Histological analysis of the motor cortex in a Copper-ATSM treated mouse model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is an incurable paralysing condition caused by the loss of cortical and spinal motor neurons. Approximately 90% of cases appear sporadic and are likely to be linked to largely undefined environmental triggers. One strong environmental risk factor for ALS is chronic dietary exposure to cycad-derived toxins, which is linked to Guamanian ALS/Parkinsonism-dementia complex (ALS-PDC). The cycad steryl glucoside β-sitosterol β-D-glucoside (BSSG) induces progressive spinal motor neuron degeneration in mice and has been proposed as an environmental neurotoxin-induced model of sporadic ALS. However, cortical pathology in this model remains incompletely characterised. We therefore examined the motor cortices of BSSG-treated mice for ALS-relevant pathology. Quantitative histological analyses revealed no evidence of cortical neurodegeneration or TDP-43 mislocalisation as a result of BSSG, with only a subtle non-significant increase in microglial signal coverage. A subset of mice was treated with the brain-penetrant copper complex CuATSM, a potential ALS therapeutic currently under clinical investigation. CuATSM did not confer clear neuroprotection in the motor cortex, although modest trends toward altered microglial process complexity were detected. Furthermore, the combination of CuATSM and BSSG was associated with a 30.7% reduction in the number of parvalbumin interneurons, suggesting a toxic interaction between these two agents.