Caspase-cleaved tau exhibits rapid memory impairment associated with tau oligomers in a transgenic mouse model

Kim, Young Doo; Choi, Hyunwoo; Lee, Won Jae; Park, Hyejin; Kam, Tae In; Hong, Se Hoon; Nah, Jihoon; Jung, Sunmin; Shin, Byung Seop; Lee, Huikyong; Choi, Tae Yong; Choo, Hyosun; Kim, Kyung Keun; Choi, Se Young; Kayed, Rakez; Jung, Yong Keun

doi:10.1016/j.nbd.2015.12.006

Cited by 59 publications

(48 citation statements)

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“…However, NFT accumulation alone may be insufficient to cause cell death, as neuropathological studies in AD patients suggest that neuronal loss and cognitive deficits precede NFT formation(Haroutunian et al , 2007). Supporting this, animal models show that tau oligomers appear prior to NFTs and contribute to learning and memory deficits and neuronal cell death, while NFTs are not associated with neuronal death(Lasagna-Reeves et al , 2011b, Cowan et al , 2012, Cook et al , 2015, Kim et al , 2016). …”

Section: Introductionmentioning

confidence: 80%

Potential mechanisms and implications for the formation of tau oligomeric strains

Gerson

Mudher

Kayed

2016

Critical Reviews in Biochemistry and Molecular Biology

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The culmination of many years of increasing research into the toxicity of tau aggregation in neurodegenerative disease has led to the consensus that soluble, oligomeric forms of tau are likely the most toxic entities in disease. While tauopathies overlap in the presence of tau pathology, each disease has a unique combination of symptoms and pathological features, however, most study into tau has grouped tau oligomers and studied them as a homogenous population. Established evidence from the prion field combined with the most recent tau and amyloidogenic protein research suggests that tau is a prion-like protein, capable of seeding the spread of pathology throughout the brain. Thus, it is likely that tau may also form prion-like strains or diverse conformational structures that may differ by disease and underlie some of the differences in symptoms and pathology in neurodegenerative tauopathies. The development of techniques and new technology for the detection of tau oligomeric strains may therefore lead to more efficacious diagnostic and treatment strategies for neurodegenerative disease.

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Section: Introductionmentioning

confidence: 80%

Potential mechanisms and implications for the formation of tau oligomeric strains

Gerson

Mudher

Kayed

2016

Critical Reviews in Biochemistry and Molecular Biology

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“…21,31,34,35 However, the data supporting a pathogenic role of δTau are correlative and/or based on aberrant overexpression of Tau and δTau. 34,36,37 Thus, the possibility that cleavage of Tau by caspases represents a negative feedback mechanism aimed to eliminate toxic forms of Tau and/or to generate 'beneficial' Tau fragments must still be considered.…”

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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“…Next, we evaluated if C-terminally caspase-3 cleaved tau, TauC3, was present in HMW AD tau. TauC3 has previously been shown to cause mitochondrial stress when overexpressed in cells and neurons [6,14,16,17]. Using an antibody against the caspase-3 cleavage site at D421, anti-TauC3, we were able to detect TauC3 in the HMW protein fraction of AD brain on an aggregate preserving semi-denaturing detergent agarose gel electrophoresis (SDD-AGE) blot (Fig 1C).…”

Section: Resultsmentioning

confidence: 74%

Characterization of TauC3 antibody and demonstration of its potential to block tau propagation

et al. 2017

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The spread of neurofibrillary tangle (NFT) pathology through the human brain is a hallmark of Alzheimer’s disease (AD), which is thought to be caused by the propagation of “seeding” competent soluble misfolded tau. “TauC3”, a C-terminally truncated form of tau that is generated by caspase-3 cleavage at D421, has previously been observed in NFTs and has been implicated in tau toxicity. Here we show that TauC3 is found in the seeding competent high molecular weight (HMW) protein fraction of human AD brain. Using a specific TauC3 antibody, we were able to substantially block the HMW tau seeding activity of human AD brain extracts in an in vitro tau seeding FRET assay. We propose that TauC3 could contribute to the templated tau misfolding that leads to NFT spread in AD brains.

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Caspase-cleaved tau exhibits rapid memory impairment associated with tau oligomers in a transgenic mouse model

Cited by 59 publications

References 48 publications

Potential mechanisms and implications for the formation of tau oligomeric strains

Potential mechanisms and implications for the formation of tau oligomeric strains

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

Characterization of TauC3 antibody and demonstration of its potential to block tau propagation

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