Astrocyte apoptosis: implications for neuroprotection

Takuma, Kazuhiro; Baba, Akemichi; Matsuda, Takehisa

doi:10.1016/j.pneurobio.2004.02.001

Cited by 393 publications

(287 citation statements)

References 323 publications

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“…Some of these cells were seen to have nuclear condensation consistent with apoptotic astrocyte death. The nuclear condensation changes are similar to those observed in the cell culture studies presented here and consistent with prior reports of delayed apoptotic changes in astrocytes after ischemia-reperfusion (Chen et al, 1997;Krupinski et al, 2000;Takuma et al, 2004). These findings are consistent with a role for acidosis and ER stress in delayed astrocyte death after ischemia, but do not exclude the possibility that factors other than acidosis may trigger or contribute to these changes in the periinfarct astrocytes.…”

Section: Discussionsupporting

confidence: 91%

Acidosis Causes Endoplasmic Reticulum Stress and Caspase-12-Mediated Astrocyte Death

Aoyama

Burns

Suh

et al. 2005

J Cereb Blood Flow Metab

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Endoplasmic reticulum (ER) stress leads to activation of caspase-12, which in turn can lead to activation of caspase-3 and cell death. Here we report that transient acidosis induces ER stress and caspase-12-mediated cell death in mouse astrocytes. After a 3-hour incubation at pH 6.0, astrocytes exhibited delayed cell death associated with nuclear condensation and fragmentation. Cell death was reduced by the protein synthesis inhibitor cycloheximide, further suggesting an active cell death program. Acidosis increased the expression of the ER chaperone protein GRP-78, indicative of ER stress. Acidosis also increased caspase-12 mRNA expression, caspase-12 protein expression, cleavage of caspase-12 to its active form, and activation of caspase-3. Each of these effects was suppressed in astrocytes pretreated with caspase-12 antisense phosphorodiamidate morpholino oligodeoxynucleotides (PMOs). Caspase-12 antisense PMOs also reduced the cell death induced by acidosis. Immunoprecipitation studies showed dissociation of both caspase-12 and Ire1-a from GRP-78, thereby suggesting a mechanism by which acidosis can initiate the ER stress response. To evaluate caspase-12 activation in vivo, rats were subjected to middle cerebral artery ischemiareperfusion. Immunostaining of brain sections harvested 24 hours later showed increased caspase-12 expression and nuclear condensation in astrocytes of the periinfarct region exposed to acidosis during ischemia. These findings suggest that acidosis induces ER stress and caspase-12 activation, and that these changes may contribute to delayed cell death after ischemia.

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Section: Discussionsupporting

confidence: 91%

Acidosis Causes Endoplasmic Reticulum Stress and Caspase-12-Mediated Astrocyte Death

Aoyama

Burns

Suh

et al. 2005

J Cereb Blood Flow Metab

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“…Astroglial cells can undergo cell death in vitro in a variety of situations such as calcium overload, oxidative stress, mitochondrial dysfunction, and treatment with apoptotic inducers like staurosporine and ceramide (Giffard and Swanson, 2005;Takuma et al, 2004), although it has been established that they are more resistant than neuronal cells (Xu et al, 2004). In this regard, studies of astroglial cell death after different types of acute injuries such as traumatic brain injury (Beer et al, 2000;Newcomb et al, 1999) and ischemia/ excitotoxicity (Biran et al, 2006;Dihne et al, 2001), have shown that apoptosis occurs only in few astrocytes, in agreement with our findings in the injured neonatal brain.…”

Section: Discussionmentioning

confidence: 99%

Caspase‐3 activation in astrocytes following postnatal excitotoxic damage correlates with cytoskeletal remodeling but not with cell death or proliferation

Acarín¹,

Villapol²,

Faiz³

et al. 2007

Glia

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Caspase-3 has classically been defined as the main executioner of programmed cell death. However, recent data supports the participation of this protease in non-apoptotic cellular events including cell proliferation, cell cycle regulation, and cellular differentiation. In this study, astroglial cleavage of caspase-3 was analyzed following excitotoxic damage in postnatal rats to determine if its presence is associated with apoptotic cell death, cell proliferation, or cytoskeletal remodeling. A well-characterized in vivo model of excitotoxicity was studied, where damage was induced by intracortical injection of N-methyl-D-asparate (NMDA) in postnatal day 9 rats. Our results demonstrate that cleaved caspase-3 was mainly observed in the nucleus of activated astrocytes in the lesioned hemisphere as early as 4 h postlesion and persisted until the glial scar was formed at 7-14 days, and it was not associated with TUNEL labeling. Caspase-3 enzymatic activity was detected at 10 h and 1 day postlesion in astrocytes, and co-localized with caspasecleaved fragments of glial fibrillary acidic protein (CCP-GFAP). However, at longer survival times, when astroglial hypertrophy was observed, astroglial caspase-3 did not generally correlate with GFAP cleavage, but instead was associated with de novo expression of vimentin. Moreover, astroglial caspase-3 cleavage was not associated with BrdU incorporation. These results provide further evidence for a nontraditional role of caspases in cellular function that is independent of cell death and suggest that caspase activation is important for astroglial cytoskeleton remodeling following cellular injury. V V C 2007 Wiley-Liss, Inc.

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“…Astrocytes are known to undergo apoptosis when challenged with strong proinflammatory stimuli (Hu and Van Eldik, 1996;Takuma et al, 2004). However, apoptotic cell death was negligible in astrocytoma cell lines upon PQ treatment (measured by active caspase 3 detection or Annexin V labeling; not shown).…”

Section: Apod Deficient Astrocytes Become Vulnerable To Oxidative Stressmentioning

confidence: 97%

Apolipoprotein D mediates autocrine protection of astrocytes and controls their reactivity level, contributing to the functional maintenance of paraquat-challenged dopaminergic systems

Bajo‐Grañeras¹,

Ganfornina²,

Martín-Tejedor³

et al. 2011

Glia

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The study of glial derived factors induced by injury and degeneration is important to understand the nervous system response to deteriorating conditions. We focus on Apolipoprotein D (ApoD), a Lipocalin expressed by glia and strongly induced upon aging, injury or neurodegeneration.Here we study ApoD function in the brain of wild type and ApoD-KO mice by combining in vivo experiments with astrocyte cultures. Locomotor performance, dopamine concentration, and gene expression levels in the substantia nigra were assayed in mice treated with paraquat (PQ). The regulation of ApoD transcription, a molecular screening of oxidative stress (OS)-related genes, cell viability and oxidation status, and the effects of adding human ApoD were tested in astrocyte cultures. We demonstrate that (1) ApoD is required for an adequate locomotor performance, modifies the gene expression profile of PQ-challenged nigrostriatal system, and contributes to its functional maintenance; (2) ApoD expression in astrocytes is controlled by the OSresponsive JNK pathway; (3) ApoD contributes to an autocrine protecting mechanism in astrocytes, avoiding peroxidated lipids accumulation and altering the PQ transcriptional response of genes involved in ROS managing and the inflammatory response to OS; (4) Addition of human ApoD to ApoD-KO astrocytes promotes survival through a mechanism accompanied by protein internalization and modulation of astroglial reactivity. Our data support that ApoD contributes to the endurance of astrocytes and decreases their reactivity level in vitro and in vivo. ApoD function as a maintenance factor for astrocytes would suffice to explain the observed protection by ApoD of OS-vulnerable dopaminergic circuits in vivo. V

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Astrocyte apoptosis: implications for neuroprotection

Cited by 393 publications

References 323 publications

Acidosis Causes Endoplasmic Reticulum Stress and Caspase-12-Mediated Astrocyte Death

Acidosis Causes Endoplasmic Reticulum Stress and Caspase-12-Mediated Astrocyte Death

Caspase‐3 activation in astrocytes following postnatal excitotoxic damage correlates with cytoskeletal remodeling but not with cell death or proliferation

Apolipoprotein D mediates autocrine protection of astrocytes and controls their reactivity level, contributing to the functional maintenance of paraquat-challenged dopaminergic systems

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