Early hippocampal dysfunction in a mouse model of dementia with Lewy bodies: Mechanisms of cellular dysfunction caused by alpha-synuclein accumulation
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Dementia with Lewy bodies (DLB) is a devastating neurodegenerative disease, accounting for 5% of all dementia cases, for which there is no cure. Whilst there are currently many different animal models currently available for researchers studying PD, there are comparatively fewer DLB-specific mouse models. The limited amount of effective DLB mouse models presents a significant issue in the pursuit for DLB treatment. In my project, I aim to determine the accuracy of a novel DLB-specific mouse model, focusing on changes in mitochondrial function. Additionally, I explore the role of the wild-type and a DLB-related mutation of the protein beta-synuclein on mitochondrial function. The novel mouse model, known as CamS120, expresses a truncated form of the human alpha-synuclein promoter, expressed under the CamKIIa promoter, which drives the expression of the transgene to the forebrain region, including the hippocampus. The CamS120 mouse model was examined for behavioural changes, and then further examined for changes in mitochondrial number, dynamics, mitochondrial membrane potential and reactive oxygen species (ROS) production. The CamS120 mouse model was complemented with an alpha-synuclein overexpressing cell line (aFL), which was used to examine further changes in mitochondrial function, including changes in mitochondrial membrane potential, ROS production and mitophagy. The CamS120 mouse model was also examined for changes in beta-synuclein protein levels and distribution. In addition, wild-type beta-synuclein and DLB-related mutated beta-synuclein (V70M) overexpressing cells were also examined for changes in mitochondrial function. From my experiments I discovered that the CamS120 mice did not show any accompanying changes in mitochondrial function. The aFL cells on the other hand showed impairment in mitochondrial dynamics, disruption in mitochondrial membrane potential and an increase in ROS production. Examining beta-synuclein protein levels in CamS120 mice found that beta-synuclein protein levels were decreased in 12 months CamS120 mice. Wild-type and V70M mutated beta-synuclein overexpressing cells seemed to have a weak effect on mitochondrial dynamics, but only mutant beta-synuclein showed a disruption of the mitochondrial membrane potential and increased generation of ROS. I concluded that while CamS120 mice showed symptoms of recognition memory impairment, changes in mitochondrial function could not be conclusively associated with this memory impairment. However, results did show a potentially interesting difference between wildtype and mutated beta-synuclein, where mutations in beta-synuclein appeared to exert a toxic effect onto the relatively innocuous wildtype protein, which if confirmed, could be a future point of scientific interest.
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