Tau Pathology In Tauopathiesmentioning

confidence: 99%

“…63 There are over 50 identified mutations in MAPT that are responsible for FTDP-17, and most of them occur in the microtubule binding domain of Tau. 63,72 It has been demonstrated that mutations in MAPT can stimulate fibrillization of Tau even in the absence of polyanionic inducers. 73 Some Tau mutants have increased tendencies to aggregate into PHFs.…”

Section: Molecular Bases Of Tau Pathology In Tauopathiesmentioning

confidence: 99%

Amyloidogenesis of Tau protein

2017

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The role of microtubule-associated protein Tau in neurodegeneration has been extensively investigated since the discovery of Tau amyloid aggregates in the brains of patients with Alzheimer's disease (AD). The process of formation of amyloid fibrils is known as amyloidogenesis and attracts much attention as a potential target in the prevention and treatment of neurodegenerative conditions linked to protein aggregation. Cerebral deposition of amyloid aggregates of Tau is observed not only in AD but also in numerous other tauopathies and prion diseases. Amyloidogenesis of intrinsically unstructured monomers of Tau can be triggered by mutations in the Tau gene, post-translational modifications, or interactions with polyanionic molecules and aggregation-prone proteins/peptides. The self-assembly of amyloid fibrils of Tau shares a number of characteristic features with amyloidogenesis of other proteins involved in neurodegenerative diseases. For example, in vitro experiments have demonstrated that the nucleation phase, which is the rate-limiting stage of Tau amyloidogenesis, is shortened in the presence of fragmented preformed Tau fibrils acting as aggregation templates ("seeds"). Accordingly, Tau aggregates released by tauopathy-affected neurons can spread the neurodegenerative process in the brain through a prion-like mechanism, originally described for the pathogenic form of prion protein. Moreover, Tau has been shown to form amyloid strains-structurally diverse self-propagating aggregates of potentially various pathological effects, resembling in this respect prion strains. Here, we review the current literature on Tau aggregation and discuss mechanisms of propagation of Tau amyloid in the light of the prion-like paradigm.

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“…Its conversion into pathogenic form, leads to its aggregation and formation 2 of neurofibrillary tangles (NFTs) which eventually form the basis of the tau pathogenesis [2]. Tau aggregation is driven by a variety of factors including post translation modifications such as phosphorylation, mutations of the MAPT (microtubule associated protein tau) gene, injury of the brain, atypical expression of tau isoforms, and spread from the neighbouring cells [3].…”

Section: Introductionmentioning

confidence: 99%

Age dependent trans-cellular propagation of human tau aggregates inDrosophiladisease models

Aqsa

Sarkar

2020

Preprint

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Tauopathies is a class of neurodegenerative disorders which involves the transformation of physiological tau into pathogenic tau. One of the prime causes reported to drive this conversion is tau hyperphosphorylation and the subsequent propagation of pathogenic protein aggregates across the nervous system. Although past attempts have been made to deduce the details of tau propagation, yet not much is known about its mechanism. A better understanding of this aspect of disease pathology can prove to be beneficial for the development of diagnostic and therapeutic approaches. In our work, we utilize the plethora of advantages procured by Drosophila to introduce a novel in-vivo tauopathy propagation model. For the first time, we demonstrate that the human tau (h-tau) possesses an intrinsic property to spread trans-cellularly in the fly nervous system irrespective of the tau allele or the neuronal tissue type. Aggregate migration restricted by targeted down-regulation of a specific kinase, elucidates the role of hyper-phosphorylation in its movement. On the contrary to the previous models, the present system enables a rapid, convenient and robust in-vivo study of tau migration pathology. Henceforth, the developed model would not only be immensely helpful in uncovering the mechanistic in-depths of tau propagation pathology but also aid in modifier and/or drug screening for amelioration of tauopathies.

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A Brief Overview of Tauopathy: Causes, Consequences, and Therapeutic Strategies

Cited by 186 publications

References 113 publications

Tau protein aggregation is associated with cellular senescence in the brain

Tau protein aggregation is associated with cellular senescence in the brain

Amyloidogenesis of Tau protein

Age dependent trans-cellular propagation of human tau aggregates inDrosophiladisease models

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