Evidence for Synaptic Apoptosis
Autor: | James G. Begley, Jeffrey N. Keller, Mark P. Mattson |
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Rok vydání: | 1998 |
Předmět: |
Programmed cell death
Dendritic spine Blotting Western Glutamic Acid Apoptosis Caspase 3 Cysteine Proteinase Inhibitors Hippocampus Membrane Potentials Rats Sprague-Dawley Synapse Developmental Neuroscience medicine Animals Annexin A5 Cells Cultured Caspase Cell Nucleus Neurons Cell-Free System biology Glutamate receptor Depolarization Rats Cell biology Cysteine Endopeptidases medicine.anatomical_structure Neurology Caspases Synapses biology.protein Calcium Female Neuron Reactive Oxygen Species Neuroscience Biomarkers Synaptosomes |
Zdroj: | Experimental Neurology. 153:35-48 |
ISSN: | 0014-4886 |
DOI: | 10.1006/exnr.1998.6863 |
Popis: | Increasing evidence indicates that neurons die by apoptosis, an active form of cell death involving a relatively stereotyped series of biochemical changes that culminate in nuclear fragmentation, in many different developmental and pathophysiological settings. In contrast to most other cell types, neurons have elaborate morphologies with complex neuritic arbors that often extend great distances from the cell body. Neuronal death signals are likely to be activated at remote synaptic sites and, indeed, overactivation of glutamate receptors and underactivation of trophic factor receptors are implicated in neurodegenerative disorders. We now report that biochemical changes consistent with apoptosis are engaged locally in synapses. Exposure of cortical synaptosomes to staurosporine and Fe2+ resulted in loss of membrane phospholipid asymmetry, caspase activation, and mitochondrial alterations (membrane depolarization, calcium overload, and oxyradical accumulation) characteristic of apoptosis. The caspase inhibitor zVAD-fmk prevented mitochondrial membrane depolarization in synaptosomes. Studies of the effects of cytosolic extracts from synaptosomes exposed to apoptotic insults, on isolated nuclei, showed that signals capable of inducing nuclear apoptosis are generated locally in synapses. Exposure of cultured hippocampal neurons to staurosporine and glutamate resulted in caspase activation and mitochondrial membrane depolarization in dendrites, and zVAD-fmk prevented the membrane depolarization. Glutamate-induced increases in caspase activity were first observed in dendrites and later in the cell body, and focal application of glutamate to individual dendrites resulted in local activation of caspases. Collectively, the data demonstrate that apoptotic biochemical cascades can be activated locally in synapses and dendrites and suggest a role for such local apoptotic signals in synapse loss and neuronal death in neurodegenerative disorders that involve excessive activation of glutamate receptors. |
Databáze: | OpenAIRE |
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