Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons. Recent studies have implicated that chronic hypoxia and insufficient vascular endothelial growth factor (VEGF)-dependent neuroprotection may lead to the degeneration of motor neurons in ALS. Expression of apelin, an endogenous ligand for the G protein-coupled receptor APJ, is regulated by hypoxia. In addition, recent reports suggest that apelin protects neurons against glutamate-induced excitotoxicity. Here, we examined whether apelin is an endogenous neuroprotective factor using SOD1G93A mouse model of ALS. In mouse CNS tissues, the highest expressions of both apelin and APJ mRNAs were detected in spinal cord. APJ immunoreactivity was observed in neuronal cell bodies located in gray matter of spinal cord. Although apelin mRNA expression in the spinal cord of wild-type mice was not changed from 4 to 18 weeks age, that of SOD1G93A mice was reduced along with the paralytic phenotype. In addition, double mutant apelin-deficient and SOD1G93A displayed the disease phenotypes earlier than SOD1G93A littermates. Immunohistochemical observation revealed that the number of motor neurons was decreased and microglia were activated in the spinal cord of the double mutant mice, indicating that apelin deficiency pathologically accelerated the progression of ALS. Furthermore, we showed that apelin enhanced the protective effect of VEGF on H2O2-induced neuronal death in primary neurons. These results suggest that apelin/APJ system in the spinal cord has a neuroprotective effect against the pathogenesis of ALS.
Highlights
Amyotrophic lateral sclerosis (ALS), the most common adultonset motor neuron disease, is caused by a selective loss of motor neurons leading to progressive paralysis of muscles and death [1]
We demonstrated that the apelin receptor APJ was detected in neuronal cell bodies located in spinal cord, that apelin expression in spinal cord of SOD1G93A mice was reduced along with the paralytic phenotype, and that apelin deficiency accelerated the progression of ALS
In the spinal cord from wild-type mice at 14 weeks of age, APJ-positive cells were located in the ventral horn and around the central canal, which were colocalized with NeuN, a neuronal marker, -positive cells throughout the spinal cord gray matter (Fig. 2A–C)
Summary
Amyotrophic lateral sclerosis (ALS), the most common adultonset motor neuron disease, is caused by a selective loss of motor neurons leading to progressive paralysis of muscles and death [1]. Transgenic animals overexpressing mutant SOD1 develop progressive motor neuron disease that resembles the clinical and pathological features of human familial ALS [3]. Chronic hypoxia and insufficient vascular endothelial growth factor (VEGF)-dependent neuroprotection has been linked to the degeneration of motor neurons in ALS. Prior to motor neuron degeneration, SOD1 mutants exhibit disruption of the bloodspinal cord barrier, endothelial damage, and hypoperfusion [6]. The cerebrospinal fluid VEGF levels are significantly increased in patients with long duration of ALS [8]. These findings suggest that chronic hypoxia have been implicated in the pathology of ALS
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
