Amyotrophic lateral sclerosis (ALS) is a fatal paralytic disorder caused by dysfunction and degeneration of motor neurons. Multiple disease-causing mutations, including in the genes for SOD1 and TDP-43, have been identified in ALS. Astrocytes expressing mutant SOD1 are strongly implicated in the pathogenesis of ALS: we have shown that media conditioned by astrocytes carrying mutant SOD1G93A contains toxic factor(s) that kill motoneurons by activating voltage-sensitive sodium (Nav) channels. In contrast, a recent study suggests that astrocytes expressing mutated TDP43 contribute to ALS pathology, but do so via cell-autonomous processes and lack non-cell-autonomous toxicity. Here we investigate whether astrocytes that express diverse ALS-causing mutations release toxic factor(s) that induce motoneuron death, and if so, whether they do so via a common pathogenic pathway. We exposed primary cultures of wild-type spinal cord cells to conditioned medium derived from astrocytes (ACM) that express SOD1 (ACM-SOD1G93A and ACM-SOD1G86R) or TDP43 (ACM-TDP43A315T) mutants; we show that such exposure rapidly (within 30–60 min) increases dichlorofluorescein (DCF) fluorescence (indicative of nitroxidative stress) and leads to extensive motoneuron-specific death within a few days. Co-application of the diverse ACMs with anti-oxidants Trolox or esculetin (but not with resveratrol) strongly improves motoneuron survival. We also find that co-incubation of the cultures in the ACMs with Nav channel blockers (including mexiletine, spermidine, or riluzole) prevents both intracellular nitroxidative stress and motoneuron death. Together, our data document that two completely unrelated ALS models lead to the death of motoneuron via non-cell-autonomous processes, and show that astrocytes expressing mutations in SOD1 and TDP43 trigger such cell death through a common pathogenic pathway that involves nitroxidative stress, induced at least in part by Nav channel activity.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which pathogenesis and death of motor neurons are triggered by non-cell-autonomous mechanisms. We showed earlier that exposing primary rat spinal cord cultures to conditioned media derived from primary mouse astrocyte conditioned media (ACM) that express human SOD1G93A (ACM-hSOD1G93A) quickly enhances Nav channel-mediated excitability and calcium influx, generates intracellular reactive oxygen species (ROS), and leads to death of motoneurons within days. Here we examined the role of mitochondrial structure and physiology and of the activation of c-Abl, a tyrosine kinase that induces apoptosis. We show that ACM-hSOD1G93A, but not ACM-hSOD1WT, increases c-Abl activity in motoneurons, interneurons and glial cells, starting at 60 min; the c-Abl inhibitor STI571 (imatinib) prevents this ACM-hSOD1G93A-mediated motoneuron death. Interestingly, similar results were obtained with ACM derived from astrocytes expressing SOD1G86R or TDP43A315T. We further find that co-application of ACM-SOD1G93A with blockers of Nav channels (spermidine, mexiletine, or riluzole) or anti-oxidants (Trolox, esculetin, or tiron) effectively prevent c-Abl activation and motoneuron death. In addition, ACM-SOD1G93A induces alterations in the morphology of neuronal mitochondria that are related with their membrane depolarization. Finally, we find that blocking the opening of the mitochondrial permeability transition pore with cyclosporine A, or inhibiting mitochondrial calcium uptake with Ru360, reduces ROS production and c-Abl activation. Together, our data point to a sequence of events in which a toxic factor(s) released by ALS-expressing astrocytes rapidly induces hyper-excitability, which in turn increases calcium influx and affects mitochondrial structure and physiology. ROS production, mediated at least in part through mitochondrial alterations, trigger c-Abl signaling and lead to motoneuron death.
Arousal depends on the concerted activity of the ascending arousal system (AAS) but specific stimuli may primarily activate some nuclei of this system. Motivated behaviours are characterized by behavioural arousal, although it is not known which AAS nuclei are active during a motivated behaviour. To address this issue, rats were rendered motivated for food by fasting them for 1 day and then were enticed with food that they could not obtain for varying periods of time. We studied the level of arousal by polysomnography or radiotelemetry, and Fos-ir in the AAS, during food enticing. We found a strong arousal and an early increase in Fos-ir in the histaminergic neurons from the tuberomammillary nucleus, after 30 min of enticing, followed by increased Fos-ir in the whole AAS if food enticing was prolonged to 1 or 2 hours. In contrast, food presentation to non-motivated rats did not increase arousal or Fos-ir in the tuberomammillary nucleus. As opposed to the active arousal of the motivated rats, passive arousal induced by sensory stimulation was associated with increased Fos-ir in the locus coeruleus and the orexin neurons, but not with increased Fos-ir in the tuberomammillary nucleus or in the other nuclei of the AAS. We conclude that the arousal during feeding-related motivated behaviour is associated primarily with the activation of the tuberomammillary nucleus, while the other arousal-related nuclei become active later on.
Background:Alzheimer’s Disease (AD) is a severe neurodegenerative disorder that includes the occurrence of behavioral disorders as well as memory and cognitive impairment as major symptoms. AD affects around 12% of the aged population in the world. Considerable research efforts have pointed to the role of innate immunity as the main culprit in the pathogenesis of AD. In this context, and according to with our neuroimmunomodulation theory, microglial activation modifies the cross-talks between microglia and neurons. We postulated that glial activation triggered by “damage signals” activates a pathological molecular cascade that finally leads to hyperphosphorylation and oligomerization of the tau protein. Interestingly, these modifications correlate with the gradual cognitive impairment of patients with the AD. Microglial activation is determined by the nature and strength of the stimulus. In the AD, a continuous activation state of microglia appears to generate neuronal injury and neurodegeneration, producing the outflow of pathological tau from the inner of neurons to the extraneuronal space. Released tau, together with the contribution of ApoE4 protein, would then produce reactivation of microglia, thus inducing a positive feedback that stimulates the vicious cycle in neurodegeneration.Conclusion:Nevertheless, from the pathophysiological perspective AD is significantly more than a loss of memory. In the initial stages of AD pathogenesis, variations in the dopaminergic pathway along with serotonin diminution play an important role. This may explain why depression is associated with the onset of AD. All these pathophysiological events take place together with immunomodulatory changes that trigger tau oligomerization in the course of neurofibrillary tangles formation. Interestingly, mood disorders appear to be followed by neuroinflammatory processes and structural/functional alterations that lead to cognitive impairment in the context of AD.
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