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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive onset of motor neuron degeneration in both the brain and spinal cord, leading to motor dysfunction. Sporadic ALS (sALS) is the dominant subtype, accounting for approximately 90% of all ALS cases, but lacks a specific disease model. To better study sALS, we developed a new murine model by intrathecally injecting the CSF of human sALS patients into experimental mice. We previously reported how this method recapitulates many symptoms of ALS, including motor disability, and lower and upper motor neuron loss. CSF filtration and proteomic analyses led to the identification of apolipoprotein B-100 (ApoB) as the neurotoxic factor in sALS CSF. Here, we explored whether ApoB also induces upper motor neuron degeneration in our animal model.
Adult C57BL/6J female mice underwent laminectomies at cervical levels 4 and 5, then received an intrathecal injection of 3 µL of either: 1) sALS CSF, 2) ApoB-depleted ALS CSF, 3) human ApoB protein or 4) saline. sALS patient CSF was depleted of ApoB through incubation with ApoB antibody-bound Dynabeads®. At one day post-injection, mice were perfused for histological analysis of the brains. Brains were post-fixed overnight in 4% paraformaldehyde, cryoprotected in 30% sucrose, then cryosectioned at 30 µm for immunostaining with the neuronal marker NeuN. All histological analyses were performed blinded.
A significant decrease in the number of NeuN+ motor neurons in the motor cortices was observed in mice injected with sALS CSF, but not in mice injected with ApoB-depleted sALS CSF. Upper motor neuron loss was also observed in ApoB-injected mice. This indicates that ApoB is likely primarily responsible for upper motor neuron degeneration in our animal model. Because the injection is performed at the cervical spinal cord, we question if the observed degeneration is triggered by the diffusion of ApoB from the injection site to the brain or if a retrograde signaling mechanism is triggered by the death of lower motor neurons. We will further investigate this question in order to better understand the pathogenesis of sALS.
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