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Title: Characterising impaired synaptic plasticity and network function in a mouse model of Alzheimer's Disease in Down Syndrome
Author: Nick, A. S.
ISNI:       0000 0004 7225 1028
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2017
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Down syndrome (DS) results from an additional copy of human chromosome 21 (Hsa21). It is a leading cause of cognitive impairment, and hippocampal function appears to be specifically affected. Individuals with DS are at an elevated risk of childhood and late-onset seizure disorders, as well as earlyonset Alzheimer’s disease (AD). Duplication of the APP gene on Hsa21 is sufficient to cause early-onset AD in the absence of any other genetic abnormalities, but Hsa21 contains many other dosage-sensitive genes, and trisomy is associated with widespread transcriptional dysregulation. Therefore, other factors in addition to APP duplication are likely to modify the risk of AD and seizures in the DS population. A double transgenic mouse model was used to investigate the interaction between trisomy of genes on Hsa21 and APP duplication. The Tc1 mouse model of DS contains a freely segregating copy of Hsa21, and is functionally trisomic for approximately 75% of Hsa21 genes, but critically, not for APP. This mouse model has been crossed with the J20 model of AD, which overexpresses mutant human APP (APPSwe/Ind). Interactions between trisomy of Hsa21 and overexpressed APPSwe/Ind have been shown to exacerbate cognitive deficits, and increase the risk of mortality in this model. The Dp1Tyb mouse model, which contains a duplication of the Hsa21 orthologous region of mouse chromosome 16 (Mmu16), was also investigated, in order to compare phenotypes across different models of DS. Long-term potentiation (LTP) was recorded in the medial perforant pathway (MPP) of acute hippocampal slices. This pathway comprises the major input to the hippocampus and has been implicated in spatial memory. No changes in baseline synaptic transmission were observed in the Tc1, J20, or double transgenic mice, nor in the Dp1Tyb mice. Tc1 mice showed a deficit in stimulation induced LTP, but not chemical LTP. This deficit could not be rescued by blocking GABAAR-mediated inhibitory neurotransmission as has been reported previously in other DS models, suggesting a novel mechanism underlies the plasticity deficit observed in these animals. No deficits were observed in the J20 animals, and no interactions were observed between APPSwe/Ind and trisomy of Hsa21. The exacerbation of cognitive deficits in these animals therefore does not appear result from greater impairment in synaptic plasticity in the MPP. Dp1tyb animals also showed a trend towards a deficit in LTP, although further data is required to determine the significance of this effect. In addition, EEG was recorded from awake and freely moving animals from the Tc1 x J20 cross, and from Dp1Tyb animals and their wildtype littermates. Neither Tc1, nor Dp1tyb, animals experienced spontaneous seizures, and Hsa21 did not exacerbate seizures related to APP in J20 mice, suggesting changes in LTP and enhanced mortality were also not related to epileptic activity at 6-months of age. However, immunohistochemistry for NPY in Tc1 x J20 cross at 16-months of age indicates that Hsa21 may be associated with an exacerbation in seizures in later life.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available