Alzheimer's disease (AD) is characterized by the presence of aggregates of amyloid beta (Aβ) in senile plaques and tau in neurofibrillary tangles, as well as marked neuron and synapse loss. Of these pathological changes, synapse loss correlates most strongly with cognitive decline. Understanding the contributions of different risk factors, toxic proteins, and protein networks to synaptic dysfunction and loss is essential to understanding and one day curing this disease. Oligomeric species of both Aβ and tau are implicated in synapse, however the interaction between them requires further exploration. The first aim of this thesis was to investigate the interaction of Aβ and tau in a novel mouse model AD. In this model APP/PS1 mice were crossed with mice expressing full length wild type human tau (hTau). Expression of hTau in APP/PS1 mice increased plaque size by~50% and increased plaque-associated dystrophic neurites. However, no increase in neurite curvature, neuron loss, or synapse loss was observed in the hTau APP/PS1 animals compared with APP/PS1 alone. The underlying cause of most cases of AD is not known, however genetic risk factors have been identified, the strongest of which is the APOE e4 allele. APOE e4 is associated with increased risk of developing AD and increased rates of cognitive decline compared to the more common APOE e3 allele. The second aim of this thesis was to detect differences in the AD synaptic proteome compared with controls and to also investigate the effect of an APOE e4 allele on those changes. Unbiased label free LC-MS/ MS based proteomics of synapses isolated from human AD and control post-mortem brains of known APOE genotypes was used. Of the 1043 proteins detected in 20 synaptic preparations 17% (173) were found to differ significantly (p < 0.05, fold change >1.2) in AD compared with control. A significant sub-set of these proteins were affected by APOE e4 allele genotype. One of these was Clusterin which was not only increased in the AD synapse but further increased in cases with an APOE e4 allele. Clusterin is closely related to ApoE has also been genetically linked to AD in genome-wide association studies. Aim three was to further investigate the involvement of Clusterin at the synapse and the interaction of ApoE with Clusterin using array tomography. Array tomography confirmed an increase in Clusterin co-localization with presynapses and postsynapses in AD cases compared with controls and found a further increase in cases with an APOE e4 allele. Array tomography also found an increase in synapses which co-localized with Clusterin and Aβ together in cases with an APOE e4 allele. This implies that Clusterin is important in Aβ mediated synapse loss in AD. To further investigate the role of synapse loss in AD aim 4 of this thesis was to develop a novel human based model of Aβ mediated synapse loss. This model uses cortical neurons derived from induced pluripotent stem cells from a control individual that are challenged with Aβ extracted from brains from AD and control individuals. This model shows a significant and concentration dependent reduction in the number of synapses in response Aβ from AD brain but not to control brain extract or AD brain extract immunodepleted of Aβ. The work presented in this thesis has investigated two novel models of AD to assess the effect of known toxic proteins in AD related synapse degeneration. This work also shows that profound protein changes occur at the synapse in AD and that many of these are affected by APOE genotype. Many of these changes potentially cause or contribute to synaptic dysfunction in AD and therefore could be important for therapeutic interventions.

abstract: The apolipoprotein E (APOE) e4 genotype is the most prevalent known genetic risk factor for Alzheimer's disease (AD). In this paper, we examined the longitudinal effect of APOE e4 on hippocampal morphometry in Alzheimer's Disease Neuroimaging Initiative (ADNI). Generally, atrophy of hippocampus has more chance occurs in AD patients who carrying the APOE e4 allele than those who are APOE e4 noncarriers. Also, brain structure and function depend on APOE genotype not just for Alzheimer's disease patients but also in health elderly individuals, so APOE genotyping is considered critical in clinical trials of Alzheimer's disease. We used a large sample of elderly participants, with the help of a new automated surface registration system based on surface conformal parameterization with holomorphic 1-forms and surface fluid registration. In this system, we automatically segmented and constructed hippocampal surfaces from MR images at many different time points, such as 6 months, 1- and 2-year follow up. Between the two different hippocampal surfaces, we did the high-order correspondences, using a novel inverse consistent surface fluid registration method. At each time point, using Hotelling's T^2 test, we found significant morphological deformation in APOE e4 carriers relative to noncarriers in the entire cohort as well as in the non-demented (pooled MCI and control) subjects, affecting the left hippocampus more than the right, and this effect was more pronounced in e4 homozygotes than heterozygotes. / Dissertation/Thesis / Masters Thesis Computer Science 2015