The self-perpetuating tau truncation circle

Žilka, Norbert; Kováčech, Branislav; Baráth, Péter; Kontseková, Eva; Novák, Michal

doi:10.1042/bst20120015

Cited by 42 publications

(44 citation statements)

References 57 publications

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“…Tau undergoes various post-translational modifications, hyperphosphorylation being the most prominent and studied changes [10]. Mounting evidence suggests that not only the hyperphosphorylation, but also tau cleavage plays an important role in the progression of AD [11, 12]. N- and C-terminal fragmentation induces toxic tau aggregation in N2a cells [13].…”

Section: Introductionmentioning

confidence: 99%

“…When cleaved at Asp421 by caspase, tau assembles more rapidly and more extensively into tau filaments in vitro [14], suggesting that cleaved tau enhances polymerization kinetics and serves as a nucleation center, promoting the pathologic assembly of tau filaments [15, 16]. Caspases [11, 12, 17], the ubiquitin-proteasome system [18], and calpains [19, 20] are all implicated in tau cleavage.…”

Section: Introductionmentioning

confidence: 99%

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Hyperglycemia-Induced Tau Cleavage in vitro and in vivo: A Possible Link Between Diabetes and Alzheimer's Disease

Kim

Backus

et al. 2013

JAD

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Multiple lines of evidence link the incidence of diabetes to the development of Alzheimer’s Disease (AD). Patients with diabetes have a 50 to 75% increased risk of developing AD. In parallel, AD patients have a higher than normal tendency to develop type 2 diabetes or impaired fasting glucose. Tau is the major component of neurofibrillary tangles (NFT), one of the hallmarks of AD pathology. The current study examined the effect of hyperglycemia on tau modification. Glucose treatment of rat embryonic cortical neurons results in concentration-dependent apoptosis and caspase-3 activation. These changes are well correlated with glucose time- and concentration-dependent tau cleavage. Aβ treatment induces tau cleavage and when added together with glucose there is an additive effect on caspase activation, apoptosis and tau cleavage. Tau cleavage is partially blocked by the caspase inhibitor, ZVAD. Cleaved tau displays a punctate staining along the neurites and colocalizes with cleaved caspase-3 in the cytoplasm. Both type 1 and type 2 diabetic mice display increased tau phosphorylation in the brain. In agreement with the effects of glucose on tau modifications in vitro, there is increased tau cleavage in the brains of ob/ob mice; however, tau cleavage is not observed in type 1 diabetic mouse brains. Our study demonstrates that hyperglycemia is one of major factors that induce tau modification in both in vitro and in vivo models of diabetes. We speculate that tau cleavage in diabetic conditions (especially in type 2 diabetes) may be a key link for the increased incidence of AD in diabetic patients.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hyperglycemia-Induced Tau Cleavage in vitro and in vivo: A Possible Link Between Diabetes and Alzheimer's Disease

Kim

Backus

et al. 2013

JAD

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“…PHFs include hyperphosphorylated and truncated forms of Tau (4). The importance of a truncated form of Tau in disease progression has been underlined by the identification of various sizes of Tau species, ranging from 10 kDa to higher molecular mass, in aggregates of human AD brains (5). On the other hand, recent studies have demonstrated that injection of brain homogenates containing mutant Tau aggregates in the brain of transgenic mice expressing wild‐type human Tau can transmit Tau pathology, suggesting a prion‐like spread of Tau (6).…”

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confidence: 99%

The FK506-binding protein FKBP52in vitroinduces aggregation of truncated Tau forms with prion-like behavior

Giustiniani¹,

Guillemeau²,

Dounane³

et al. 2015

The FASEB Journal

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Tauopathies, including Alzheimer's disease (AD), are neurodegenerative diseases associated with the pathologic aggregation of human brain Tau protein. Neuronal Tau is involved in microtubule (MT) formation and stabilization. We showed previously that the immunophilin FK506-binding protein of MW ∼52 kDa (FKBP52) interferes with this function of full-length Tau and provokes aggregation of a disease-related mutant of Tau. To dissect the molecular interaction between recombinant human FKBP52 and Tau, here, we study the effect of FKBP52 on a functional Tau fragment (Tau-F4, Ser 208 -Ser 324 ) containing part of the proline-rich region and MT-binding repeats. Therefore, we perform MT assembly and light-scattering assays, blue native PAGE analysis, electron microscopy, and Tau seeding experiments in SH-SY5Y human neuroblastoma cells. We show that FKBP52 (6 mM) prevents MT formation generated by Tau-F4 (5 mM) and induces Tau-F4 oligomerization and aggregation. Electron microscopy analyses show granular oligomers and filaments of Tau-F4 after short-time FKBP52 incubation. We demonstrate that the terminal parts of Tau interfere with the effects of FKBP52. Finally, we find that FKBP52-induced Tau-F4 oligomers cannot only generate in vitro, direct conformational changes in full-length Tau and that their uptake into neuronal cells can equally lead to aggregation of wild-type endogenous Tau. This suggests a potential prion-like property of these particular Tau-F4 aggregates. Collectively, our results strengthen the hypothesis of FKBP52 involvement in the Tau pathogenicity process.-Giustiniani, J., Guillemeau, K., Dounane, O., Sardin, E., Huvent, I., Schmitt, A., Hamdane, M., Buée, L., Landrieu, I., Lippens, G., Baulieu, E. E., Chambraud, B. The FK506-binding protein FKBP52 in vitro induces aggregation of truncated Tau forms with prion-like behavior. FASEB J. 29, 3171-3181 (2015). www.fasebj.org

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“…It has been proposed that in disease conditions such as AD, rare species of toxic TAU exist that need to be removed in order to restore neuronal functions. Other possibilities include a role for non-coding RNAs including mi-RNAs and truncated forms of TAU in toxicity, as discussed elsewhere (Schonrock et al, 2010; Hebert et al, 2012; Zilka et al, 2012). As discussed here, simply reducing TAU levels may be therapeutically beneficial.…”

Section: Discussionmentioning

confidence: 99%

What Renders TAU Toxic

Götz¹,

Xia²,

Leinenga³

et al. 2013

Front. Neurol.

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TAU is a microtubule-associated protein that under pathological conditions such as Alzheimer’s disease (AD) forms insoluble, filamentous aggregates. When 20 years after TAU’s discovery the first TAU transgenic mouse models were established, one declared goal that was achieved was the modeling of authentic TAU aggregate formation in the form of neurofibrillary tangles. However, as we review here, it has become increasingly clear that TAU causes damage much before these filamentous aggregates develop. In fact, because TAU is a scaffolding protein, increased levels and an altered subcellular localization (due to an increased insolubility and impaired clearance) result in the interaction of TAU with cellular proteins with which it would otherwise either not interact or do so to a lesser degree, thereby impairing their physiological functions. We specifically discuss the non-axonal localization of TAU, the role phosphorylation has in TAU toxicity and how TAU impairs mitochondrial functions. A major emphasis is on what we have learned from the four available TAU knock-out models in mice, and the knock-out of the TAU/MAP2 homolog PTL-1 in worms. It has been proposed that in human pathological conditions such as AD, a rare toxic TAU species exists which needs to be specifically removed to abrogate TAU’s toxicity and restore neuronal functions. However, what is toxic in one context may not be in another, and simply reducing, but not fully abolishing TAU levels may be sufficient to abrogate TAU toxicity.

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The self-perpetuating tau truncation circle

Cited by 42 publications

References 57 publications

Hyperglycemia-Induced Tau Cleavage in vitro and in vivo: A Possible Link Between Diabetes and Alzheimer's Disease

Hyperglycemia-Induced Tau Cleavage in vitro and in vivo: A Possible Link Between Diabetes and Alzheimer's Disease

The FK506-binding protein FKBP52in vitroinduces aggregation of truncated Tau forms with prion-like behavior

What Renders TAU Toxic

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