Widespread activation of calcium-activated neutral proteinase (calpain) in the brain in Alzheimer disease: a potential molecular basis for neuronal degeneration.

Saitô, Kenichi; Elce, John S.; Hamos, James E.; Nixon, Ralph A.

doi:10.1073/pnas.90.7.2628

Cited by 546 publications

(401 citation statements)

References 59 publications

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“…However, these studies showed different modes of calpain activation depending on the cell types and degenerative regions. Moreover, as for the degree of the calpain activation, normal aged human brain did not show activated calpain as much as Alzheimer's diseased brain (Saito et al, 1993;Tsuji et al, 1998). From these, we concluded that the lack of cleavage of fodrin and p35 processing in aged cortex of SD rats might be due to the differences in strains and/or species as mentioned by Kimura et al and less extent of normal aging than that of degenerative disorders.…”

Section: Discussionmentioning

confidence: 49%

Neuronal loss in primary long-term cortical culture involves neurodegeneration-like cell death via calpain and p35 processing, but not developmental apoptosis or aging

Kim

Oh²,

Park³

et al. 2007

Exp Mol Med

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Primary neuronal culture is a powerful tool to study neuronal development, aging, and degeneration. However, cultured neurons show signs of cell death after 2 or 3 weeks. Although the mechanism underlying this phenomenon has not been elucidated, several preventive methods have been identified. Here we show that the neuronal loss in primary cortical culture involves calpain activation and subsequent neuronal cell death. Neuronal loss during cultivation showed destruction of neurites and synapses, and a decrease in neuron numbers. µ-Calpain and m-calpain were initially activated and accumulated by increased RNA expression. This neuronal death exhibited neurodegenerative features, such as conversion of p35 to p25, which is important in the developmental process and in the pathogenesis of Alzheimer's disease. But, postnatal and aged rat cortex did not show calpain activation and prolonged processing of p35 to p25, in contrast to the long-term culture of cortical neurons. In addition, the inhibition of calpains by ALLM or ALLN blocked the conversion of p35 to p25, indicating that the calpain activity is essential for the neurodegenerative features of cell death. Taken together, this study shows that the neuronal loss in primary cortical cultures involves neurodegeneration-like cell death through the activation of calpains and the subsequent processing of p35 to p25, but not developmental apoptosis or aging. Our results suggest that the long term primary culture of cortical neurons represent a valuable model of neurodegeneration, such as Alzheimer's disease.

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Section: Discussionmentioning

confidence: 49%

Neuronal loss in primary long-term cortical culture involves neurodegeneration-like cell death via calpain and p35 processing, but not developmental apoptosis or aging

Kim

Oh²,

Park³

et al. 2007

Exp Mol Med

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“…An increase in the intracellular free Ca +2 concentration triggers the calpain activation that cleaves many cytoskeletal and myelin proteins, which eventually results in apoptosis 2,17,28,51 . The overactivation of calpain is involved in the pathophysiology of neurodegenerative disorders and diseases and increases the lesion size as time passes after SCI 5,27,37,38,48 . After a primary injury to the spinal cord, the process of secondary injury progresses over time in the both rostral and caudal areas; this increases the lesion size and the rate Research has revealed that an SCI evokes an increase in the intracellular free Ca +2 level, which in turn results in the activation of calpain 17,51 .…”

Section: Discussionmentioning

confidence: 99%

Calpain inhibitor AK 295 inhibits calpain-induced apoptosis and improves neurologic function after traumatic spinal cord injury in rats

et al. 2009

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SummaryBackground. An increase in the level of intracellular calcium activates the calcium-dependent neutral protease calpain, which in turn leads to cellular dysfunction and cell death after an insult to the central nervous system. In this study, we evaluated the effect of a calpain inhibitor, AK 295, on spinal cord structure, neurologic function, and apoptosis after spinal cord injury (SCI) in a murine model.Methods. Thirty albino Wistar rats were divided into 3 groups of 10 each: the sham-operated control group (group 1), the spinal cord trauma group (group 2), and the spinal cord trauma plus AK 295 treatment group (group 3). After having received a combination of ketamine 60 mg/kg and xylazine 9 mg/kg to induce anesthesia, the rats in groups 2 and 3 were subjected to thoracic trauma by the weight drop technique (40 g-cm). One hour after having been subjected to that trauma, the rats in groups 2 and 3 were treated with an intraperitoneal injection of either dimethyl sulfoxide 2 mg/kg or AK 295 2 mg/kg. The effects of the injury and the efficacy of AK 295 were determined by an assessment of the TUNEL technique and the results of examination with a light microscope. The neurologic performance of 5 rats from group 2 and 5 from group 3 was assessed by means of the inclined plane technique and the modified Tarlov's motor grading scale 1, 3, and 5 days after spinal cord trauma.Findings. Light-microscopic examination of spinal cord specimens from group 2 revealed hemorrhage, edema, necrosis, and vascular thrombi 24 hours after trauma. Similar (but less prominent) features were seen in specimens obtained from group 3 rats. Twenty-four hours after injury, the mean apoptotic cell numbers in groups 1 and 2 were zero and 4.57 ± 0.37 cells, respectively. In group 3, the mean apoptotic cell number was 2.30 ± 0.34 cells, a value significantly lower than that in group 2 (P < .05). Five days after trauma, the injured rats in group 2 demonstrated significant motor dysfunction (P < .05). In comparison, the motor scores exhibited by group 3 rats were markedly better (P < .05).Conclusions. AK 295 inhibited apoptosis via calpaindependent pathways and provided neuroprotection and improved neurologic function in a rat model of SCI. To our knowledge, this is the first study to evaluate the use of AK 295, a calpain inhibitor, after SCI. Our data suggest that AK 295 might be a novel therapeutic compound for the neuroprotection of tissue and the recovery of function in patients with a SCI.KEY WORDS: AK 295. Apoptosis. Calpain inhibitor. Secondary damage. Spinal cord trauma.El inhibidor de la calpaina AK 295 inhibe la apoptosis inducida por calpaina y mejora la función neurológica tras traumatismo medular en ratas ResumenIntroducción. Una lesión en el sistema nervioso central origina un incremento en los niveles de calcio intracelular que activa la proteasa neutral calciodependiente calpaina, que a su vez conduce a la producción de disfunción y muerte celular. En este estudio evaluamos el efecto de un inhibidor de la calpaina, AK 295, so...

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“…On the other hand calpain activity could be also negatively regulated by phosphorylation through PKA or its endogenous inhibitor calpastatin (Melloni et al, 1984;Inomata et al, 1988;Saido et al, 1992;Croall and McGrody, 1994;Moldoveanu et al, 2001;Shiraha et al, 2002;Dedieu et al, 2003(a)). The calpain family is thought to be involved in a range of various diseases such as cataract formation, diabetes, rheumatoid arthritis, ischemia, neurodegenerative diseases and muscular dystrophies (David et al, 1993;Saito et al, 1993;Mouatt-Prigent et al, 1996;Hirsch et al, 1997;Ishikawa et al, 1999;Horikawa et al, 2000;Richard et al, 2000;Tidball and Spencer 2000;Tamada et al, 2001;Trumbeckaite et al, 2003). Moreover, calpains play pivotal roles in physiological and biological phenomena such as signal transduction, cell spreading and motility, apoptosis, regulation of cell cycle, and regulation of muscle cell differentiation (Huttenlocher et al, 1997;Potter et al, 1998;Villa et al, 1998;Atencio et al, 2000;Barnoy et al, 2000;Cottin et al, 2000;Patel and Lane, 2000;Dourdin et al, 2001;Glading et al, 2001;Sato and Kawashima, 2001).…”

Section: Introductionmentioning

confidence: 99%

Myoblast migration is prevented by a calpain‐dependent accumulation of MARCKS

Dedieu

Mazères

Poussard

et al. 2003

Biology of the Cell

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Calpains, also called calcium activated neutral cysteine proteases are presently known to play pivotal roles in physiological and biological phenomena such as signal transduction, cell spreading and motility, apoptosis, regulation of cell cycle and regulation of muscle cell differentiation. Concerning this last point, calpains have been shown to play a crucial role during the earlier myogenesis. In this study we have analyzed the involvement of calpains during an important step of myogenesis: myoblast migration. Our findings show that myoblast migration was drastically reduced when the expression of µ-and m-calpain was decreased. We have also observed that MARCKS (myristoylated alanine rich C kinase substrate), a protein localized at focal adhesion sites, was significantly accumulated when the expression levels of calpains were decreased. Also, using phorbol myristate acetate, (an activator of PKC) and plasmids carrying the full-length cDNA of MARCKS or a cDNA fragment lacking the phosphorylation site domain, we demonstrated that normal myoblast migration is dependent on MARCKS phosphorylation and localization.

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Widespread activation of calcium-activated neutral proteinase (calpain) in the brain in Alzheimer disease: a potential molecular basis for neuronal degeneration.

Cited by 546 publications

References 59 publications

Neuronal loss in primary long-term cortical culture involves neurodegeneration-like cell death via calpain and p35 processing, but not developmental apoptosis or aging

Neuronal loss in primary long-term cortical culture involves neurodegeneration-like cell death via calpain and p35 processing, but not developmental apoptosis or aging

Calpain inhibitor AK 295 inhibits calpain-induced apoptosis and improves neurologic function after traumatic spinal cord injury in rats

Myoblast migration is prevented by a calpain‐dependent accumulation of MARCKS

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