Caspase activation precedes and leads to tangles

Calignon, Alix de; Fox, Leora M.; Pitstick, Rose; Carlson, George A.; Bacskai, Brian J.; Spires‐Jones, Tara L.; Hyman, Bradley T.

doi:10.1038/nature08890

Cited by 475 publications

(466 citation statements)

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“…To this end, a fluorescent indicator of caspase activation (FLICA) (27) was applied topically to the cortex of the brain in vivo and imaged with multiphoton microscopy. We found that most oxidized neurons were FLICA positive (39 of 44), suggesting a caspase-dependent programmed cell death in most of the neurons with oxidative stress (Fig.…”

Section: Resultsmentioning

confidence: 99%

Rapid cell death is preceded by amyloid plaque-mediated oxidative stress

Xie

Hou

Jiang

et al. 2013

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

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Neuronal loss is the ultimate outcome in a variety of neurodegenerative diseases and central nerve system disorders. Understanding the sequelae of events that leads to cell death would provide insight into neuroprotective approaches. We imaged neurons in the living brain of a mouse model of Alzheimer's disease that overexpresses mutant human amyloid precursor protein and presenilin 1 and followed the death of individual neurons in real time. This mouse model exhibited limited neurodegeneration and atrophy, but we were able to identify a small fraction of vulnerable cells that would not have been detectable by using standard approaches. By exploiting a genetically encoded reporter of oxidative stress, we identified susceptible neurons by their increased redox potential. The oxidative stress was most dramatic in neurites near plaques, propagated to cell bodies, and preceded activation of caspases that led to cell death within 24 h. Thus, local oxidative stress surrounding plaques contributes to longrange toxicity and selective neuronal death in Alzheimer's disease.in vivo imaging | reduction-oxidation sensitive GFP A lzheimer's disease (AD) is underscored by neurodegeneration and is the most common form of dementia. The pathological hallmarks of this disease include amyloid plaques, neurofibrillary tangles, and neuronal loss. Early-onset familial AD is caused by genetic mutations of amyloid precursor protein (APP) or presenilin 1 and 2 (PS1 and PS2). Although recent genetic studies have revealed risk factors for late onset AD, the pathogenic pathways for sporadic AD remain largely unknown. The development of mouse models of AD that develop senile plaques similar to those found in AD patients was a critical step in identifying the role of amyloid β (Aβ) on neuronal function. A major disappointment of most of the mouse models is the lack of overt neuronal loss that is a hallmark of the human disease. Many, in fact, have used this lack of neuronal death as evidence that amyloid is not relevant to dementia in AD. We and others (1-4) have identified structural and functional alterations of neurons in the brains of APP mice that implicate amyloid-mediated toxicity, but we have never detected neuronal death. The ability to monitor cell death in an experimental model provides the opportunity to intervene with neuroprotective agents that could be applied to the spectrum of neurodegenerative diseases and CNS disorders.We were able to identify vulnerable cells by quantitatively imaging the redox potential of neurons in the living brain. Our hypothesis was that amyloid-mediated increases in oxidative stress are the initiators of the toxic cascade that leads to cell loss. Accumulating evidence supports a role for oxidative stress in the pathogenesis of neuronal degeneration and death in AD (5-8). The evidence supporting oxidative stress in AD comes largely from postmortem samples and includes increased lipid peroxidation, decreased polyunsaturated fatty acids (9-12), increased protein oxidation (13,14), and DNA oxidation (15, ...

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Section: Resultsmentioning

confidence: 99%

Rapid cell death is preceded by amyloid plaque-mediated oxidative stress

Xie

Hou

Jiang

et al. 2013

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

Self Cite

146

120

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“…41 Although there is still considerable support for amyloid being a cause of AD, 42 there is also evidence to indicate that Casp6 can be upstream or parallel to Ab and NFT production: lack of correlation between Ab and memory performance despite a strong correlation with Casp6 and PHF-1 in aged hippocampi, 6 Casp6-dependent Ab production in human CNS primary neuron cultures, 15,16 Casp6-dependent, but Ab-independent, neuritic degeneration in APP-transfected human primary neurons, 14 and caspase activity leading to NFT in mice. 8 Targeting Casp6, in addition to Ab and NFT, may be required to efficiently prevent AD progression. In summary, we have shown that hCasp6 expression in mouse CA1 neurons induces neurodegeneration and memory deficits as observed in aged human individuals.…”

Section: Discussionmentioning

confidence: 99%

“…7 In mouse, caspase activity precedes and leads to the formation of NFT-like aggregation. 8 Casp6 activity is involved in axonal degeneration of mouse PNS neurons via amyloid precursor protein (APP) interaction with death receptor 6 9 and in nerve growth factor (NGF)-deprived dorsal root ganglion neurons. 10 Furthermore, Casp6-dependent axonal degeneration is modulated by NGF deprivation of the axonal compartment.…”

mentioning

confidence: 99%

Caspase-6 activity in the CA1 region of the hippocampus induces age-dependent memory impairment

et al. 2014

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Active Caspase-6 is abundant in the neuropil threads, neuritic plaques and neurofibrillary tangles of Alzheimer disease brains. However, its contribution to the pathophysiology of Alzheimer disease is unclear. Here, we show that higher levels of Caspase-6 activity in the CA1 region of aged human hippocampi correlate with lower cognitive performance. To determine whether Caspase-6 activity, in the absence of plaques and tangles, is sufficient to cause memory deficits, we generated a transgenic knock-in mouse that expresses a self-activated form of human Caspase-6 in the CA1. This Caspase-6 mouse develops agedependent spatial and episodic memory impairment. Caspase-6 induces neuronal degeneration and inflammation. We conclude that Caspase-6 activation in mouse CA1 neurons is sufficient to induce neuronal degeneration and age-dependent memory impairment. These results indicate that Caspase-6 activity in CA1 could be responsible for the lower cognitive performance of aged humans. Consequently, preventing or inhibiting Caspase-6 activity in the aged may provide an efficient novel therapeutic approach against Alzheimer disease. Cell Death and Differentiation (2014) 21, 696-706; doi:10.1038/cdd.2013; published online 10 January 2014The underlying molecular pathway for neuronal degeneration and dysfunction in Alzheimer's disease (AD) remains unknown. Yet, the identification of critical events initiating neuronal degeneration could provide a novel therapeutic approach to stem the progressive dementia of AD. We propose that Caspase-6 (Casp6), a cysteinyl protease of the caspase family, has a critical role in AD neuronal degeneration and cognitive impairment. Casp6 activity is intimately associated with the neuritic plaques (NP), neurofibrillary tangles (NFT), and neuropil threads (NPT) of AD. 1 Casp6 activity is abundant in familial AD 2 and at all stages of sporadic AD. 3 Although no Casp6 activity is present in younger brains, 1 several aged non-cognitively impaired (NCI) brains show significant amounts of Casp6 activity in the entorhinal cortex (ERC), 3 the first area showing NFT pathology in AD according to Braak staging. 4,5 Furthermore, higher levels of Casp6 activity in the ERC and cornu ammonis 1 (CA1) region of NCI brains correlate with lower episodic memory (EP) performance, one of the types of memory also affected early in AD. 6 Active Casp6 induces several parallel degenerative pathways associated with AD neuropathology. First, Casp6 activity disrupts the neuronal cytoskeleton. Casp6 cleaves neuronal microtubule protein alpha-tubulin, microtubuleassociated protein Tau, and actin-regulating post-synaptic density proteins, Spinophilin, Drebrin, and Actinins. 7 In mouse, caspase activity precedes and leads to the formation of NFT-like aggregation. 8 Casp6 activity is involved in axonal degeneration of mouse PNS neurons via amyloid precursor protein (APP) interaction with death receptor 6 9 and in nerve growth factor (NGF)-deprived dorsal root ganglion neurons. 10 Furthermore, Casp6-dependent axonal degeneration i...

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“…20,21,[31][32][33] Hence, caspase-mediated Tau cleavage is viewed as an early pathological event triggering NFT pathology and δTau as a critical toxic moiety underlying neurodegeneration. 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%

“…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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Caspase activation precedes and leads to tangles

Cited by 475 publications

References 30 publications

Rapid cell death is preceded by amyloid plaque-mediated oxidative stress

Rapid cell death is preceded by amyloid plaque-mediated oxidative stress

Caspase-6 activity in the CA1 region of the hippocampus induces age-dependent memory impairment

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

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