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Computational investigation of Amyloid-β-induced location- and subunit-specific disturbances of NMDAR at hippocampal dendritic spine in Alzheimer’s disease

In Alzheimer’s disease (AD), dysregulation of intracellular Ca(2+) signalling has been observed as an early event prior to the presence of clinical symptoms and is believed to be a crucial factor contributing to AD pathogenesis. Amyloid-β oligomers (AβOs) disturb the N-methyl-D-aspartate receptor (N...

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Autores principales: Liang, Jingyi, Kulasiri, Don, Samarasinghe, Sandhya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570373/
https://www.ncbi.nlm.nih.gov/pubmed/28837653
http://dx.doi.org/10.1371/journal.pone.0182743
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author Liang, Jingyi
Kulasiri, Don
Samarasinghe, Sandhya
author_facet Liang, Jingyi
Kulasiri, Don
Samarasinghe, Sandhya
author_sort Liang, Jingyi
collection PubMed
description In Alzheimer’s disease (AD), dysregulation of intracellular Ca(2+) signalling has been observed as an early event prior to the presence of clinical symptoms and is believed to be a crucial factor contributing to AD pathogenesis. Amyloid-β oligomers (AβOs) disturb the N-methyl-D-aspartate receptor (NMDAR)-mediated postsynaptic Ca(2+) signalling in response to presynaptic stimulation by increasing the availability of extracellular glutamate as well as directly disturbing the NMDARs. The abnormal Ca(2+) response can further lead to impairments in long-term potentiation (LTP), an important process in memory formation. In this study, we develop a mathematical model of a CA1 pyramidal dendritic spine and conduct computational experiments. We use this model to mimic alterations by AβOs under AD conditions to investigate how they are involved in the Ca(2+) dysregulation in the dendritic spine. The alterations in glutamate availability, as well as NMDAR availability and activity, are studied both individually and globally. The simulation results suggest that alterations in glutamate availability mostly affect the synaptic response and have limited effects on the extrasynaptic receptors. Moreover, overactivation of extrasynaptic NMDARs in AD is unlikely to be induced by presynaptic stimulation, but by upregulation of the resting level of glutamate, possibly resulting from these alterations. Furthermore, internalisation of synaptic NR2A-NMDAR shows greater damage to the postsynaptic Ca(2+) response in comparison with the internalisation of NR2B-NMDARs; thus, the suggested neuroprotective role of the latter is very limited during synaptic transmission in AD. We integrate a CaMKII state transition model with the Ca(2+) model to further study the effects of alterations of NMDARs in the CaMKII state transition, an important downstream event in the early phase of LTP. The model reveals that cooperation between NR2A- and NR2B-NMDAR is required for LTP induction. Under AD conditions, internalisation of membrane NMDARs is suggested to be the cause of the loss of synapse numbers by disrupting CaMKII-NMDAR formation.
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spelling pubmed-55703732017-09-09 Computational investigation of Amyloid-β-induced location- and subunit-specific disturbances of NMDAR at hippocampal dendritic spine in Alzheimer’s disease Liang, Jingyi Kulasiri, Don Samarasinghe, Sandhya PLoS One Research Article In Alzheimer’s disease (AD), dysregulation of intracellular Ca(2+) signalling has been observed as an early event prior to the presence of clinical symptoms and is believed to be a crucial factor contributing to AD pathogenesis. Amyloid-β oligomers (AβOs) disturb the N-methyl-D-aspartate receptor (NMDAR)-mediated postsynaptic Ca(2+) signalling in response to presynaptic stimulation by increasing the availability of extracellular glutamate as well as directly disturbing the NMDARs. The abnormal Ca(2+) response can further lead to impairments in long-term potentiation (LTP), an important process in memory formation. In this study, we develop a mathematical model of a CA1 pyramidal dendritic spine and conduct computational experiments. We use this model to mimic alterations by AβOs under AD conditions to investigate how they are involved in the Ca(2+) dysregulation in the dendritic spine. The alterations in glutamate availability, as well as NMDAR availability and activity, are studied both individually and globally. The simulation results suggest that alterations in glutamate availability mostly affect the synaptic response and have limited effects on the extrasynaptic receptors. Moreover, overactivation of extrasynaptic NMDARs in AD is unlikely to be induced by presynaptic stimulation, but by upregulation of the resting level of glutamate, possibly resulting from these alterations. Furthermore, internalisation of synaptic NR2A-NMDAR shows greater damage to the postsynaptic Ca(2+) response in comparison with the internalisation of NR2B-NMDARs; thus, the suggested neuroprotective role of the latter is very limited during synaptic transmission in AD. We integrate a CaMKII state transition model with the Ca(2+) model to further study the effects of alterations of NMDARs in the CaMKII state transition, an important downstream event in the early phase of LTP. The model reveals that cooperation between NR2A- and NR2B-NMDAR is required for LTP induction. Under AD conditions, internalisation of membrane NMDARs is suggested to be the cause of the loss of synapse numbers by disrupting CaMKII-NMDAR formation. Public Library of Science 2017-08-24 /pmc/articles/PMC5570373/ /pubmed/28837653 http://dx.doi.org/10.1371/journal.pone.0182743 Text en © 2017 Liang et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Liang, Jingyi
Kulasiri, Don
Samarasinghe, Sandhya
Computational investigation of Amyloid-β-induced location- and subunit-specific disturbances of NMDAR at hippocampal dendritic spine in Alzheimer’s disease
title Computational investigation of Amyloid-β-induced location- and subunit-specific disturbances of NMDAR at hippocampal dendritic spine in Alzheimer’s disease
title_full Computational investigation of Amyloid-β-induced location- and subunit-specific disturbances of NMDAR at hippocampal dendritic spine in Alzheimer’s disease
title_fullStr Computational investigation of Amyloid-β-induced location- and subunit-specific disturbances of NMDAR at hippocampal dendritic spine in Alzheimer’s disease
title_full_unstemmed Computational investigation of Amyloid-β-induced location- and subunit-specific disturbances of NMDAR at hippocampal dendritic spine in Alzheimer’s disease
title_short Computational investigation of Amyloid-β-induced location- and subunit-specific disturbances of NMDAR at hippocampal dendritic spine in Alzheimer’s disease
title_sort computational investigation of amyloid-β-induced location- and subunit-specific disturbances of nmdar at hippocampal dendritic spine in alzheimer’s disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570373/
https://www.ncbi.nlm.nih.gov/pubmed/28837653
http://dx.doi.org/10.1371/journal.pone.0182743
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