Under normal conditions, neurofilaments, proteins that form the neuronal cytoskeleton, are released at low levels into the extracellular space. From there, they gradually enter the cerebrospinal fluid (CSF) and the bloodstream. Throughout life, levels of neurofilaments—especially neurofilament light chain, a protein crucial for neuronal structural stability—gradually increase in blood and CSF circulation (Beydoun et al., 2021). When neurons are injured, however, NfL release rises significantly, making it a sensitive and quantifiable indicator of neuro-axonal damage (Ahmad et al., 2024). 

Leverage clinically relevant Neurofilament light chain as a biomarker in InnoSer’s in vivo neurodegeneration models 

In humans, plasma NfL levels are consistently elevated relative to healthy controls across a range of neurodegenerative diseases. Reported increases are typically around two-fold in Alzheimer’s disease (AD), approximately one-fold in Parkinson’s disease (PD), four- to five-fold in multiple sclerosis (MS), and up to twenty-fold in amyotrophic lateral sclerosis (ALS) (Gaetani et al., 2019). Although slight variations can occur across studies, disease stages, and subtypes, NfL concentrations remain consistently higher in affected individuals, underscoring its robustness as a marker of neuroaxonal injury and establishing it as a crucial disease progression marker.  

Importantly, NfL’s high sensitivity and its adoption in clinical trials make it a powerful translational biomarker in preclinical studies, enabling not only early detection of neuronal damage in mouse models of neurodegeneration, but also quantitative assessment of therapeutic efficacy.  

At InnoSer, we have validated this translational biomarker across multiple in vivo models of neurodegenerative disease, demonstrating that increased plasma and/or CSF NfL levels consistently reflect the underlying neurodegenerative disease pathophysiology. NfL is measured using MSD or ELISA assays, requiring only small sample volumes. This makes it possible to monitor NfL levels over multiple time points and easily pair the data with additional analyses, such as PK/PD or additional blood-based endpoints, within a single study. 

Below, we present data from several of our models, comparing wild-type animals with disease models at a single time point or across multiple stages of disease progression. 

Neurofilament light chain in Alzheimer’s disease mouse models

The APP[V717I]xPS1[A246E] mouse model shows elevated levels of NfL in CSF and plasma at 9 months of age

FIGURE 1. NfL is elevated in the plasma and CSF of APP[V717I]xPS1[A246E] mice at 9 months of age, indicating neuroaxonal damage. This APPxPS1 mouse model represents a mouse model with aggressive, early-onset (6 mo onwards) amyloidosis pathology, suitable for preclinical evaluation of therapies targeting Aβ accumulation, neuroinflammation, and cognitive impairment. Learn more about the APP[V717I]xPS1[A246E] model here.

Homozygous Tau[P301S] mice show progressive elevations in the plasma NfL levels

FIGURE 2. Longitudinal analysis shows a progressive increase in plasma NfL levels in homozygous Tau[P301S] transgenic mice. Given that the Tau[P301S] mouse model develops an early and robust phenotype (motor and pathological onset around 3-4 months), this model is especially suitable for rapid efficacy screening of Tau-targeted interventions in a short time window. Learn more about the Tau[P301S] model here.

Plasma NfL levels increase with disease progression and correlate with plasma pTau181 in the combined APP[V717I]×Tau[P301S] mouse model

FIGURE 3. A significant positive correlation was observed between plasma NfL and pTau181 levels, supporting the utility of plasma NfL and pTau181 as complementary plasma biomarkers for disease progression. The APP[V717I]xTau[P301S] mouse model is ideal for evaluating disease-modifying therapies targeting both amyloid and tau pathologies simultaneously. Learn more about the APP[V717I]xTau[P301S] model here.

Neurofilament light chain in ALS mouse models

SOD1(G93A) mice show increased levels of NfL at 11 weeks

FIGURE 4. Compared to WT littermates, SOD1(G93A) mice show significantly higher concentrations of plasma NfL at 11 weeks of age, even before the onset of robust motor dysfunction. The SOD1(G93A) mouse model represents a well-established mouse model of ALS, allowing preclinical testing of therapeutics targeting SOD1 proteinopathy. Learn more about the SOD1(G93A) model here.

Plasma NfL is elevated in TDP43(Q331K) mice starting at 5 weeks of age and remains elevated up to 9 months

Figure 5. Longitudinal measurements of plasma NfL from 5 to 14 weeks of age show that female TDP-43(Q331K) mice exhibit significant elevations in plasma NfL compared to wild-type littermates, indicating an early-onset and progressive neuronal injury phenotype. Plasma NfL remains elevated up to 9 months of age in TDP-43(Q331K) mice (not shown here). We’ve previously shown that the TDP-43(Q331K) mouse model represents a robust model of TDP-43-associated pathophysiology; learn more about TDP-43(Q331K) mice here. 

Neurofilament light chain in Huntington’s disease mouse model

Figure 6. Progressive increases of NfL in CSF reflect the progressive pathology in this Huntington’s disease model. The zQ175 knock-in mouse model represents a widely used preclinical research model; learn more about the zQ175 knock-in model here.

Neurofilament light chain in Multiple Sclerosis mouse model

Figure 7. Compared to non-induced (negative control) mice, vehicle-treated EAE mice showed a significant increase in plasma NfL at day 16 (**P<0.01) and 28 post-immunization (**P<0.01), corresponding to peak disease activity. The EAE mouse model represents a relevant preclinical model to study efficacy of novel treatments against Multiple Sclerosis, learn more about the EAE mouse model here.

Quantify the neuroprotective efficacy of your therapeutic compound and strengthen the translational impact of your preclinical studies by integrating plasma or CSF NfL as a readout. Ready to elevate your preclinical research? Let’s work together to ensure your therapy achieves optimal clinical outcomes.