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Quantitative systems pharmacology model for neurofilament L dynamics in Alzheimer
EP39012
Poster Title: Quantitative systems pharmacology model for neurofilament L dynamics in Alzheimer's disease pathology
Submitted on 07 Jul 2022
Author(s): Polina Pchelintseva, Tatiana Karelina
Affiliations: InSysBio
This poster was presented at ACoP12
Poster Views: 195
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Poster Information
Abstract: Background: Neurofilaments are neuronal cytoskeleton proteins, their increased concentration in plasma and cerebrospinal fluid (CSF) is considered as a marker of axonal degeneration in neurodegenerative diseases, including Alzheimer’s Disease (AD) and traumatic brain injury. Neurofilament light (NfL) is potentially useful in both AD diagnosis and for studying the disease's preclinical stages of pathogenic progression [1]. In addition, neurofilaments are contained in the neurofibrillary tangles, one of the hallmarks of AD [2]; neurons expressing neurofilaments are much more vulnerable to tau pathology and degeneration, neurofilament compactions (pathological aggregates of neurofilaments) are the earliest markers of axonal injury. Concentration of NfL correlates with white matter hyperintensities (WMH), marker of axonal damage.
The goal is to develop translational quantitative systems pharmacology (QSP) model describing relationship between violation of intraneuronal processes and the change of the concentration of neurofilament L in the brain and cerebrospinal fluid during the progression of Alzheimer’s disease.

Methods: The model describes synthesis of neurofilaments and their degradation by calpain, proteasome and autophagic system; phosphorylation/dephosphorylation, formation of pathological
aggregates, and the release of neurofilament proteins from degenerating axons into the extracellular space with distribution to the CSF. Description of the processes is partially based on neuron homeostasis model developed earlier [3]. To calibrate the model, we used literature data on the concentration of neurofilaments in brain and cerebrospinal fluid, the level of phosphorylation, and in vitro data on degradation of neurofilaments in different conditions. Influence of tau and amyloid pathology, and of impaired axonal transport are introduced as explicit functions.

Result: With tau and amyloid accumulation corresponding to the data, the model correctly describes the increase of the Nfl concentration in cerebrospinal fluid in Alzheimer’s disease versus healthy subjects. It predicts accumulation of neurofilaments in the brain cells, corresponding to increase of WMH.The model can be further expanded to describe the concentration of Nfl in plasma.

Conclusion: The described model allows to describe axonal damage and its markers and can be used as a part of QSP platforms of different neurodegenerative disease to predict treatment efficacy.
Summary: The described model allows to describe axonal damage and its markers and can be used as a part of QSP platforms of different neurodegenerative disease to predict treatment efficacy.
References: 1. Alzheimers Dement (Amst). 2020 Feb 27;12(1):e12005.
2. Proc Natl Acad Sci U S A. 1985 Jun;82(11):3916-20.
3. CPT: Pharmacometrics & Systems Pharmacology, December 2020, 1–8.
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