Neurofilament L dynamics description in the model of tauopathy

Abstract

AbstractBackgroundNeurofilament proteins are important constituents of neuronal cytoskeleton along with microtubules. Increased concentration of neurofilament light protein in cerebrospinal fluid(CSF) and plasma is considered as a potential biomarker of axonal degeneration [1]. Together with tau, neurofilaments are contained in the neurofibrillary tangles (NFT), the biomarker of Alzheimer’s disease and other tauopathies [2]. The goal of this study was to develop a quantitative systems pharmacology (QSP) model to describe neurofilament dynamics during progression of tauopathies both in human patients and in transgenic P301L Tau mice.MethodThe quantitative model correctly describes the dynamics of neurofilament proteins during neurodegeneration processes, which include cytoskeletal degradation by calpain, proteasome, autophagy and caspase, formation of pathological aggregates, release of neurofilament proteins from degenerated axons to cerebrospinal fluid and plasma. These processes are dependent on pathological processes in tauopathy models, such as changes in protein degradation, axonal transport deficits, pathological hyperphosphorylated tau accumulation. To calibrate the model, the literature data on neurofilament concentration in brain, cerebrospinal fluid and plasma, phosphorylation and degradation level were used. Description of the processes is partially based on neuron homeostasis model developed earlier [3]. The model was validated on taupathy P301L transgenic mice, amyloid APP/PS1 mice and on Alzheimer’s disease patients’ data.ResultThe described model correctly predicts the increase of neurofilament light protein concentration in CSF and plasma both in P301L transgenic mice model of tauopathy and in human patients versus controls. Pathological changes of microtubule dynamics and cytoskeleton breakdown are also described. Model predicts the reduction of NfL concentration in CSF during potential tau targeting therapy in P301L transgenic mice and humans.ConclusionThe developed model can be helpful in simulating potential effects of therapeutics used in neurodegeneration diseases treatment.