title: Modeling the short time-scale dynamics of β-amyloid-neuron interactions.
abstract: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the formation of senile plaques and neurofibrillary tangles. The primary protein components of these two histopathological features, β-amyloid peptide (Aβ) and tau, respectively, have been implicated in neuronal death. Despite extensive research into the disease etiology, its underlying molecular processes remain unknown. Researchers hypothesize that Aβ interacts with the cell surface preceding neuronal dysfunction and cell death; however, there is no consensus about the functional role of Aβ at the cell surface. Utilizing a mathematical model of a neuron, we compared simulation results under voltage-clamp, current-clamp and high [K(+)] membrane depolarized conditions of two hypothesized mechanisms of Aβ-neuron interactions: the Aβ blocking of fast-inactivating K(+) (IA) channels and the Aβ-induced increase in membrane conductance. Our model predicts that both mechanisms may lead to changes in ion conductances, cell excitability and Ca(2+) influx under voltage- and current-clamp conditions. Interestingly, membrane depolarization simulations predict very different correlations in Ca(2+) influx between the two mechanisms and may provide data that distinguishes the mechanisms. Our results suggest that our computational modeling methodology may enhance experimental design such that mechanisms of Aβ-induced action on a neuron can be discriminated.
authors: Department of Chemical, Biochemical and Environmental Engineering, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA. natasha1@umbc.edu
authors: Natasha P
authors: NP
authors: Wilson
authors: Bradford
authors: B
authors: Gates
authors: Mariajosé
authors: M
authors: Castellanos
mesh_terms: D000465:Algorithms; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D017136:Ion Transport / Q000187:drug effects; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D008959:Models, Neurological; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D002118:Calcium