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Okadaic acid induces cycloheximide and caspase sensitive apoptosis in immature neurons
1Department of Anatomy, University of Ulsan College of Medicine, Seoul, Korea. dhkim@www.amc.seoul.kr
Abstract:
Previous studies have shown that okadaic acid (OA) evokes tau phosphorylation and neurofibrillary changes in vivo, and in cultured neurons, that resemble Alzheimer's disease pathogenesis. In order to investigate the mechanism of OA-neurotoxicity, we treated cultured rat neurons with OA and examined nuclear morphology, phosphatidylserine (PS) externalization, alpha-fodrin cleavage, and the effects of cell death inhibitors. Our results demonstrated that cycloheximide (CHX) and the broad-spectrum caspase inhibitor, ZVAD, significantly reduced cell death in a dose-dependent manner. Nuclear fragmentation, a hallmark of apoptosis, occurred after OA treatment and was inhibited by CHX or ZVAD. PS externalization was apparent in 6-12 h in neurites and in cell bodies, and peaked at 24 h after OA treatment. Cleavage of alpha-fodrin as visualized by the appearance of 150- and 120-kDa bands appeared with a time course similar to PS externalization. These results suggest that OA induce CHX and caspase sensitive neuronal apoptosis.
Insights
Okadaic acid (OA) triggers caspase-dependent neuronal apoptosis, mimicking Alzheimer's disease pathology. Cell death inhibitors like cycloheximide (CHX) and Z-VAD significantly reduced OA-induced neurotoxicity and apoptosis markers.
Area of Science:
- Neuroscience
- Cell Biology
- Toxicology
Background:
- Okadaic acid (OA) induces tau phosphorylation and neurofibrillary changes, resembling Alzheimer's disease (AD) pathogenesis.
- Understanding the precise mechanisms of OA-induced neurotoxicity is crucial for AD research.
Purpose of the Study:
- To investigate the molecular mechanisms underlying okadaic acid (OA) neurotoxicity in cultured rat neurons.
- To determine the role of apoptosis and specific cellular events in OA-induced neuronal death.
Main Methods:
- Cultured rat neurons were treated with okadaic acid (OA).
- Assessed nuclear morphology, phosphatidylserine (PS) externalization, and alpha-fodrin cleavage.
- Evaluated the effects of cell death inhibitors, including cycloheximide (CHX) and a broad-spectrum caspase inhibitor (Z-VAD).
Main Results:
- OA treatment led to nuclear fragmentation, a hallmark of apoptosis.
- Phosphatidylserine (PS) externalization and alpha-fodrin cleavage occurred in a time-dependent manner.
- Cell death was significantly reduced by CHX and Z-VAD, indicating a caspase-sensitive apoptotic pathway.
Conclusions:
- Okadaic acid (OA) induces neuronal apoptosis through a mechanism sensitive to cycloheximide (CHX) and caspases.
- These findings provide insights into the molecular pathways of OA-induced neurotoxicity, relevant to Alzheimer's disease.
- OA-induced neurodegeneration involves key apoptotic events like nuclear fragmentation and PS externalization.