Conformational change as one of the earliest alterations of tau in Alzheimer's disease

Weaver, Charles L.; Espinoza, Marisol; Kress, Yvonne; Davies, Peter

doi:10.1016/s0197-4580(00)00157-3

Cited by 291 publications

(272 citation statements)

References 37 publications

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“…MC1 is a conformation‐dependent antibody that recognizes an early pathological Tau conformation (Weaver et al ., 2000). As showed in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We found that the conformational change of Tau is significant after normalization of the bands with GADPH antibody (2.5‐fold) and remains slightly significant after normalization with total Tau (1.6‐fold). Because the conformational change recognized by MC1 is found in PHF, but not in normal brain, it has been suggested that the formation of the MC1 epitope is one of the earliest pathological alterations of Tau in AD (Weaver et al ., 2000). For this reason, we presumed that the effect mediated by Aβ142 monomers on conformation of Tau is not invalidated by the increase of total Tau.…”

Section: Resultsmentioning

confidence: 99%

“…Our experiments show that Aβ monomers, but not oligomers, after 3 h of intraventricular injection in mice expressing wild‐type human Tau, change Tau conformation, displaying an epitope present only in pathological Tau aggregates (Weaver et al ., 2000). In the same experimental conditions, Aβ monomers induce two phosphorylated epitopes not present in normal Tau (Ser396 and Ser422) and activate GSK3β and MAPK, two kinases responsible for phosphorylation at these two residues.…”

Section: Discussionmentioning

confidence: 99%

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Beta‐amyloid 1‐42 monomers, but not oligomers, produce PHF ‐like conformation of Tau protein

et al. 2016

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SummaryThe mechanistic relationship between amyloid β1‐42 (Aβ1‐42) and the alteration of Tau protein are debated. We investigated the effect of Aβ1‐42 monomers and oligomers on Tau, using mice expressing wild‐type human Tau that do not spontaneously develop Tau pathology. After intraventricular injection of Aβ1‐42, mice were sacrificed after 3 h or 4 days. The short‐lasting treatment with Aβ monomers, but not oligomers, showed a conformational PHF‐like change of Tau, together with hyperphosphorylation. The same treatment induced increase in concentration of GSK3 and MAP kinases. The inhibition of the kinases rescued the Tau changes. Aβ monomers increased the levels of total Tau, through the inhibition of proteasomal degradation. Aβ oligomers reproduced all the aforementioned alterations only after 4 days of treatment. It is known that Aβ1‐42 monomers foster synaptic activity. Our results suggest that Aβ monomers physiologically favor Tau activity and dendritic sprouting, whereas their excess causes Tau pathology. Moreover, our study indicates that anti‐Aβ therapies should be targeted to Aβ1‐42 monomers too.

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“…MC1 is a conformation‐dependent antibody that recognizes an early pathological Tau conformation (Weaver et al ., 2000). As showed in Fig.…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Beta‐amyloid 1‐42 monomers, but not oligomers, produce PHF ‐like conformation of Tau protein

et al. 2016

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“…Antibodies developed against pathological tau have helped to identify these changes. An aberrant folded conformational change in tau, recognized with antibody MC1, appears to be one of the earliest tau pathological events (9)(10)(11)(12). The antibody AT8 recognizes tau phosphorylated at both serine 202 and threonine 205, which are the first residues to be hyperphosphorylated, whereas the antibody PHF-1 recognizes phosphorylation at serines 396 and 404 and reacts with more mature hyperphosphorylated forms of tau found primarily within late-stage tangles (13)(14)(15).…”

Section: Introductionmentioning

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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“…In particular, we observed that compared with controls, P301S‐treated mice had significantly decreased levels of tau phosphorylation at specific epitopes, which have been implicated in the development of the tau neurofibrillary tangles pathology (Kelleher, Garwood, Hanger, Anderton & Noble, 2007; Weaver, Espinoza, Kress & Davies, 2000). By contrast, no differences between the two groups of mice were observed when the levels of total soluble tau were measured.…”

Section: Discussionmentioning

confidence: 87%

Antileukotriene therapy by reducing tau phosphorylation improves synaptic integrity and cognition of P301S transgenic mice

2018

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SummaryThe 5‐lipoxygenase (5LO) is a source of inflammatory leukotrienes and is upregulated in Alzheimer's disease and related tauopathies. However, whether it directly modulates tau phosphorylation and the development of its typical neuropathology in the absence of Aβ or is a secondary event during the course of the disease pathogenesis remains to be fully elucidated. The goal of this study was to evaluate the effect that pharmacologic blockade of this inflammatory pathway has on the phenotype of a transgenic mouse model of tauopathy, the P301S mice. Starting at 3 months of age, P301S mice were randomized to receive zileuton, a specific 5LO blocker, for 7 months; then, its effect on their behavioral deficits and neuropathology was assessed. Inhibition of leukotrienes formation was associated with a reduction in tau phosphorylation and an amelioration of memory and learning as well as synaptic integrity, which were secondary to a downregulation of the cdk5 kinase pathway. Our results demonstrate that the 5LO enzyme is a key player in modulating tau phosphorylation and pathology and that blockade of its enzymatic activity represents a desirable disease‐modifying therapeutic approach for tauopathy.

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Conformational change as one of the earliest alterations of tau in Alzheimer's disease

Cited by 291 publications

References 37 publications

Beta‐amyloid 1‐42 monomers, but not oligomers, produce PHF ‐like conformation of Tau protein

Beta‐amyloid 1‐42 monomers, but not oligomers, produce PHF ‐like conformation of Tau protein

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

Antileukotriene therapy by reducing tau phosphorylation improves synaptic integrity and cognition of P301S transgenic mice

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