From reaction kinetics to dementia: A simple dimer model of Alzheimer's disease etiology.

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 compl...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Michael R Lindstrom, Manuel B Chavez, Elijah A Gross-Sable, Eric Y Hayden, David B Teplow
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/3c582736fd1d498ab466555361aee08a
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:3c582736fd1d498ab466555361aee08a
record_format	dspace
spelling	oai:doaj.org-article:3c582736fd1d498ab466555361aee08a2021-12-02T19:57:31ZFrom reaction kinetics to dementia: A simple dimer model of Alzheimer's disease etiology.1553-734X1553-735810.1371/journal.pcbi.1009114https://doaj.org/article/3c582736fd1d498ab466555361aee08a2021-07-01T00:00:00Zhttps://doi.org/10.1371/journal.pcbi.1009114https://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Oligomers 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.Michael R LindstromManuel B ChavezElijah A Gross-SableEric Y HaydenDavid B TeplowPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 17, Iss 7, p e1009114 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Michael R Lindstrom Manuel B Chavez Elijah A Gross-Sable Eric Y Hayden David B Teplow From reaction kinetics to dementia: A simple dimer model of Alzheimer's disease etiology.
description	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.
format	article
author	Michael R Lindstrom Manuel B Chavez Elijah A Gross-Sable Eric Y Hayden David B Teplow
author_facet	Michael R Lindstrom Manuel B Chavez Elijah A Gross-Sable Eric Y Hayden David B Teplow
author_sort	Michael R Lindstrom
title	From reaction kinetics to dementia: A simple dimer model of Alzheimer's disease etiology.
title_short	From reaction kinetics to dementia: A simple dimer model of Alzheimer's disease etiology.
title_full	From reaction kinetics to dementia: A simple dimer model of Alzheimer's disease etiology.
title_fullStr	From reaction kinetics to dementia: A simple dimer model of Alzheimer's disease etiology.
title_full_unstemmed	From reaction kinetics to dementia: A simple dimer model of Alzheimer's disease etiology.
title_sort	from reaction kinetics to dementia: a simple dimer model of alzheimer's disease etiology.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/3c582736fd1d498ab466555361aee08a
work_keys_str_mv	AT michaelrlindstrom fromreactionkineticstodementiaasimpledimermodelofalzheimersdiseaseetiology AT manuelbchavez fromreactionkineticstodementiaasimpledimermodelofalzheimersdiseaseetiology AT elijahagrosssable fromreactionkineticstodementiaasimpledimermodelofalzheimersdiseaseetiology AT ericyhayden fromreactionkineticstodementiaasimpledimermodelofalzheimersdiseaseetiology AT davidbteplow fromreactionkineticstodementiaasimpledimermodelofalzheimersdiseaseetiology
_version_	1718375834040926208

From reaction kinetics to dementia: A simple dimer model of Alzheimer's disease etiology.

Ejemplares similares