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dc.contributor.authorLiang, Jingyi
dc.date.accessioned2016-12-14T23:48:25Z
dc.date.available2016-12-14T23:48:25Z
dc.date.issued2016-08-25
dc.identifier.urihttps://hdl.handle.net/10182/7661
dc.description.abstractAlzheimer’s disease (AD) is a devastating, incurable neurodegenerative disease affecting millions of people worldwide. Dysregulation of intracellular Ca2+ signalling has been observed as an early event prior to the presence of clinical symptoms of AD and is believed to be a crucial factor contributing to its pathogenesis. Mathematical modelling and computational analysis offer great opportunities to overcome the experimental limitation and investigate alterations in AD to advance our understanding of the Ca2+ dysregulations of AD and their contributions to disease pathology. In this study, we develop a mathematical model of a CA1 pyramidal dendritic spine, integrating essential components and reactions related to NMDAR-mediated Ca2+ response in the dendritic spine. We conduct computational experiments using this model to mimic alterations 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 individually and globally. The simulation results suggest that alterations in glutamate availability mostly affect synaptic response and have limited effects on extrasynaptic receptors. Overactivation of extrasynaptic NMDARs in AD is unlikely induced by presynaptic stimulation, but by upregulation of resting level of glutamate, possibly resulted from these alterations. Furthermore, internalisation of synaptic NR2A-NMDAR shows great damage to postsynaptic Ca2+ response in comparison with the internalisation of NR2B-NMDARs, thus, the suggested neuroprotective role of the latter one is very limited during synaptic transmission in AD. We also simulate alterations of the internal Ca2+ store, ER, under AD conditions by including ER-related components to the model and investigate how these alterations affect the roles of ER in NMDAR-mediated Ca2+ response in the spine head. Simulation results suggest that the proposed neuroprotective function of up-regulation in RyR expression may make the cell more vulnerable by amplifying the cytosolic Ca2+ level. The simulation results also suggest alterations in ER may have more impacts in basal synaptic transmission than high frequency-induced transmissions in AD. In addition, the simulation results predict that inhibition of SERCA pumps may be beneficial to rescue the spine head from Ca2+ dysregulation by ER Ca2+ overload in AD. To further study the effects of alterations of NMDARs in their roles in downstream events, we add a CaMKII state transition model to the downstream of our Ca2+ model to study how alterations of NMDAR affect CaMKII state transition, an important event in the early phase of LTP. Simulation results suggest a cooperation between NR2A- and NR2B-NMDAR is required for LTP induction. Under AD conditions, internalisation of membrane NMDARs may be the cause of loss of synapse number by disrupting CaMKII-NMDAR formation.en
dc.language.isoenen
dc.publisherLincoln Universityen
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.urihttps://researcharchive.lincoln.ac.nz/page/rights*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectNMDARen
dc.subjectCaMKII-NMDAR formationen
dc.subjectparameter esitimationen
dc.subjectordinary differential equationsen
dc.subjectAMPARen
dc.subjectAlzheimer's diseaseen
dc.subjectAmyloid betaen
dc.subjectcalcium ionsen
dc.subjectglutamate transmissionen
dc.subjectendoplasmic reticulumen
dc.subjectmathematical modellingen
dc.titleModelling and investigation of NMDAR-mediated calcium signalling at Hippocampal Dendritic Spine in Alzheimer’s diseaseen
dc.typeThesisen
thesis.degree.grantorLincoln Universityen
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen
lu.thesis.supervisorKulasiri, Don
lu.contributor.unitDepartment of Wine, Food and Molecular Biosciencesen
dc.subject.anzsrc010202 Biological Mathematicsen
dc.subject.anzsrc060114 Systems Biologyen
dc.subject.anzsrc080110 Simulation and Modellingen


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