Date of Award
Fall 11-22-2024
Document Type
Dissertation
Degree Name
Ph.D.
Organizational Unit
College of Natural Science and Mathematics, Chemistry and Biochemistry
First Advisor
Daniel Paredes
Second Advisor
Scott Horowitz
Third Advisor
Michelle Knowles
Fourth Advisor
Sunil Kumar
Copyright Statement / License for Reuse
All Rights Reserved.
Keywords
Alzheimer's, Neurotransmitter, Polyamines, Senescence
Abstract
Polyamines (PA) are ubiquitous in cells and highly involved in several important cellular functions and thus the dysregulation of their biosynthetic pathway is potentially associated with the progression of age-related diseases like Alzheimer’s’ disease (AD). Though there is research describing how PA content changes in organisms as they age or in those experiencing rapid aging from increased rates of senescence, as in Down syndrome (DS), it is not clear how this connection occurs and whether modulating this pathway may reveal downstream effects on related disease progression. This study examines how the modulation of the PA biosynthetic pathway by inhibition of the rate-limiting enzyme ornithine decarboxylase (ODC) by α-difluoromethylornithine (DFMO) affects the expression of Alzheimer’s and senescence-related biomarkers and PA biosynthesis in human fibroblasts. Proteomics and metabolomics were employed to compare data from human fibroblasts and brain tissues of individuals with Alzheimer’s disease and Down syndrome. Also, the regulation of excitatory and inhibitory neurotransmitters and how DFMO will be described in differentiated mouse hippocampal cell cultures. ODC inhibition was found to significantly affect related metabolic pathways, demonstrating polyamine’s regulatory role and alternative routes for Ornithine metabolism. In DS, the triplication of amyloid precursor protein (APP) contributes to AD amyloidogenesis and DFMO treatment reduced its expression in fibroblasts. In addition, DFMO treatment was capable of increasing cell viability and reducing senescence markers, challenging previous notions on PAs necessity for preventing buildup of senescence. Finally, we found that DFMO rescued several GABAergic synapse proteins while describing their dysregulation in AD/DS brain tissue. The complete data supports PA modulation as a factor in expression of disease-associated proteins that can be rescued by inhibition at the start. Further research could explore additional PA regulation strategies that are associated with AD and senescence that, combined with DFMO, may offer potential therapeutic methods for the progression of age-related diseases linked to PAs dysregulation.
Copyright Date
11-2024
Publication Statement
Copyright is held by the author. User is responsible for all copyright compliance.
Rights Holder
Andres D. Sola
Provenance
Received from author
File Format
application/pdf
Language
English (eng)
Extent
126 pgs
File Size
4.9 MB
Supplementary File Description
Supplemental Figures
File Format: application/pdf
Language: English (eng)
Extent: 13 pgs
File Size: 1.9 MB
Recommended Citation
Sola, Andres D., "Dysfunction of Polyamine Metabolism in Down Syndrome Related to Cellular Senescence and β-Amyloid Production" (2024). Electronic Theses and Dissertations. 2518.
https://digitalcommons.du.edu/etd/2518
Supplemental Figures