A thesis submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Doctor of Philosophy. Johannesburg, 2014. / Alzheimer’s Disease (AD) is characterized by neurofibrillary tangles, senile plaques and neuronal loss. Although the mechanisms underlying Amyloid beta 42 (Aβ42) neurotoxicity have not been firmly established, it is proposed that the neuronal loss is elicited through associations with cell surface receptors. The cellular prion protein (PrPc) has been identified as an Aβ42 receptor and as a regulator of the amyloidogenic cleavage pathway. As Aβ42 shares common binding partners with the 37kDa/67kDa laminin receptor (LRP/LR), including PrPc, we investigated whether these proteins interact and assessed the pathological significance of this association. LRP/LR was found to co-localize with Aβ on the cell surface. The occurrence of FRET suggested that an interaction between LRP/LR and Aβ indeed exists at the cell surface. Furthermore, pull down assays and Aβ-specific ELISAs demonstrated that LRP/LR forms a physical association with endogenously shed Aβ, thereby verifying the physiological relevance of this association. Antibody blockade by IgG1-iS18 and shRNAmediated downregulation of LRP/LR significantly enhanced cell viability and proliferation and decreased apoptosis in cells co-treated with Aβ42 when compared to cells incubated with Aβ42 alone. In addition, antibody blockade and shRNA-mediated downregulation of LRP/LR significantly impeded Aβ42 internalization. These results suggest that LRP/LR acts as an internalization receptor for Aβ42 and may thereby contribute to the cytotoxicity of the neuropeptide by facilitating intracellular Aβ42 accumulation and aggregation - which has consequences for cell proliferation and may promote apoptosis. These findings recommend anti-LRP/LR specific antibodies and shRNAs as potential therapeutic tools for Alzheimer’s Disease treatment.

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Previous studies have found nutritional status to predict better functional and cognitive ability in dementia. The current study investigated the relationship between nutritional status and progression of neuropsychological impairment in a U.S. sample of persons with dementia. Participants were studied for up to 6 years in the population-based Cache County, UT, study. Baseline sample included 240 persons with dementia (71.3% Alzheimer’s disease, 52.1% female). Mean (SD) age and dementia duration at baseline was 85.6 (5.2) and 3.4 (1.9) years, respectively. Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuropsychological test battery and Boston Naming Test (30-item) were administered annually. Nutritional status was assessed using a modified Mini Nutritional Assessment (mMNA). Components of nutritional status were chosen for further investigation (dietary intake and BMI). Linear mixed effects models examined change in nutritional status and food consumption over time as well as the association between mMNA and its components (time-varying) with each neuropsychological measure and rate of decline over time. The following covariates were tested as appropriate: dementia type, gender, age of dementia onset and duration (at baseline), education, neuropsychiatric symptoms, caregiver coresidence, place of residence, overall health, and dementia severity. mMNA scores decreased by .22 pts/year (p = .006), though this was confounded by dementia severity (β = -.12, p = .108). Consumption of carbohydrates (β = -.09), protein (β = -.07) and fruit/vegetables (β = -.08) also declined over time, all p < .05). Better nutritional status was associated with better neuropsychological test scores across all visits in verbal learning (β = .23), praxis drawing (β = .23), praxis memory (β = .08), verbal fluency (β = .34) and confrontation naming (β = .31), while mMNA predicted rate of decline in verbal recognition memory (β = .13); all p < .001, with the inclusion of covariates. Higher protein intake was associated with worse verbal learning, while higher BMI predicted better scores on all neuropsychological tests except for confrontation naming. The results emphasize the importance of nutritional status in dementia and raises the possibility of nutritional interventions that may improve patient outcomes.