Gillian Ciaccio1, Sarah Kovalev1, Annie McDermott1, Jamie Wong1, Saud Sadiq1
1Tisch Multiple Sclerosis Research Center of New York
Objective:
To validate a recently established cerebrospinal fluid (CSF)-mediated mouse model of sporadic amyotrophic lateral sclerosis (sALS).
Background:
ALS is a neurodegenerative disease characterized by motor neuron degeneration. Only 10% of ALS cases are familial (fALS) while 90% of cases arise sporadically. Previously, we identified apolipoprotein B-100 (ApoB) as a neurotoxic factor in sALS CSF which induces motor disability, motor neuron degeneration and TDP-43 cytoplasmic translocation when delivered intrathecally in mice. This was not observed with fALS CSF from patients with mutations in SOD1, C9orf72, or TARDBP. Recent studies have found an association between CSF ApoB and Alzheimer’s disease (AD) pathology. To validate the specificity of our sALS animal model, we tested CSF samples from additional cohorts of patients with sALS, fALS, and AD.
Design/Methods:
C57BL/6J mice underwent laminectomies at cervical levels C4 and C5, after which 3µL of CSF from patients with either: 1) sALS; 2) SOD1 ALS; 3) C9orf72 ALS; 4) TARDBP ALS; or 5) AD was injected into the subarachnoid space. Control mice were injected with either saline or CSF from healthy individuals. Mice were perfused 1-day post-injection following evaluation of forelimb motor function. Spinal cords were co-immunostained for ChAT and TDP-43. Numbers of ChAT+ motor neurons and ChAT+ motor neurons expressing cytoplasmic TDP-43 were quantified.
Results:
sALS CSF-injected mice demonstrated significant motor disability compared to fALS CSF-injected, AD CSF-injected, and control mice. Furthermore, sALS CSF-injected mice exhibited significantly fewer ChAT+ motor neurons and a significantly increased percentage of motor neurons expressing cytoplasmic TDP-43.
Conclusions:
Impairments in motor function, motor neuron loss and cytoplasmic TDP-43 translocation are induced specifically by sALS CSF and not fALS or AD CSF. This provides validation for the use of sALS CSF injections into the cervical subarachnoid space as a novel model for investigating sALS.