Die Rolle der Neuropeptide Calcitonin gene-related Peptide und Pituitary adenylate cyclase-activating Peptide im Superoxiddismutase 1 Mausmodell der amyotrophen Lateralsklerose
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Philipps-Universität Marburg
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Abstract
Amyotrophic lateral sclerosis (ALS) is an adult-onset, neurodegenerative disease characterised by the selective loss of upper and lower motor neurones, resulting in progressive paralysis and death due to respiratory failure. Up to date no effective cure is available and the multifaceted molecular causes are poorly understood. In this context, two aspects are of special interest: first, the participation of neuroinflammatory processes in the genesis and progression
of the disease and, second, molecular differences between motor neurons which are vulnerable or resistant to disease pathology, respectively.
While the neuroprotective properties of various neuropeptides are well studied in Parkinson’s and Alzheimer’s disease as well as in ischemia and axotomy, but their role in ALS is not known. Therefore, the present study investigates the involvement of the two most promising candidates Calcitonin gene-related Peptide (CGRP) and Pituitary adenylate cyclaseactivating Polypeptide (PACAP) in the pathogenesis of the SOD1G93A mouse model of ALS.
During ALS pathology no up-regulation of CGRP expression was observed in motor neurons of SOD1 transgenic mice. Instead, CGRP-immunoreactive vacuoles occurred in the neurites of brain stem motor neurons, starting at postnatal day (P) 40 and increasing in diameter with age. After degeneration of the motor neuron they become freely localized in the neuropil without any assignment to a cell type or compartment. These chances in CGRPimmunoreactivity clearly preceded the onset of clinical symptoms at P90-100 and showed a close spatiotemporal association with the activation of astroglia. Additionally, starting at P40
as well, CGRP-positive vacuoles appeared in other brain areas, e.g. hypothalamus and substantia nigra. Because some ALS patients show nigral or extra motoric deficits as well, these findings within the SOD1 mouse model are an additional strong hint for ALS being a multisystem disorder with different subtypes rather than a motor neuron specific disease.
Furthermore, CGRP was identified as the first molecular biomarker for vulnerable motor neurones.
Three different types of motor neurones were defined based on their CGRP expression level: neurons with high or low expression levels (high and lowCGRP), respectively, and neurons without CGRP expression (nonCGRP). NonCGRP motor neurons were found to be ALS resistant, whereas CGRP-expressing motor neurones were vulnerable, in a way that the higher their CGRP expression, the more prone to degenerate they were. The hitherto existing seperation of the resistant, extra ocular motor nuclei from other vulnerable motor nuclei in the
brain stem also was based on CGRP expression. As an example, the oculomotor nucleus nearly exclusively consists of resistant nonCGRP motor neurons, whereas the highly vulnerable ambiguus nucleus is mostly build up by highCGRP motor neurons.
Whereas a deletion of αCGRP had no effect on the time course of the disease in SOD1G93A mice, a deletion of the CGRP specific receptor component receptor affinity modifying protein 1 (RAMP1) resulted in an earlier onset of the motor dysfunctions, followed by a deceleration of disease progression. On the histological level, these changes were associated with a reduced neuroinflammation, most notably the absence of lymphocyte infiltration and a reduced astroglial activation. Therefore, the functional role of CGRP in ALS may be to activate and drive neuroinflammation and to stimulate lymphocyte infiltration into the brain parenchyma.
Given the earlier disease onset but slower progression in RAMP1-deficient mice with lower extent of neuroinflammation, one could conclude that the neuroinflammation itself has a neuroprotective impact in early disease stages whereas in later stages, the effect changes to neurotoxic characteristics. Thus, in the already diseased ALS patient, application of CGRP antagonist may be a potent therapeutic strategy to reduce toxic components of the neuroinflammation and thereby slowing disease progression.
PACAP was found not to be expressed to a significant extent in wildtype motor neurons. An induction of PACAP gene expression was only observed in a few single motor neurons in the ALS model studied here. But, in spite of these minimal changes , a depletion of PACAP in SOD1G93A mice resulted in an extension of life time of about 5,5%. Thus, in contrast to neurodegenerative
disorders like Alzheimer’s and Parkinson’s disease or neuronal damage during
axotomy or ischemia, PACAP seems so play a neurodestructive role during ALS pathology.
On the histological level, a change in microglial number and morphology was observed, suggesting a different degree or later onset of activation in PACAP-deficient mice. This, in turn, may result in a reduction of the neurotoxic effects of the neuroinflammation in the late stage of the disease. Therefore, the use of antagonists against PACAP may exert some therapeutic potential as well.
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Created: 2011Issued: 2011-12-19Updated: 2011-12-21
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
Keywords
motorneurone disease
DFG-subjects
Myatrophische Lateralsklerose
DDC-Numbers
610
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Ringer, Cornelia (112462057): Die Rolle der Neuropeptide Calcitonin gene-related Peptide und Pituitary adenylate cyclase-activating Peptide im Superoxiddismutase 1 Mausmodell der amyotrophen Lateralsklerose. : Philipps-Universität Marburg 2011-12-19. DOI: https://doi.org/10.17192/z2011.0782.
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This item has been published with the following license: In Copyright