Abstract
Alzheimer's disease is a devastating progressive neurodegenerative disorder characterised by deposits of amyloid-β in extracellular plaques, intracellular neurofibrillary tangles comprising highly phosphorylated and aggregated tau species, synaptic dysfunction and neuronal death. Although several transgenic mouse models of Alzheimer's disease have been developed, in vivo studies using transgenic mice are time- and cost- consuming, and it is imperative that more ethically sustainable alternatives, which allow faster translation to the clinic, are developed. This thesis aims to determine if organotypic brain slice cultures from 3xTg-AD mice recapitulate key features of in vivo brain and can be used in mechanistic and pre-clinical Alzheimer's disease studies.Organotypic brain slice cultures prepared from 3xTg-AD mouse pups and maintained in culture for several weeks developed highly phosphorylated and high molecular weight tau species, increased amounts of β-amyloid and showed increased activation of cyclin-dependent kinase 5 over time. These biochemical changes closely recapitulate the molecular changes observed in in vivo models and post-mortem Alzheimer's disease brain. In addition, brain slices from wild-type and 3xTg-AD mice showed altered tau release characteristics, indicating a distinction in the mechanisms underlying physiological and pathological tau release. These data support the notion that brain slice cultures can be used to understand the mechanisms and pathways underlying the development and progression of Alzheimer's disease.
| Date of Award | 2016 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Diane Hanger (Supervisor) & Wendy Noble (Supervisor) |