Background: ALS is a progressive neurodegenerative disorder characterized by motor neuron death. We have previously reported that motor deficits and motor neuron degeneration are induced in mice following intrathecal administration of sporadic ALS cerebrospinal fluid (sALS CSF) into the cervical subarachnoid space by 1 day post injection (1DPI). This suggests there are neurotoxic factors present in sALS CSF which may be filterable.
Objectives: To assess whether filtration of sALS CSF can remove pathological factors responsible for inducing neurotoxic effects in mice.
Approach: CSF obtained from sALS patients was passed through a tangential flow filtration system for 3 filtration cycles to remove CSF components larger than 5kDa. 8-10 week old C57Bl/6 mice underwent laminectomies at cervical levels 4 and 5, then 3μl of sALS or filtered sALS CSF was injected under the dura mater into the subarachnoid space. Control mice were injected with saline. Functional deficits were assessed by evaluating forelimb reaching accuracy, grip strength and tail flaccidity at 1DPI, then mice were immediately perfused for histological analyses of the spinal cord.
Results: Filtration of sALS CSF reduced protein concentration and Coomassie blue staining confirmed the removal of proteins larger than 5kDa. sALS CSF-injected mice exhibited significantly impaired forelimb function and weaker grip strength compared to saline controls and mice injected with filtered sALS CSF. Increased death of motor neurons was revealed by significantly fewer ChAT-positive motor neurons in the cervical spinal cords of sALS CSF-injected mice compared to saline and filtered sALS CSF-injected mice.
Conclusions: Neurotoxic factors in sALS CSF can be removed by filtration, which alleviates motor deficits and motor neuron degeneration. This suggests that CSF pheresis may be a therapeutic option. Identification of the pathological factors in sALS CSF responsible for these neurotoxic effects is an important next step.