Cerebrospinal fluid neurofilament light chain as a biomarker of neurodegeneration in the Tg4510 and MitoPark mouse models

Abstract

A challenge in working with preclinical models of neurodegeneration has been how to non-invasively monitor disease progression. Neurofilament proteins are established axonal damage markers and have been found to be elevated in cerebrospinal fluid (CSF) and blood from patients with neurodegenerative disorders like Alzheimer’s disease (AD), Parkinson’s disease (PD) and tauopathies. We hypothesized that CSF neurofilament light (NF-L) can be used to track progression of neurodegeneration and potentially monitor the efficacy of novel therapeutic agents in preclinical development. To substantiate this, we examined whether changes in NF-L levels in brain, plasma, and CSF reflect the changing disease status of preclinical models of neurodegeneration. Using Western Blot and ELISA we characterized NF-L and disease-related proteins in brain, CSF and plasma samples from Tg4510 mice (tauopathy/AD), MitoPark mice (PD), and their age-matched control littermates. We found that CSF NF-L clearly discriminates Tg4510 from control littermates, which was not observed for the MitoPark model. However, both Tg4510 and MitoPark showed altered expression and solubilization of NFs compared to control littermates. We found a significant correlation between CSF NF-L and plasma NF-L in Tg4510, suggesting a similar biomarker potential of plasma NF-L. Also, CSF NF-L correlated significantly with tau in Tg4510 brains, suggesting a surrogate biomarker potential of CSF NF-L. Overall, our findings provide further evidence that NF-L correlates with disease severity and our results suggests, that CSF NF-L has utility as a surrogate or adjunct biomarker for neurodegeneration in the Tg4510 model, but independent validation is warranted.