Filtration reduces neurotoxicity of sporadic ALS cerebrospinal fluid in a mouse model

Nadia M. Celestin, Taylor M. Shue, Joseph M. Beaty, Jamie K. Wong, Saud A. Sadiq, MD Presented at the American Academy of Neurology (AAN) Annual Meeting held April 17-22, 2021

Objective: To determine the molecular weight range of neurotoxic components in sporadic amyotrophic lateral sclerosis (sALS) cerebrospinal fluid (CSF) responsible for triggering ALS-like features in mice.

Background: ALS is a fatal neurodegenerative disorder characterized by motor neuron death. We have previously demonstrated that intrathecal injection of sALS CSF into the cervical subarachnoid space of mice results in motor deficits and motor neuron degeneration by 1-day post injection (1DPI). Moreover, removal of sALS CSF components larger than 5 kDa via filtration reduced its neurotoxic capacity. Here we determined whether removal of sALS CSF factors larger than 100kDa attenuates the ability of sALS CSF to induce motor deficits and pathology.

Design/Methods: CSF obtained from sALS patients was passed through a tangential flow filtration system 3 times for removal of components larger than 100kDa. Laminectomies at cervical levels 4 and 5 were performed on 8-10-week-old C57Bl/6 mice, then 3μl of sALS CSF, filtered sALS CSF, or saline were injected into the subarachnoid space. Forelimb reaching accuracy, grip strength, and tail flaccidity were measured at 1DPI to assess motor deficits. Post clinical assessment, mice were perfused for histological analyses of the spinal cord.

Results: Coomassie blue staining confirmed removal of proteins larger than 100kDa. Mice injected with sALS CSF showed significantly impaired forelimb function and weaker grip strength compared to mice injected with filtered sALS CSF or saline. sALS CSF-injected mice also exhibited the greatest extent of motor neuron death, as indicated by a significant reduction in ChAT-positive motor neurons in the cervical spinal cord.

Conclusions: Filtration eliminated the capacity of sALS CSF to induce neurotoxic effects in vivo, suggesting that neurotoxic factors are larger than 100kDa and CSF pheresis may be a therapeutic option for sALS. Currently we are investigating candidate proteins larger than 100kDa to identify the neurotoxic component(s) present in sALS CSF.

Abstract Date

April 21, 2021

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