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dc.contributor.authorGilbert, James Patricken_US
dc.date.accessioned2016-02-04T20:00:45Z
dc.date.available2016-02-04T20:00:45Z
dc.date.issued2014
dc.identifier.urihttps://hdl.handle.net/2144/14293
dc.description.abstractAccumulation of amyloid beta (Aβ) in the brain is a pathological hallmark of Alzheimer's disease (AD) and has been shown to lead to synaptic dysfunction and cognitive decline. Recent studies have indicated synapse dysfunction as an early pathology in AD, but how synaptic function is altered by Aβ remains unclear. We hypothesize that neuronal functional stability may be altered by Aβ via dysregulation of homeostatic synaptic plasticity (HSP), a negative-feedback-based regulation that serves to restrain neuronal activity within a physiological range. Here, I show that Aβ can regulate HSP in response to activity deprivation with an over scaling up of postsynaptic AMPAR expression and excitatory synaptic currents. Aβ treatment during activity deprivation increases the surface expression of both calcium-permeable (Cp), GluA2-lacking (CpAMPARs) and regular, GluA2-containing AMPARs. This in turn may make neurons more vulnerable to neuronal injury after a toxic glutamatergic challenge. Homeostatic synaptic scaling requires the PI3K/Akt signaling pathway and expression of CpAMPARs. Consistent with this, I found that blockade of either PI3K or CpAMPARs occludes over-scaling in the presence of Aβ, suggesting that the enhancement of HSP is mediated through homeostatic mechanisms. Furthermore, challenging neurons with glutamate after Aβ-mediated enhancement of HSP shows increased neuronal death. These findings provide a novel mechanism by which Aβ alters neuronal plasticity and calcium homeostasis in the brain, suggesting that the HSP pathway may be a target in clinical treatment of Alzheimer's disease.en_US
dc.language.isoen_US
dc.subjectNeurosciencesen_US
dc.subjectAlzheimer's diseaseen_US
dc.subjectAMPARen_US
dc.subjectAmyloid betaen_US
dc.subjectHomeostatic synaptic plasticityen_US
dc.titleRegulation of homeostatic synaptic plasticity by amyloid Beta in cultured rat hippocampal neuronsen_US
dc.typeThesis/Dissertationen_US
dc.date.updated2016-01-22T18:55:31Z
etd.degree.nameM.A.en_US
etd.degree.levelmastersen_US
etd.degree.disciplineBiologyen_US
etd.degree.grantorBoston Universityen_US


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