Apoptotic and non-apoptotic roles of caspases in neuronal physiology and pathophysiology.
ABSTRACT Caspases are cysteine proteases that mediate apoptosis, which is a form of regulated cell death that effectively and efficiently removes extra and unnecessary cells during development. In the mature nervous system, caspases are not only involved in mediating cell death but also regulatory events that are important for neural functions, such as axon pruning and synapse elimination, which are necessary to refine mature neuronal circuits. Furthermore, caspases can be reactivated to cause cell death as well as non-lethal changes in neurons during numerous pathological processes. Thus, although a global activation of caspases leads to apoptosis, restricted and localized activation may control normal physiology and pathophysiology in living neurons. This Review explores the multiple roles of caspase activity in neurons.
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ABSTRACT: Methylphenidate (MPH) is commonly prescribed for children who have been diagnosed with attention deficit hyperactivity disorder (ADHD); however, the action mechanisms of methylphenidate have not been fully elucidated. Studies have been shown a relationship between apoptosis signaling pathways and psychiatric disorders, as well as in therapeutic targets for such disorders. So, we investigated if chronic treatment with MPH at the doses of 1, 2 and 10 mg/kg could alter the levels of pro-apoptotic protein, Bax, anti-apoptotic protein, Bcl-2, caspase-3 and cytochrome c in the brain of young and adult Wistar rats. Our results showed that MPH at all doses increased Bax in the cortex; the Bcl-2 and caspase-3 were increased with MPH (1 mg/kg) and were reduced with MPH (2 and 10 mg/kg); the cytochrome c reduced in the cortex after treatment with MPH at all doses; in the cerebellum there was an increase on Bax with MPH at all doses, however, there was a reduced on Bcl-2, caspase-3, and cytochrome c with MPH (2 and 10 mg/kg); in the striatum the treatment with MPH (10 mg/kg) decreased caspase-3 and cytochrome c; treatment with MPH (2 and 10 mg/kg) increased Bax and decreased Bcl-2 in the hippocampus; the caspase-3 and cytochrome c were reduced in the hippocampus with MPH (10 mg/kg). In conclusion, our results suggest that MPH influences plasticity in the brain of young and adult rats; however, the effects were dependent of age and brain area, on the one hand activating the initial cascade of apoptosis, increasing Bax and reducing Bcl-2, but otherwise inhibiting apoptosis by reduction of caspase-3 and cytochrome c.Brain Research 10/2014; 1583. DOI:10.1016/j.brainres.2014.08.010 · 2.83 Impact Factor
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ABSTRACT: Alzheimer's disease (AD) is associated with alterations in the distribution, number, and size of inputs to hippocampal neurons. Some of these changes are thought to be neurodegenerative, whereas others are conceptualized as compensatory, plasticity-like responses, wherein the remaining inputs reactively innervate vulnerable dendritic regions. Here, we provide evidence that the axospinous synapses of human AD cases and mice harboring AD-linked genetic mutations (the 5XFAD line) exhibit both, in the form of synapse loss and compensatory changes in the synapses that remain. Using array tomography, quantitative conventional electron microscopy, immunogold electron microscopy for AMPARs, and whole-cell patch-clamp physiology, we find that hippocampal CA1 pyramidal neurons in transgenic mice are host to an age-related synapse loss in their distal dendrites, and that the remaining synapses express more AMPA-type glutamate receptors. Moreover, the number of axonal boutons that synapse with multiple spines is significantly reduced in the transgenic mice. Through serial section electron microscopic analyses of human hippocampal tissue, we further show that putative compensatory changes in synapse strength are also detectable in axospinous synapses of proximal and distal dendrites in human AD cases, and that their multiple synapse boutons may be more powerful than those in non-cognitively impaired human cases. Such findings are consistent with the notion that the pathophysiology of AD is a multivariate product of both neurodegenerative and neuroplastic processes, which may produce adaptive and/or maladaptive responses in hippocampal synaptic strength and plasticity.Brain Structure and Function 07/2014; DOI:10.1007/s00429-014-0848-z · 4.57 Impact Factor