NFL in CSF and serum, a potential translational dynamic biomarker of neurodegeneration in preclinical models

Abstract

Accumulation of Neurofilaments (NFs), the major constituents of the neuronal cytoskeleton, is a distinctive feature of neurological diseases and several studies have shown that soluble NFs can be detected in the cerebrospinal fluid (CSF) of patients with neurological diseases, such as multiple sclerosis and frontotemporal dementia. We have used an inducible transgenic mouse model of neurodegeneration, CamKII-TetOp25 mice (Tsai et al., 2003), to evaluate whether NF-L levels in CSF or blood can be used as a biochemical biomarker of neurodegeneration. Induction of p25 transgene brain expression led to increases in CSF and serum NF-L levels that correlated with increased neuronal stress and neurodegeneration. When p25 transgene expression was switched off this prevented further increases in both CSF and serum NF-L levels which correlated with the block of further increases in neuronal stress and neuronal loss. The levels of CSF NF-L detected in p25 mice are about 4–fold higher than the CSF levels detected in patients with chronic neurodegenerative diseases, such as symptomatic FTD (bvFTD). We also report increase with aging in CSF and plasma NFL in two other transgenic mouse models, ThyTau22 (Schindowski et al., 2006) and APPxPS1 mice (Balnchard et al., 2003). Finally, Western blot and NanoLC-MS/MS data indicate that the NF-L detected in CSF is most likely a cleaved form of NF-L. These results suggest that CSF and serum NF-L could be used as potential translational dynamic biomarkers of neurodegeneration in preclinical animal models and in clinical studies.