Caspase activation in the limbic cortex of subjects with early Alzheimer's disease

Gastard, Myriam; Troncoso, Juan C.; Koliatsos, Vassilis E.

doi:10.1002/ana.10680

Cited by 102 publications

(60 citation statements)

References 22 publications

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“…These enzymes can be broadly divided into initiator and executioner caspases, with the former functioning to initiate apoptosis by activating executioner caspases and the latter acting on downstream effector substrates that result in the progression of apoptosis and the appearance of hallmark morphological changes such as cell shrinkage, nuclear fragmentation, and membrane blebbing (19). Increasing evidence suggests that caspases are activated in the AD brain (20)(21)(22)(23)(24)(25)(26). Furthermore, components of the neuronal cytoskeleton, including tau, are targeted by caspases following apoptotic stimuli (23,(27)(28)(29)(30)(31)(32)(33)(34).…”

Section: Introductionmentioning

confidence: 99%

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

Rissman¹,

Poon²,

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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Section: Introductionmentioning

confidence: 99%

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

Rissman¹,

Poon²,

et al. 2004

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“…Apoptosis is a genetically programmed cell death pathway that typically involves caspase activation and distinct morphological changes in the cell. Neurons exhibiting apoptotic features have been observed in postmortem tissue of individuals affected by stroke and from patients diagnosed with Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS) (Tatton et al, 1998;Martin, 1999;Gastard et al, 2003;Chan, 2004). Furthermore, a number of studies have demonstrated that molecular and pharmacological inhibitors of caspases can reduce or delay neuronal cell death in animal models of cerebral ischemia and neurodegenerative disease (Li, 2000;Le et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Puma Is a Dominant Regulator of Oxidative Stress Induced Bax Activation and Neuronal Apoptosis

Steckley¹,

Karajgikar²,

Dale³

et al. 2007

J. Neurosci.

133

144

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Oxidative stress has been implicated as a key trigger of neuronal apoptosis in stroke and neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. The Bcl-2 homology 3 (BH3)-only subfamily of Bcl-2 genes consists of multiple members that can be activated in a cell-type-and stimulus-specific manner to promote cell death. In the present study, we demonstrate that, in cortical neurons, oxidative stress induces the expression of the BH3-only members Bim, Noxa, and Puma. Importantly, we have determined that Puma؊/؊ neurons, but not Bim؊/؊ or Noxa؊/؊ neurons, are remarkably resistant to the induction of apoptosis by multiple oxidative stressors. Furthermore, we have determined that Bcl-2-associated X protein (Bax) is also required for oxidative stress induced cell death and that Puma plays a dominant role in regulating Bax activation. Specifically, we have established that the induction of Puma, but not Bim or Noxa, is necessary and sufficient to induce a conformational change in Bax to its active state, its translocation to the mitochondria and mitochondrial membrane permeabilization. Finally, we demonstrate that whereas both Puma and Bim EL can bind to the antiapoptotic family member Bcl-X L , only Puma was found to associate with Bax. This suggests that in addition to neutralizing antiapoptotic members, Puma may play a dominant role by complexing with Bax and directly promoting its activation. Overall, we have identified Puma as a dominant regulator of oxidative stress induced Bax activation and neuronal apoptosis, and suggest that Puma may be an effective therapeutic target for the treatment of a number of neurodegenerative conditions.

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“…In addition, activation of caspase 3 was found to occur in the parahippocampal gyrus in brains from patients with mild forms of Alzheimer's disease. Caspase 3 immunoreactivity was also co-localized with paired helical filaments in neurons, suggesting that caspase 3 activation may contribute to the formation of neurofibrillary tangles [79]. This premise was further supported by a study that demonstrated the existence of fodrin caspase-cleavage product in the hippocampus of Alzheimer's patients, which was co-localized with neurofibrillary tangles [190].…”

Section: Onset Of Apoptotic Injury By Caspases and Their Association mentioning

confidence: 76%

Stress in the brain: novel cellular mechanisms of injury linked to Alzheimer's disease

Chong

Maiese

2005

Brain Research Reviews

135

121

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More than a century has elapsed since the description of Alois Alzheimer's patient Auguste D. Yet, the well-documented generation of β-amyloid aggregates and neurofibrillary tangles that define Alzheimer's disease is believed to represent only a portion of the cellular processes that can determine the course of Alzheimer's disease. Understanding of the complex nature of this disorder has evolved with an increased appreciation for pathways that involve the generation of reactive oxygen species and oxidative stress, apoptotic injury that leads to nuclear degradation in both neuronal and vascular populations, and the early loss of cellular membrane asymmetry that mitigates inflammation and vascular occlusion. Recent work has identified novel pathways, such as the Wnt pathway and the serine-threonine kinase Akt, as central modulators that oversee cellular apoptosis and the formation of neurofibrillary tangles through their downstream substrates that include glycogen synthase kinase-3β, Bad, and Bcl-x L . Other closely integrated pathways control microglial activation, release of inflammatory cytokines, and caspase and calpain activation for the processing of amyloid precursor protein, tau protein cleavage, and presenilin disposal. New therapeutic avenues that are just open to exploration, such as with nicotinamide adenine dinucleotide modulation, cell cycle modulation, metabotropic glutamate system modulation, and erythropoietin targeted expression, may provide both attractive and viable alternatives to treat Alzheimer's disease.

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Caspase activation in the limbic cortex of subjects with early Alzheimer's disease

Cited by 102 publications

References 22 publications

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

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

Puma Is a Dominant Regulator of Oxidative Stress Induced Bax Activation and Neuronal Apoptosis

Stress in the brain: novel cellular mechanisms of injury linked to Alzheimer's disease

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