Neurofilament-light chain protein (NF-L), a biomarker of axon degeneration and neuron death
February 6, 2025
NF-L is a validated biomarker for assessing disease progression, intensity, and treatment response across a wide range of neurodegenerative disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), traumatic brain injury (TBI), and others. It meets all criteria to be a reliable biomarker in both clinical and pre-clinical settings. NF-L is measurable and predictive of both normal biological and pathogenic processes. Additionally, NF-L serves as a pharmacodynamic biomarker, as it can be used to access pharmacologic responses to therapeutic interventions.
Plasma and CSF NF-L levels are Increased in Mouse Models of Neurodegenerative Disorders
Figure 1: Increases in NF-L levels in plasma (A) and CSF (B) in various neurodegenerative models at the indicated ages compared to age-matched WT controls. R62 and Q175 are mouse models of Huntingtin’s disease (HD). APP/PS1 and rTg4510 are mouse models of amyloid and tau pathology of Alzheimer’s disease (AD) respectively. The rNLS8 mouse, which represents dysfunction of the TDP-43 protein, is a model of ALS. It is important to note that increase of NF-L levels in CSF have been reported in patients with AD, HD, and ALS compared to their healthy controls (Gaetani et al. 2019).
Age-dependent increase in NFL levels following Doxycycline (DOX) withdrawal in rNLS8 mice
Figure 2: Measurement of neurofilament light chain protein (NF-L) in plasma and CSF samples of rNLS8 mice, which utilize Tet-Off system in conjugation with the neurofilament heavy chain promoter to conditionally expresses human TDP-43 lacking a nuclear localization sequence in neurons of the brain and spinal cord. This leads to cytoplasmic TDP-43 pathology and progressive motor dysfunction. Their tTA expressing littermate mice served as control. All animals were fed a DOX diet from birth to 5 weeks of age. Afterward, DOX was withdrawn to allow for pathology to develop until mice were 7, 8, or 10 weeks of age. An age-dependent increase in NF-L levels was observed in both plasma and CSF.
Dox treatment reverses the increased NF-L levels in rNLS8 mice, suggesting a rescue after the cessation of mutated hTDP-43 gene expression and clearance of pathological agent.
Figure 3: rNLS8 mice displayed increased NF-L levels when taken off the doxycycline diet, resulting in the expression of the mutated human TDP-43 gene and subsequent neurodegeneration over a period of 4 weeks of DOX cessation (group A). Interestingly, when mice were returned to a doxycycline-containing diet for 3 weeks, plasma and CSF NF-L levels were significantly reduced, indicating a “rescue” effect (group B). This rescue effect was more pronounced with 7-week DOX treatment (Group C). Reversibility of NF-L levels, achieved through turning off mutated human TDP-43 gene expression, clearly demonstrates the utility of NF-L as a reliable biomarker in efficacy studies in this mouse model.
Reference: Gaetani, L., K. Blennow, P. Calabresi, M. Di Filippo, L. Parnetti, and H. Zetterberg. 2019. ‘Neurofilament light chain as a biomarker in neurological disorders’, J Neurol Neurosurg Psychiatry, 90: 870-81.
