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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

Research Archive

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

Liang, Jingyi ; Kulasiri, Gamalathge D. ; Samarasinghe, Sandhya
Type: Journal Article
Permalink: https://hdl.handle.net/10182/8693
Originally published: 2017-08-24 by Public Library of Science and available at https://doi.org/10.1371/journal.pone.0182743
Rights: © 2017 Liang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: Alzheimer's disease; intracellular Ca²⁺ signalling; Amyloid-β oligomers (AβOs); N-methyl-D-aspartate receptor (NMDAR); long-term potentiation (LTP); General Science & Technology; Hippocampus; Dendritic Spines; Animals; Alzheimer Disease; Calcium; Receptors, N-Methyl-D-Aspartate; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Amyloid beta-Peptides
Fields of Research: 111702 Aged Health Care; 1109 Neurosciences; 110905 Peripheral Nervous System; 110904 Neurology and Neuromuscular Diseases; MD Multidisciplinary

Abstract:

In Alzheimer's disease (AD), dysregulation of intracellular Ca²⁺ 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 Ca²⁺ signalling in response to presynaptic stimulation by increasing the availability of extracellular glutamate as well as directly disturbing the NMDARs. The abnormal Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ 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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