Truncated tau from sporadic Alzheimer's disease suffices to drive neurofibrillary degeneration in vivo

Žilka, Norbert; Filipčík, Peter; Koson, Peter; Fialová, Ľubica; Škrabana, Rostislav; Žilková, Monika; Rolkova, Gabriela; Kontseková, Eva; Novák, Michal

doi:10.1016/j.febslet.2006.05.029

Cited by 225 publications

(215 citation statements)

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“…When truncated at the N terminus, tau cannot form filaments in cellfree systems, but may do so in vivo, and has been implicated in NFT formation and neurodegeneration (35,36). Given the granular appearance of the aggregates, another potential structural candidate for these aggregates are tau oligomers, which are monomeric or dimeric accumulations of highly phosphorylated or truncated tau (37,38). Tau oligomers have been detected in tau transgenic mice and in presymptomatic AD (1,(39)(40)(41).…”

Section: Discussionmentioning

confidence: 99%

Corticotropin-releasing factor receptor-dependent effects of repeated stress on tau phosphorylation, solubility, and aggregation

Rissman

Staup

Lee

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Exposure and/or sensitivity to stress have been implicated as conferring risk for development of Alzheimer's disease (AD). Although the basis for such a link remains unclear, we previously reported differential involvement of corticotropin-releasing factor receptor (CRFR) 1 and 2 in acute stress-induced tau phosphorylation (tau-P) and solubility in the hippocampus. Here we examined the role of CRFRs in tau-P induced by repeated stress and the structural manifestations of altered tau solubility. Robust tau-P responses were seen in WT and CRFR2 null mice exposed to repeated stress, which were sustained at even 24 h after the final stress exposure. A portion of phosphorylated tau in these mice was sequestered in detergent-soluble cellular fractions. In contrast, CRFR1 and CRFR double-KO mice did not exhibit repeated stress-induced alterations in tau-P or solubility. Similarly, treatment with CRFR1 antagonist attenuated repeated stress-induced tau-P. Using histochemical approaches in a transgenic CRFR1 reporter mouse line, we found substantial overlap between hippocampal CRFR1 expression and cells positive for phosphorylated tau after exposure to repeated stress. Ultrastructural analysis of negatively stained extracts from WT and CRFR2 null mice identified globular aggregates that displayed positive immunogold labeling for tau-P, as well as conformational changes in tau (MC1) seen in early AD. Given that repeated stress exposure results in chronic increases in hippocampal tau-P and its sequestration in an insoluble (and potentially prepathogenic) form, our data may define a link between stress and an AD-related pathogenic mechanism.neurofibrillary tangles | western blot | pathology | electron microscopy A lzheimer's disease (AD) is definitively characterized by the presence of β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs). NFTs are insoluble intracellular inclusions composed of aggregated hyperphosphorylated forms of the cytoskeletal protein tau that accumulate initially within the hippocampal formation (1). A critical step in NFT formation is thought to be the transition of these phosphorylated tau species into aggregated insoluble fibrils. Hyperphosphorylated tau has a reduced ability to bind microtubules and has been reported to self-aggregate into paired helical filaments (PHFs), which compose NFTs (2, 3). The development of NFTs is positively correlated with cognitive decline and neuronal loss in AD (4, 5).The majority of AD cases are of sporadic origin, with age the primary risk factor. In addition, recent work has implicated environmental influences, such as stress, as also conferring risk for the development of AD (6, 7). In line with this, stress exposure can increase Aβ production and induce deficits in hippocampal cell proliferation and contextual memory in AD transgenic mice (8, 9). Moreover, exposure to a variety of physiological stressors can activate tau kinases and induce tau phosphorylation (tau-P) in rodents (reviewed in refs. 10-16). We previously reported that acute exposure to an emo...

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Section: Discussionmentioning

confidence: 99%

Corticotropin-releasing factor receptor-dependent effects of repeated stress on tau phosphorylation, solubility, and aggregation

Rissman

Staup

Lee

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…In this study, we focused on truncated t protein, which has been shown to be a driving force behind neurofibrillary degeneration in transgenic rats expressing misfolded truncated t (44,45). We have previously demonstrated that in the transgenic rat brain, neurofibrillary lesions and axonal degeneration are closely associated with the distribution of reactive microglia and macrophages (40).…”

Section: Human Truncated T Stimulates Activation Of Microglia Throughmentioning

confidence: 99%

Misfolded Truncated Protein τ Induces Innate Immune Response via MAPK Pathway

Kováč

Žilka

Kazmerova

et al. 2011

The Journal of Immunology

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Neuroinflammation plays a key role in the pathogenesis of Alzheimer’s disease and related tauopathies. We have previously shown that expression of nonmutated human truncated τ (151-391, 4R), derived from sporadic Alzheimer's disease, induced neurofibrillary degeneration accompanied by microglial and astroglial activation in the brain of transgenic rats. The aim of the current study was to determine the molecular mechanism underlying innate immune response induced by misfolded truncated τ. We found that purified recombinant truncated τ induced morphological transformation of microglia from resting into the reactive phenotype. Simultaneously, truncated τ caused the release of NO, proinflammatory cytokines (IL-1β, IL-6, TNF-α), and tissue inhibitor of metalloproteinase-1 from the mixed glial cultures. Notably, when the pure microglial culture was activated with truncated τ, it displayed significantly higher levels of the proinflammatory cytokines, suggesting a key role of microglia in the τ-mediated inflammatory response. Molecular analysis showed that truncated τ increased the mRNA levels of three MAPKs (JNK, ERK1, p38β) and transcription factors AP-1 and NF-κB that ultimately resulted in enhanced mRNA expression of IL-1β, IL-6, TNF-α, and NO. Our results showed for the first time, to our knowledge, that misfolded truncated protein τ is able to induce innate immune response via a MAPK pathway. Consequently, we suggest that misfolded truncated protein τ represents a viable target for immunotherapy of Alzheimer’s disease.

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“…N-terminal truncated, MtBr containing, tau fragments exhibit an increased tendency to aggregate. 88,89 MtBr-fragments are readily secreted and may induce calpain 84 /caspase 85 activation in recipient neurons increased resulting in self-regenerating tau lesion propagation. (C) tau/PrP interactions in exosomal secretion.…”

Section: Discussionmentioning

confidence: 99%

Is tau ready for admission to the prion club?

Hall

Patuto

2012

Prion

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A ggregation-prone proteins associated with neurodegenerative disease, such as α-synuclein and β-amyloid, now appear to share key prion-like features with mammalian prion protein, such as the ability to recruit normal proteins to aggregates and to translocate between neurons. These features may shed light on the genesis of stereotyped lesion development patterns in conditions such as Alzheimer disease and Lewy body dementia. We discuss the qualifications of tau protein as a possible "prionoid" mediator of lesion spread based on recent characterizations of the secretion, uptake and transneuronal transfer of human tau isoforms in a variety of tauopathy models, and in human patients. In particular, we consider (1) the possibility that prionoid behavior of misprocessed tau in neurodegenerative disease may involve other aggregation-prone proteins, including PrP itself and (2) whether "prionlike" tau lesion propagation might include mechanisms other than protein-protein templating. Prions and TSEs as a General Model for Neurodegenerative DiseaseThe formation of abnormal protein aggregates provides a common element in the pathogenesis of the vast majority of neurodegenerative diseases in humans, including Alzheimer disease (AD), non-AD tauopathies, α-synucleinopathies such as Lewy body dementia, transmissible spongiform encephalopathies (TSEs), trinucleotide repeat diseases and amyotrophic lateral sclerosis. Since aggregate formation is generally considered (and has been modeled) as a cell-autonomous Is tau ready for admission to the prion club?Garth F. Hall* and Brian A. PatutoDepartment of Biological Sciences; University of Massachusetts Lowell; Lowell, MA USA process, investigations into the pathogenesis of most neurodegenerative diseases have until very recently focused on cytotoxicity mechanisms associated with aggregate formation. As a consequence, intercellular aspects of most neurodegenerative diseases have been relatively neglected until very recently, and remain poorly understood. An exception to this pattern has been the study of TSEs, in which the consequences of prion protein (PrP) misfolding were addressed at the organismal level years before meaningful studies of cellular mechanisms could be attempted. This is because the transmissability and bizarre epidemiology of these diseases made a basic understanding of the transmission mechanism prerequisite to any meaningful studies of TSE cytopathogenesis. However, during the 1980s and 1990s, PrP was progressively established as the necessary and sufficient agent for TSE transmission via the promulgation, systematic testing and validation of the "Prion Hypothesis." [1][2][3] Since then, the study of PrP biology and pathobiology at the molecular, cellular and organismal levels has led to a deepening appreciation of the subtlety with which specific misfolded conformers of PrP can reproduce and propagate disease-specific properties that define specific TSEs. Investigators have recently begun to use PrP propagation in TSEs as a model to address interneuronal aspect...

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Truncated tau from sporadic Alzheimer's disease suffices to drive neurofibrillary degeneration in vivo

Cited by 225 publications

References 31 publications

Corticotropin-releasing factor receptor-dependent effects of repeated stress on tau phosphorylation, solubility, and aggregation

Corticotropin-releasing factor receptor-dependent effects of repeated stress on tau phosphorylation, solubility, and aggregation

Misfolded Truncated Protein τ Induces Innate Immune Response via MAPK Pathway

Is tau ready for admission to the prion club?

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