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Determinants for Alzheimer’s Disease: An Exploration of Metabolic and Clinical Risk Factors.
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Alarcon, Juan Marcos
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Spring 2023
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2023-04-14
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Doctoral Dissertation
Adobe PDF, 6.48 MB
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Alzheimer’s Disease (AD) is characterized by the pathological deposition of amyloid plaques or tau tangles in the brain. Currently, most therapeutic treatments for AD focus on arresting and reversing amyloid and tau pathologies. To date, unfortunately, clinical trials for drugs targeting amyloid or tau depositions have proven ineffective. Genome-wide and transcriptome-wide association studies have identified various genes and genetic variants in lipid metabolism that are associated with AD. Particularly, dysregulation of sphingomyelin (SM) metabolism has been implicated in AD, leading to the speculation that modulators of the SM pathway could emerge as candidate targets for therapeutic AD treatment. However, the effectiveness of modulators of the SM pathway remains understudied. This study tested whether the SM pathway activator Fingolimod (FTY720), a Sphingosine-1-Phosphate (S1P) signaling modulator, can rescue the behavioral and functional deficits associated with the pathology observed in mouse models of AD. We examined two mouse models, one expressing the amyloid pathology (APP/PS1) and the other the tau pathology (Tg4510), which are known to exhibit severe cognitive and synaptic plasticity impairments. We found that after two months of exposure to Fingolimod in drinking water, the mice showed recovered cognitive function measured in novel object recognition and Barnes maze memory tasks and rescued expression of synaptic plasticity measured in long-term synaptic potentiation in the entorhinal cortex and hippocampal synapses. Our findings suggest that upregulation of the SM pathway via modulation of S1P signaling may have protective effects in AD.
Citation
Buitrago-Soto, L. (2023). Determinants for Alzheimer’s Disease: An Exploration of Metabolic and Clinical Risk Factors. [Doctoral dissertation, SUNY Downstate Health Sciences University]. SUNY Open Access Repository. https://soar.suny.edu/handle/20.500.12648/16203
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Doctoral Dissertation