Differential Expression of Rat Brain Caspase Family Proteins during Development and Aging

Shimohama, Shun; Tanino, Hiroko; Fujimoto, Sadaki

doi:10.1006/bbrc.2001.6108

Cited by 46 publications

(32 citation statements)

References 17 publications

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“…Most notably, we found a marked developmental downregulation of the brain mRNA expression of caspase-3, a downstream caspase in both the "extrinsic" and "intrinsic" cell death pathways (reviewed in reference 55), which plays an important role in brain apoptosis (30; reviewed in reference 72). Our findings are consistent with other reports describing a reduction in caspase-3 levels with mouse (3) and rat (45,63,75) brain maturation. Decreased levels of caspase-3 expression with increased postnatal age may contribute not only to age-related resistance to Sindbis virus-induced neuronal apoptosis but also to age-related resistance to apoptosis induced by other neurotropic viruses and by other neurotoxic stimuli, such as hypoxiaischemia and excitotoxic injury (4,10,21,26,54).…”

Section: Discussionsupporting

confidence: 93%

Age-Dependent Resistance to Lethal Alphavirus Encephalitis in Mice: Analysis of Gene Expression in the Central Nervous System and Identification of a Novel Interferon-Inducible Protective Gene, MouseISG12

Labrada

Liang

Wang

et al. 2002

J Virol

110

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Several different mammalian neurotropic viruses produce an age-dependent encephalitis characterized by more severe disease in younger hosts. To elucidate potential factors that contribute to age-dependent resistance to lethal viral encephalitis, we compared central nervous system (CNS) gene expression in neonatal and weanling mice that were either mock infected or infected intracerebrally with a recombinant strain, dsTE12Q, of the prototype alphavirus Sindbis virus. In 1-day-old mice, infection with dsTE12Q resulted in rapidly fatal disease associated with high CNS viral titers and extensive CNS apoptosis, whereas in 4-week-old mice, dsTE12Q infection resulted in asymptomatic infection with lower CNS virus titers and undetectable CNS apoptosis. GeneChip expression comparisons of mock-infected neonatal and weanling mouse brains revealed developmental regulation of the mRNA expression of numerous genes, including some apoptosis regulatory genes, such as the proapoptotic molecules caspase-3 and TRAF4, which are downregulated during development, and the neuroprotective chemokine, fractalkine, which is upregulated during postnatal development. In parallel with increased neurovirulence and increased viral replication, Sindbis virus infection in 1-day-old mice resulted in both a greater number of host inflammatory genes with altered expression and greater changes in levels of host inflammatory gene expression than infection in 4-week-old mice. Only one inflammatory response gene, an expressed sequence tag similar to human ISG12, increased by a greater magnitude in infected 4-week-old mouse brains than in infected 1-day-old mouse brains. Furthermore, we found that enforced neuronal ISG12 expression results in a significant delay in Sindbis virus-induced death in neonatal mice. Together, our data identify genes that are developmentally regulated in the CNS and genes that are differentially regulated in the brains of different aged mice in response to Sindbis virus infection.

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Section: Discussionsupporting

confidence: 93%

Age-Dependent Resistance to Lethal Alphavirus Encephalitis in Mice: Analysis of Gene Expression in the Central Nervous System and Identification of a Novel Interferon-Inducible Protective Gene, MouseISG12

Labrada

Liang

Wang

et al. 2002

J Virol

110

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“…The anti-fractin antibody originally described by Yang et al (55) also did not detect any immunoreactive signal (data not shown). These observations are consistent with a previous report by Shimohama et al (56) demonstrating that cortical caspase-3 and caspase-7, which are highly expressed in the embryonic stage and up to 2 weeks postnatally, become virtually undetectable from 4 to 96 weeks after birth in rat brains.…”

Section: Fig 4 Expression and Activation Of Caspase-3 And Proteolyssupporting

confidence: 93%

“…Hippocampal homogenates were subjected to Western blot analysis using an antibody to ICAD. ICAD-L, long form of ICAD; ICAD-S, short form of ICAD (56). KA, kainate.…”

Section: Fig 4 Expression and Activation Of Caspase-3 And Proteolysmentioning

confidence: 99%

Calpain Mediates Excitotoxic DNA Fragmentation via Mitochondrial Pathways in Adult Brains

Takano

Tomioka²,

Tsubuki³

et al. 2005

Journal of Biological Chemistry

170

153

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Calpain has been implicated in excitotoxic neurodegeneration, but its mechanism of action particularly in adult brains remains unclear. We generated mutant mice lacking or overexpressing calpastatin, the only solely calpain-specific inhibitor ever identified or synthesized. Modulation of calpastatin expression caused no defect in the mice under normal conditions, indicating that calpastatin functions as a negative regulator of calpain only under pathological conditions. Kainateevoked excitotoxicity in hippocampus resulted in proteolytic activation of a proapoptotic Bcl-2 subfamily member (Bid), nuclear translocation of mitochondriaderived DNA fragmentation factors (apoptosis-inducing factor and endonuclease G), DNA fragmentation, and nuclear condensation in pyramidal neurons. These apoptotic responses were significantly augmented by calpastatin deficiency. Consistently calpastatin overexpression suppressed them. No evidence of caspase-3 activation was detected. Our results demonstrated that calpain mediates excitotoxic signals through mobilization of proapoptotic factors in a caspase-independent manner. These mutant mice will serve as useful tools for investigating calpain involvement in various diseases.

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“…These suggest the importance of early neural cell death in postnatal neural development, which is supported by the dramatic phenotype changes when death is prevented by capase-3, caspase-9 or Apaf1 gene disruption (Kuida et al, 1996;Honarpour et al, 2000). Also, it has been reported that caspase-3 is upregulated and activated in the perinatal developing brains (Mooney and Miller, 2000;Shimohama et al, 2001). Thus, neuronal loss due to long term embryonal cortex culture was compared with developmental cerebral cortex apoptosis, because primary neuronal culture is usually set up at 16-18 embryonal days and thus neuronal loss in culture might be a part of the developmental apoptosis.…”

Section: Discussionmentioning

confidence: 95%

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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Differential Expression of Rat Brain Caspase Family Proteins during Development and Aging

Cited by 46 publications

References 17 publications

Age-Dependent Resistance to Lethal Alphavirus Encephalitis in Mice: Analysis of Gene Expression in the Central Nervous System and Identification of a Novel Interferon-Inducible Protective Gene, MouseISG12

Age-Dependent Resistance to Lethal Alphavirus Encephalitis in Mice: Analysis of Gene Expression in the Central Nervous System and Identification of a Novel Interferon-Inducible Protective Gene, MouseISG12

Calpain Mediates Excitotoxic DNA Fragmentation via Mitochondrial Pathways in Adult Brains

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

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