DNA Damage and Activated Caspase-3 Expression in Neurons and Astrocytes: Evidence for Apoptosis in Frontotemporal Dementia

Su, Jianping; Nichol, Kathryn; Sitch, Tom; Sheu, Phillip C.‐Y.; Chubb, Charlie; Miller, Bruce L.; Tomaselli, Kevin J.; Kim, Ronald C.; Cotman, Carl W.

doi:10.1006/exnr.2000.7340

Cited by 102 publications

(78 citation statements)

References 45 publications

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“…Similarly, in vitro studies have also suggested that caspase-3 proteolytic activity plays a crucial role in excitotoxin-induced neuronal apoptosis (Allen et al, 1999;Du et al, 1997;Tenneti and Lipton, 2000). In addition, expression of caspase-3 has been described in oligodendrocytes (Beer et al, 2000;Nottingham and Springer, 2003) and astrocytes following CNS damage (Beer et al, 2000;Benjelloun et al, 2003;Mouser et al, 2006;Su et al, 2000). The present study demonstrates that following Mn exposure, activation of the caspase-3 precursor protein is observed in cultured astrocytes.…”

Section: Discussionsupporting

confidence: 76%

Mitochondrial-dependent manganese neurotoxicity in rat primary astrocyte cultures

Yin

Aschner

Santos³

et al. 2008

Brain Research

117

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Chronic exposure to excessive levels of Mn results in a movement disorder termed manganism, which resembles Parkinson's disease (PD). The pathogenic mechanisms underlying this disorder are not fully understood. Several lines of evidence implicate astrocytes as an early target of Mn neurotoxicity. In the present study, we investigated the effects of Mn on mitochondrial function. Primary astrocyte cultures were prepared from cerebral cortices of one-day-old Sprague-Dawley rats. We have examined the cellular toxicity of Mn and its effects on the phosphorylation of extracellular signalregulated kinase (ERK) and activation of the precursor protein of caspase-3. The potentiometric dye, tetramethylrhodamine ethyl ester (TMRE), was used to assess the effect of Mn on astrocytic mitochondrial inner membrane potential (ΔΨ m ). Our studies show that, in a concentration-dependent manner, Mn induces significant (p<0.05) activation of astrocyte caspase-3 and phosphorylated extracellular signal-regulated kinase (p-ERK). Mn treatment (1 and 6 hrs) also significantly (p<0.01) dissipates the ΔΨm in astrocytes as evidenced by a decrease in mitochondrial TMRE fluorescence. These results suggest that activations of astrocytic caspase-3 and ERK are involved in Mn-induced neurotoxicity via mitochondrial-dependent pathways.

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Section: Discussionsupporting

confidence: 76%

Mitochondrial-dependent manganese neurotoxicity in rat primary astrocyte cultures

Yin

Aschner

Santos³

et al. 2008

Brain Research

117

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“…This finding should be interpreted in conjunction with recent studies, which identified molecular mechanisms surrounding neuronal loss in typical FTD. In particular, apoptotic phenomena in both neurons and astrocytes [29,33,38] as well as a depletion of all six tau isoforms [49] have been described in this disease, both contributing to rapid neuronal death. It is thus likely that neuronal loss in typical FTD cases is neither a progressive phenomenon which would be expected to be more pronounced with increased disease duration nor a marker of disease aggressiveness.…”

Section: Discussionmentioning

confidence: 94%

Cortical ubiquitin-positive inclusions in frontotemporal dementia without motor neuron disease: a quantitative immunocytochemical study

et al. 2004

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Ubiquitin-positive tau-negative inclusions were initially described in the rare form of frontotemporal dementia (FTD) associated with motor neuron disease. However, recent studies have indicated that these inclusions are also present in typical FTD, which is usually characterized by nonspecific histological changes. To examine the contribution of these inclusions to neuronal loss and to explore their relationship with disease duration, we performed a quantitative immunocytochemical analysis of 38 typical FTD cases. Relationships between neuron and ubiquitin inclusion densities as well as between duration of illness and neuropathological parameters was studied using linear regression in both univariate and multivariate models. Ubiquitin-positive tau-negative intracytoplasmic inclusions were present in 65.8% of cases in the dentate gyrus, 57.9% in temporal cortex and 31.6% in frontal cortex. The highest densities of ubiquitin-positive inclusions were consistently observed in the dentate gyrus, followed by the temporal and frontal cortex. There was no statistically significant relationship between neuron and ubiquitin-positive inclusion densities in any of the areas studied. In contrast, ubiquitin-positive inclusion densities in the dentate gyrus were negatively related to the duration of illness. Our data suggest that the development of ubiquitin-related pathology is the rule and not the exception in typical FTD, yet is not causally related to neuronal loss. They also reveal that the development of ubiquitin-positive inclusion densities in the dentate gyrus may be associated with a more aggressive form of the disease.

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“…Activated caspase-3 immunoreactivity has been detected in both neurons and astrocytes and found elevated in frontotemporal dementia (Su et al, 2000) and AD (Su et al, 2001). PtdSer exposure due to apoptosis has been found to occur downstream of caspase activation in some cell types (Mandal et al, 2002;Martin et al, 1996;Vanags et al, 1996); in non-neuronal cells like human erythrocytes, caspase activation is associated with loss of aminophospholipid translocase activity and subsequent PtdSer externalization (Mandal et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Loss of phospholipid asymmetry and elevated brain apoptotic protein levels in subjects with amnestic mild cognitive impairment and Alzheimer disease

Lange

Cenini

Piroddi

et al. 2008

Neurobiology of Disease

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Oxidative stress, a hallmark of Alzheimer disease (AD), has been shown to induce lipid peroxidation and apoptosis disrupting cellular homeostasis. Normally, the aminophospholipid phosphatidylserine (PtdSer) is asymmetrically distributed on the cytosolic leaflet of the lipid bilayer. Under oxidative stress conditions, asymmetry is altered, characterized by the appearance of PtdSer on the outer leaflet, to initiate the first stages of an apoptotic process. PtdSer asymmetry is actively maintained by the ATP-dependent translocase flippase, whose function is inhibited if covalently bound by lipid peroxidation products, 4-hydroxynonenal (HNE) and acrolein, within the membrane bilayer in which they are produced. Additionally, pro-apoptotic proteins Bax and caspase-3 have been implemented in the oxidative modification of PtdSer resulting in subsequent asymmetric collapse, while antiapoptotic protein Bcl-2 has been found to prevent this process.The current investigation focused on detection of PtdSer on the outer leaflet of the bilayer in synaptosomes from brain of subjects with AD and amnestic mild cognitive impairment (MCI), as well as expression levels of apoptosis-related proteins Bcl-2, Bax, and caspase-3. Fluorescence and Western blot analysis suggest PtdSer exposure on the outer leaflet is significantly increased in brain from subjects with MCI and AD contributing to early apoptotic elevation of pro-and anti-apoptotic proteins and finally neuronal loss. MCI is considered a possible transition point between normal cognitive aging and probable AD. Brain from subjects with MCI is reported to have increased levels of tissue oxidation; therefore, the results of this study could mark the progression of patients with MCI into AD. This study contributes to a model of apoptosis-specific oxidation of phospholipids consistent with the notion that PtdSer exposure is required for apoptotic-cell death.

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DNA Damage and Activated Caspase-3 Expression in Neurons and Astrocytes: Evidence for Apoptosis in Frontotemporal Dementia

Cited by 102 publications

References 45 publications

Mitochondrial-dependent manganese neurotoxicity in rat primary astrocyte cultures

Mitochondrial-dependent manganese neurotoxicity in rat primary astrocyte cultures

Cortical ubiquitin-positive inclusions in frontotemporal dementia without motor neuron disease: a quantitative immunocytochemical study

Loss of phospholipid asymmetry and elevated brain apoptotic protein levels in subjects with amnestic mild cognitive impairment and Alzheimer disease

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