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Biomedical subjects

Steven Estus

Publications and source records attributed to Steven Estus.

8 recordsLinked to original sources
PubMed2003

Glutamate regulates caveolin expression in rat hippocampal neurons.

Caveolae are cholesterol-rich, membrane microdomains that appear critical to signaling between extracellular and intracellular macromolecules as well as cholesterol homeostasis. Caveolae formation is modulated by caveolin, a protein family that is the proteinaceous hallmark of caveolae. Very little is known regarding the events that modulate caveolin expression and regulation in neurons. To detect caveolin expression in neurons, primary rat hippocampal neurons were harvested at embryonic day 18, maintained for 7 days in vitro, and then analyzed for caveolin immunofluorescence. Caveolin-1 immunoreactivity was detected in cells that were identified as neurons by morphology and concurrent microtubule-associated protein (MAP2) staining. Changes in caveolin-1 expression were evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR) analyses of RNA isolated from hippocampal neurons treated with glutamate receptor agonists. Glutamate induced a concentration-dependent increase in caveolin-1 mRNA. The largest increases in caveolin-1 mRNA were detected after 6 hours of treatment. Kainate and AMPA both mimicked glutamate effects on caveolin-1 mRNA expression. Western blot analyses revealed that caveolin was induced at the protein level as well. Taken together, these data suggest that glutamate can regulate caveolin expression through kainate and AMPA ionotropic glutamate receptors.

Animals↗
PubMed2003

4-hydroxynonenal contributes to NGF withdrawal-induced neuronal apoptosis.

Reactive oxygen species are a necessary triggering event for apoptosis of sympathetic neurons after nerve growth factor (NGF) withdrawal. Reactive oxygen species can lead to the generation of 4-hydroxynonenal (HNE), a highly reactive aldehyde that forms adducts with proteins. This covalent modification can activate or inhibit signal transduction pathways involved in the induction of apoptosis. This process may be clinically relevant because HNE-adduct immunoreactivity increases in several disease states. Here we evaluate the role of HNE-adducts in sympathetic neurons undergoing NGF-deprivation-induced apoptosis, a model of developmental programmed cell death. We show that HNE-adduct immunoreactivity is dramatically increased after NGF-withdrawal in an NADPH oxidase-dependent manner. Moreover, HNE-adducts appear to contribute to NGF-deprivation-induced apoptotic signal transduction because microinjected HNE-adduct antiserum protects sympathetic neurons from NGF withdrawal. In conclusion, this report suggests the direct contribution of endogenously generated HNE in the stimulation of apoptotic signal transduction in neurons.

Aldehydes↗
PubMed2002

JNK3 contributes to c-jun induction and apoptosis in 4-hydroxynonenal-treated sympathetic neurons.

4-hydroxynoneal (HNE), an end product of lipid peroxidation, induces apoptosis in many cell types, including neural cells. HNE toxicity is often accompanied by activation of the c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) pathway. Here we have evaluated the hypothesis that the primary JNK associated with neurons, JNK3, contributes to HNE-induced neuronal apoptosis. First, we demonstrate that HNE induces caspase-dependent apoptosis in sympathetic neurons. Second, we show that HNE-induced c-Jun phosphorylation and c-jun induction are attenuated in JNK3-deficient neurons. Third, we show that HNE neurotoxicity is significantly inhibited by JNK3 deficiency. In summary, these results indicate that JNK3 plays a critical role in HNE-induced c-Jun activation and apoptosis in sympathetic neurons.

Aldehydes↗
PubMed2002

Urokinase-type plasminogen activator inhibits amyloid-beta neurotoxicity and fibrillogenesis via plasminogen.

Amyloid-beta (Abeta) appears central to Alzheimer's disease (AD), aggregates spontaneously, and is neurotoxic to neurons in vitro. Recently, several groups reported a familial AD locus on chromosome 10. Here, we note that urokinase-type plasminogen activator (uPA) is located within this locus. Previously, we reported that uPA and its functional homolog, tissue-type plasminogen activator, are induced by Abeta treatment of neurons in vitro as well as in a mouse model of Abeta accumulation in vivo. Moreover, the target of plasminogen activators, plasmin, degraded nonaggregated and aggregated Abeta and modulated Abeta toxicity and deposition. Here, we have evaluated the effects of uPA and plasminogen on Abeta fibril formation and neurotoxicity. We report that the combination of uPA and plasminogen, but neither alone, inhibits Abeta toxicity, reduces Abeta deposition in vitro, and inhibits Abeta fibrillogenesis. We interpret these observations as suggesting that uPA represents a possible candidate gene for the chromosome 10 familial AD locus.

Alzheimer Disease↗
PubMed2002

Calpain activates caspase-3 during UV-induced neuronal death but only calpain is necessary for death.

While caspases have been strongly implicated in delayed neuronal death in a variety of experimental paradigms, other proteases such as calpain can also contribute to neuronal death. To evaluate the relative roles of caspase and calpain, we used a model system wherein UV treatment induced moderate or severe delayed cortical neuronal death, as quantified by propidium iodide and calcein AM. UV treatment led to increases in both caspase and calpain activation. Calpain inhibitor III (MDL-28170) reduced caspase activation, suggesting that caspase activation was mediated by calpain. Calpain contributed to neuronal death, as indicated by strong neuroprotection provided by calpain inhibitor III, calpeptin, or Ca2+-free medium. In contrast, caspase inhibitors were not neuroprotective. These results suggest that UV neurotoxicity is mediated by a loss of Ca2+ homeostasis which leads to a calpain-dependent, caspase-independent cell death. That calpain, but not caspase, may mediate death in instances involving the activation of both proteases may have relevance to other neuronal death models.

Animals↗
PubMedDate not supplied

The JNK/c-Jun cascade and Alzheimer's disease.

Emerging evidence indicates that the JNK/c-Jun cascade is activated in neurons of the Alzheimer's disease brain and suggests its involvement in abnormal processes, ranging from tau phosphorylation to neuronal death. Substantial new data have accumulated on the functional relevance of causative genes in familial Alzheimer's disease and the pathological processes that occur within neurons. In this review, we summarize reported findings of the JNK/c-Jun cascade in Alzheimer's disease and discuss the relationship between the cascade and other pathological processes. We suggest that the effort to connect amyloid deposition with intracellular activation of the JNK/c-Jun cascade may modify the amyloid theory of Alzheimer's disease. Therapeutic approaches targeting the JNK/c-Jun cascade and other signaling may complement therapeutic strategies directed at reducing amyloid deposition.

Alzheimer Disease↗