Alzheimer´s disease (AD) is an age-related, irreversible and progressive neurodegenerative pathology that deteriorates cognitive function including learning and memory. AD is characterised neuropathologically by the presence of neuritic plaques (Aβ), neurofibrillary tangles (NFTs), synaptic loss and neuronal death. AD affects specific brain regions involved in mnestic function such as the neocortex and the hippocampus. The dorsal (DR) and the median raphe (MR) nuclei give rise to serotonergic (5-HT) projections that innervate multiple brain regions including the cortex and the hippocampus, playing an important role in learning and memory processes. For a long time the degeneration of cholinergic (ACh) system was considered as the main neurochemical changes in AD brains, however, more recent studies highlight the involvement of other neurotransmitter systems including 5-HT. This thesis entitled "Altered serotonergic neurotransmission as a main player in the pathophysiology of Alzheimer's disease: structural and ultrastructural studies in a triple transgenic mouse model of the disease" demonstrates that there exist specific alterations in the serotonergic projections of the hippocampus during the progression of AD using the triple transgenic (3xTg-AD) mouse model of the disease, which closely resemble human AD. Mr. Harun N. Noristani is submitting this thesis to the University of Manchester for the degree of PhD in the Faculty of Life Science. The results obtained in this thesis show for the first time a biphasic increase in serotonergic fibre sprouting in the 3xTg-AD mouse model of AD that occurs in parallel with evident intraneuronal/extracellular Aβ deposition in the hippocampus (Chapter 3). In addition, serotonergic fibre sprouting correlated with reduced perforated synapses in the hippocampus, suggesting a structural remodeling process to maintain hippocampal connectivity (Chapter 4). Increased 5-HT neurotransmission (via high dietary intake of tryptophan, 5-HT precursor) reduced intraneuronal Aβ accumulation in the hippocampus, suggesting a direct role of 5-HT neurotransmission in modifying AD neuropathology (Chapter 5). Given the protective role of increased 5-HT neurotransmission, treatment with 5-HT enhancing drugs may be beneficial in reducing the underlying pathology as well as improving the behavioural and cognitive abnormalities associated with AD. Nevertheless, the role of specific 5-HT receptors responsible for such neuro-protective effect of 5-HT in AD awaits further research.
|Date of Award||3 Jan 2013|
- The University of Manchester
|Supervisor||Jose Rodriguez Arellano (Supervisor) & Owen Jones (Supervisor)|
- Alzheimer's disease, serotonin, serotonin transporter, hippocampus, raphe nuclei