From reaction kinetics to dementia: A simple dimer model of Alzheimer's disease etiology
| Autor: | Elijah A. Gross-Sable, David B. Teplow, Eric Y. Hayden, Michael Lindstrom, Manuel B. Chavez |
|---|---|
| Přispěvatelé: | Lytton, William W |
| Rok vydání: | 2020 |
| Předmět: |
Traumatic
0301 basic medicine Male Aging Critical Care and Emergency Medicine Traumatic Brain Injury Basic science Epidemiology Disease Neurodegenerative Alzheimer's Disease Hippocampus Mathematical Sciences Pathogenesis Chromosomal Disorders 0302 clinical medicine Medical Conditions Models Brain Injuries Traumatic Medicine and Health Sciences 2.1 Biological and endogenous factors Aetiology Biology (General) Materials Trauma Medicine Neurons Ecology Chemistry Monomers Neurodegenerative Diseases Statistical Biological Sciences Middle Aged Computational Theory and Mathematics Neurology Modeling and Simulation Neurological Physical Sciences Female Traumatic Injury Research Article Down syndrome Amyloid QH301-705.5 Bioinformatics Materials Science Models Biological Chemical kinetics 03 medical and health sciences Cellular and Molecular Neuroscience Alzheimer Disease Information and Computing Sciences Mental Health and Psychiatry Acquired Cognitive Impairment Genetics medicine Dementia Humans Viability assay Dimers Molecular Biology Ecology Evolution Behavior and Systematics Aged Clinical Genetics Amyloid beta-Peptides Models Statistical Neurosciences Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Computational Biology Biological medicine.disease Polymer Chemistry Brain Disorders Kinetics 030104 developmental biology Brain Injuries Oligomers Medical Risk Factors Protein Multimerization Down Syndrome Neuroscience Neurotrauma 030217 neurology & neurosurgery |
| Zdroj: | PLoS Computational Biology PLoS computational biology, vol 17, iss 7 PLoS Computational Biology, Vol 17, Iss 7, p e1009114 (2021) |
| ISSN: | 1553-7358 |
| Popis: | Oligomers of the amyloid β-protein (Aβ) have been implicated in the pathogenesis of Alzheimer’s disease (AD) through their toxicity towards neurons. Understanding the process of oligomerization may contribute to the development of therapeutic agents, but this has been difficult due to the complexity of oligomerization and the metastability of the oligomers thus formed. To understand the kinetics of oligomer formation, and how that relates to the progression of AD, we developed models of the oligomerization process. Here, we use experimental data from cell viability assays and proxies for rate constants involved in monomer-dimer-trimer kinetics to develop a simple mathematical model linking Aβ assembly to oligomer-induced neuronal degeneration. This model recapitulates the rapid growth of disease incidence with age. It does so through incorporation of age-dependent changes in rates of Aβ monomer production and elimination. The model also describes clinical progression in genetic forms of AD (e.g., Down’s syndrome), changes in hippocampal volume, AD risk after traumatic brain injury, and spatial spreading of the disease due to foci in which Aβ production is elevated. Continued incorporation of clinical and basic science data into the current model will make it an increasingly relevant model system for doing theoretical calculations that are not feasible in biological systems. In addition, terms in the model that have particularly large effects are likely to be especially useful therapeutic targets. Author summary Oligomeric assemblies of Aβ are hypothesized to be seminal pathologic agents in Alzheimer’s disease (AD). Mechanistic studies of oligomerization and neurotoxicity in humans are currently impossible, yet such studies promise to advance efforts toward target identification and drug development. To overcome this hurdle, we developed a simple, mathematical model parameterized using experimental data extant. The model couples the kinetics of oligomerization with oligomer toxicity and enables determination of age-related changes in AD risk and hippocampal volume, the effects of traumatic brain injury on lifetime AD risk, gene dosage effects, and the effects of spatial variation in Aβ monomer concentrations on millimeter scales. The model is easily interpretable and provides a foundation for development of more comprehensive models of AD development and progression. |
| Databáze: | OpenAIRE |
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