NF-L in cerebrospinal fluid and serum is a biomarker of neuronal damage in an inducible mouse model of neurodegeneration

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. Here we have used an inducible transgenic mouse model of neurodegeneration, CamKII-TetOp25 mice, 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 increase in CSF and serum NF-L levels that correlated with ongoing neurodegeneration. Switching off p25 prevented further increases in both CSF and serum NF-L levels and concomitantly stopped the progression of neurodegeneration. 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). In addition, our 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 are of interest to be further explored as potential translational dynamic biomarkers of neurodegeneration or as pharmacodynamics biomarkers at least in preclinical animal studies.

Serum neurofilament light chain levels as a marker of upper motor neuron degeneration in patients with Amyotrophic Lateral Sclerosis

“…Intriguingly, it is not clear yet how NfL is shed into the peripheral blood in ALS. Brureau and colleagues have identified in CSF of Thy-Tau22 mice a 10-kDa fragment of NfL but not the full-length NfL that is detected with a commercial enzyme-linked immunosorbent assay using the same pair of antibodies as in our study [21]. This might suggest that studies in human body fluids also detect short fragments of NfL that might give clues on which mechanisms are involved in the shedding of NfL from brain into blood.…”

“…In a mouse model where neuronal injury was induced by cranial irradiation, increase in serum NfL was observed, independently of the blood-brain barrier permeability [20]. The CNS origin of elevated levels of NfL in CSF and in serum is further confirmed by the correlation between rising levels of serum and CSF NfL with activation of neurodegeneration in an inducible mouse model of neurodegeneration [21]. Furthermore, elevated levels of serum and CSF NfL have been reported in other neurodegenerative diseases mainly affecting the cerebral cortex such as Alzheimer's disease [16], FTD [22] and Huntington's disease [23].…”

Correlations between serum and CSF pNfH levels in ALS, FTD and controls: a comparison of three analytical approaches

“…In addition, NFL in CSF and serum is also a biomarker reflecting induced neuronal damage in a mouse model, where NFL is increased after induction of neurodegeneration but does not increase after the induction is stopped, suggesting that NFL mirrors the ongoing neurodegeneration and neuronal loss [129]. The levels of NFL also correlated with the extent of neuronal damage (assessed through immunostaining), suggesting that NFL could be used as a dynamic marker of neurodegeneration [129]. This is a confirmation that NFL is also increased in a pre-clinical model where neurodegeneration can be induced, concluding that NFL is a translational biomarker that can be used when developing therapeutics to monitor treatment effects.…”

“…Also further studies in the protein structure are needed since it has been postulated that NFL in CSF could be degraded and/or aggregated [129]. This would give insight into the dynamics of neurofilament degradation that could also vary in different neurodegenerative diseases, similarly to the phosphorylation status of NFH.…”

Serum Neurofilament Light Is Elevated Differentially in Older Adults with Uncomplicated Mild Traumatic Brain Injuries

“…Proteolytic (i.e., enzyme breakdown) processes that occur during axonal degeneration lead to incomplete neurofilament degradation (Schlaepfer et al, 1984). Therefore, following axonal damage (Schlaepfer et al, 1984) or neuronal degeneration (Disanto et al, 2017), neurofilaments are released and are present in both the cerebrospinal fluid and the bloodstream (Bacioglu et al, 2016;Brureau et al, 2017).…”