Constitutive secretion of tau protein by an unconventional mechanism

Chai, Xiyun; Dage, Jeffrey L.; Citron, Martin

doi:10.1016/j.nbd.2012.05.021

Cited by 205 publications

(202 citation statements)

References 47 publications

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“…Recent data suggest that a fraction of Tau protein is localized extracellularly. [1][2][3][4] However, the biological function of extracellular tau is unknown.…”

Section: Introductionmentioning

confidence: 99%

Abolishing Tau cleavage by caspases at Aspartate421 causes memory/synaptic plasticity deficits and pre-pathological Tau alterations

et al. 2017

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TAU mutations are genetically linked to fronto-temporal dementia (FTD) and hyper-phosphorylated aggregates of Tau form neurofibrillary tangles (NFTs) that constitute a pathological hallmark of Alzheimer disease (AD) and FTD. These observations indicate that Tau has a pivotal role in the pathogenesis of neurodegenerative disorders. Tau is cleaved by caspases at Aspartate 421 , to form a Tau metabolite known as δTau; δTau is increased in AD, due to the hyper-activation of caspases in AD brains. δTau is considered a critical toxic moiety underlying neurodegeneration, which initiates and facilitates NFT formation. As Tau is a therapeutic target in neurodegeneration, it is important to rigorously determine whether δTau is a toxic Tau species that should be pharmacologically attacked. To directly address these questions, we have generated a knock-in (KI) mouse called Tau DN -that expresses a Tau mutant that cannot be cleaved by caspases. Tau DN mice present short-term memory deficits and synaptic plasticity defects. Moreover, mice carrying two mutant Tau alleles show increased total insoluble hyper-phosphorylated Tau in the forebrain. These data are in contrast with the concept that δTau is a critical toxic moiety underlying neurodegeneration, and suggest that cleavage of Tau by caspases represents a negative feedback mechanism aimed to eliminate toxic Tau species. Alternatively, it is possible that either a reduction or an increase in δTau leads to synaptic dysfunction, memory impairments and Tau pathology. Both possibilities will have to be considered when targeting caspase cleavage of Tau in AD therapy.

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“…Recent data suggest that a fraction of Tau protein is localized extracellularly. [1][2][3][4] However, the biological function of extracellular tau is unknown.…”

Section: Introductionmentioning

confidence: 99%

Abolishing Tau cleavage by caspases at Aspartate421 causes memory/synaptic plasticity deficits and pre-pathological Tau alterations

et al. 2017

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“…In contrast, increased CSF tau seems to reflect the neurodegeneration observed in these mice, consistent with an increased cellular release of tau in disease [52]. However, tau levels do not correlate with lactate dehydrogenase or tubulin release into the media [53,54], implying that release is not due to increased cell death. This observation is supported by evidence that monomeric tau secretion is an active process, as tau release is inhibited at low temperatures [53], and has been linked to synaptic activity [55].…”

Section: Escape Of Aggregates From Neuronsmentioning

confidence: 69%

“…2 Several explanations have been proposed for tau release. These include unconventional secretion directly into the media [53,54], vesicle-associated release [56] and exosomeassociated release [57,58]. While certain studies show a subset of secreted tau is found in the exosomal fraction of conditioned media [58], others show little to no tau in this fraction [53,54].…”

Section: Escape Of Aggregates From Neuronsmentioning

confidence: 99%

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Prion-Like Propagation of Protein Aggregation and Related Therapeutic Strategies

Kaufman

Diamond

2013

Neurotherapeutics

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“…34,35 It is secreted from cells by unconventional exocytosis or exosome [36][37][38] and its aggregates are taken up by cells via a hitherto unknown mechanism. 39 In addition, extracellular tau has been shown to be toxic to cultured neuronal cells, 40 and prion-like intercellular spreading of tau aggregates has been reported both in vivo and in vitro.…”

Section: Introductionmentioning

confidence: 99%

Proteolytic clearance of extracellular α-synuclein as a new therapeutic approach against Parkinson disease

Park

Kim

2013

Prion

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Constitutive secretion of tau protein by an unconventional mechanism

Cited by 205 publications

References 47 publications

Abolishing Tau cleavage by caspases at Aspartate421 causes memory/synaptic plasticity deficits and pre-pathological Tau alterations

Abolishing Tau cleavage by caspases at Aspartate421 causes memory/synaptic plasticity deficits and pre-pathological Tau alterations

Prion-Like Propagation of Protein Aggregation and Related Therapeutic Strategies

Proteolytic clearance of extracellular α-synuclein as a new therapeutic approach against Parkinson disease

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