Intermittent Hypoxia Can Aggravate Motor Neuronal Loss and Cognitive Dysfunction in ALS Mice

Abstract

BackgroundPatients with ALS may be exposed to variable degrees of chronic intermittent hypoxia. However, all previous experimental studies on the effects of hypoxia in ALS have only used a sustained hypoxia model and it is possible that chronic intermittent hypoxia exerts effects via a different molecular mechanism from that of sustained hypoxia. No study has yet shown that hypoxia (either chronic intermittent or sustained) can affect the loss of motor neurons or cognitive function in an in vivo model of ALS. ObjectiveTo evaluate the effects of chronic intermittent hypoxia on motor and cognitive function in ALS mice.MethodsSixteen ALS mice and 16 wild-type mice were divided into 2 groups and subjected to either chronic intermittent hypoxia or normoxia for 2 weeks. The effects of chronic intermittent hypoxia on ALS mice were evaluated using the rotarod, Y-maze, and wire-hanging tests. In addition, numbers of motor neurons in the ventral horn of the spinal cord were counted and western blot analyses were performed for markers of oxidative stress and inflammatory pathway activation.ResultsCompared to ALS mice kept in normoxic conditions, ALS mice that experienced chronic intermittent hypoxia had poorer motor learning on the rotarod test, poorer spatial memory on the Y-maze test, shorter wire hanging time, and fewer motor neurons in the ventral spinal cord. Compared to ALS-normoxic and wild-type mice, ALS mice that experienced chronic intermittent hypoxia had higher levels of oxidative stress and inflammation.ConclusionsChronic intermittent hypoxia can aggravate motor neuronal death, neuromuscular weakness, and probably cognitive dysfunction in ALS mice. The generation of oxidative stress with activation of inflammatory pathways may be associated with this mechanism. Our study will provide insight into the association of hypoxia with disease progression, and in turn, the rationale for an early non-invasive ventilation treatment in patients with ALS.

Gene expression signatures in motor neurone disease fibroblasts reveal dysregulation of metabolism, hypoxia‐response and RNA processing functions

“…The lack of this response, even when the hypoxia is chronic, has been shown to have significant effects in the SOD1 G93A ALS mouse model. Mutant SOD1 mice which experienced chronic intermittent hypoxia showed reduced performance on the rotarod, reduced ability in the wire hanging test, poorer spatial memory as assessed by the Y-maze, and a greater loss of motor neurones, compared to the SOD1 G93A mice under normoxia conditions [81]. This correlates with data recorded from ALS patients, which compared nocturnal hypoxia with cognitive dysfunction [82].…”

Vascular Defects and Spinal Cord Hypoxia in Spinal Muscular Atrophy

“…In addition to the gross defects in vascular development, defects in key BSCB proteins are also present in SMA mouse spinal cord. Given the known sensitivity of lower motor neurons to hypoxia in vivo, 32 these findings highlight a novel link between systemic vascular pathology and the particular vulnerability of the neuromuscular system in SMA. This novel description of vascular defects in severe forms of SMA suggests that therapeutic targeting of the vascular system in order to ameliorate functional hypoxia and BSCB defects is likely to be required in order to deliver a systemic rescue of SMA.…”

The Peripheral Immune System and Amyotrophic Lateral Sclerosis

“…A gene expression study found evidence of hypoxia related genes in peripheral blood of ALS patients (55). In an animal model of ALS, hypoxia aggravates the loss of motor neurons (154). The significance of these findings is presently unclear, but this is further evidence of peripheral immune changes in ALS.…”