Inhibition of Tau Polymerization by Its Carboxy-Terminal Caspase Cleavage Fragment

Berry, Robert W.; Abraha, Aida; Lagalwar, Sarita; LaPointe, Nichole E.; Gamblin, T. Chris; Cryns, Vincent L.; Binder, Lester I.

doi:10.1021/bi027348m

Cited by 134 publications

(117 citation statements)

References 22 publications

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“…The MC1 conformation may involve the intramolecular interaction between the N-and C-termini of tau (folded conformation). Caspase-cleavage of tau may initiate the MC1 conformation by removing a portion of the C-terminus that inhibits tau aggregation in vitro (46), and allowing tau to adopt this conformation.…”

Section: Discussionmentioning

confidence: 99%

Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology

et al. 2004

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Neurofibrillary tangles (NFTs) are composed of abnormal aggregates of the cytoskeletal protein tau. Together with amyloid β (Aβ) plaques and neuronal and synaptic loss, NFTs constitute the primary pathological hallmarks of Alzheimer disease (AD). Recent evidence also suggests that caspases are activated early in the progression of AD and may play a role in neuronal loss and NFT pathology. Here we demonstrate that tau is cleaved at D421 (ΔTau) by executioner caspases. Following caspase-cleavage, ΔTau facilitates nucleation-dependent filament formation and readily adopts a conformational change recognized by the early pathological tau marker MC1. ΔTau can be phosphorylated by glycogen synthase kinase-3β and subsequently recognized by the NFT antibody PHF-1. In transgenic mice and AD brains, ΔTau associates with both early and late markers of NFTs and is correlated with cognitive decline. Additionally, ΔTau colocalizes with Aβ 1-42 and is induced by Aβ 1-42 in vitro. Collectively, our data imply that Aβ accumulation triggers caspase activation, leading to caspase-cleavage of tau, and that this is an early event that may precede hyperphosphorylation in the evolution of AD tangle pathology. These results suggest that therapeutics aimed at inhibiting tau caspase-cleavage may prove beneficial not only in preventing NFT formation, but also in slowing cognitive decline.

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Section: Discussionmentioning

confidence: 99%

Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology

et al. 2004

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“…C-terminal residues would be compatible with an amphiphilic R-helix which could interact with other domains of tau or partners of tau (9,11). The hexapeptide motifs in R2 and R3 (Figure 1) are predicted to form extended structure, ready to enter -sheet interactions.…”

Section: Discussionmentioning

confidence: 99%

Tau Paired Helical Filaments from Alzheimer's Disease Brain and Assembled in Vitro Are Based on β-Structure in the Core Domain

2004

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Tau protein, a neuronal microtubule-associated protein, forms insoluble fibers ("paired helical filaments") in Alzheimer's disease and other tauopathies. Conflicting views on the structure of the fibers have been proposed recently, ranging from mainly R-helical structure to mainly -sheet, or a mixture of mostly random coil and -sheet. We have addressed this issue by studying tau fibers immunopurified from Alzheimer brain tissue by a conformation-specific antibody and comparing them with fibers reassembled from recombinant tau or tau constructs in vitro, using a combination of electron microscopy and spectroscopic methods. Brain-derived fibers and reassembled fibers both exhibit a typical twisted appearance when examined by electron microscopy. The soluble tau protein is a natively unfolded protein dominated by random coil structure, whereas Alzheimer PHFs and reassembled fibers show a shift toward an increase in the level of -structure. The results support a model in which the repeat domain of tau (which lies within the core of PHFs) adopts an increasing level of -structure during aggregation, whereas the N-and C-terminal domains projecting away from the PHF core are mostly random coil.

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“…Neurons with active caspase-3 often showed Asp421-cleaved tau. Caspase-3 cleavage of tau is thought to induce abnormal conformations by removing part of the C-terminal region, which is essential to inhibit tau aggregation in vitro (29,30). Although early apoptosis also may represent a developmental-related phenomenon (11), it is clear that the cleavage of tau is a toxic process with potentially important neurodegenerative repercussions.…”

Section: A P O P T O S I S I N a T R A N S G E N I C M O D E L O F T mentioning

confidence: 99%

Apoptosis in Transgenic Mice Expressing the P301L Mutated Form of Human Tau

Ramalho

Viana

Castro

et al. 2008

Mol Med

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The rTg4510 mouse is a tauopathy model, characterized by massive neurodegeneration in Alzheimer's disease (AD)-relevant cortical and limbic structures, deficits in spatial reference memory, and progression of neurofibrillary tangles (NFT). In this study, we examined the role of apoptosis in neuronal loss and associated tau pathology. The results showed that DNA fragmentation and caspase-3 activation are common in the hippocampus and frontal cortex of young rTg4510 mice. These changes were associated with cleavage of tau into smaller intermediate fragments, which persist with age. Interestingly, active caspase-3 was often co-localized with cleaved tau. In vitro, fibrillar Aβ 1-42 resulted in nuclear fragmentation, caspase activation, and caspase-3-induced cleavage of tau. Notably, incubation with the antiapoptotic molecule tauroursodeoxycholic acid abrogated apoptosis-mediated cleavage of tau in rat cortical neurons. In conclusion, caspase-3-cleaved intermediate tau species occurred early in rTg54510 brains and preceded cell loss in Aβ-exposed cultured neurons. These results suggest a potential role of apoptosis in neurodegeneration.

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Inhibition of Tau Polymerization by Its Carboxy-Terminal Caspase Cleavage Fragment

Cited by 134 publications

References 22 publications

Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology

Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology

Tau Paired Helical Filaments from Alzheimer's Disease Brain and Assembled in Vitro Are Based on β-Structure in the Core Domain

Apoptosis in Transgenic Mice Expressing the P301L Mutated Form of Human Tau

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