This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. In this project, I plan to first examine the amyloid beta hypothesis of Alzheimer's disease (AD) and apply it to a novel Down Syndrome (DS) model by developing a mechanism in which the p3 fragment of the DS preamyloid can possibly be equivalent to the earliest stage of Alzheimer Disease, mild cognitive impairment (MCI). Secondly, by specifically focusing on glycolytic protein oxidation in this model, a basis for the reduced glucose metabolism observed in Alzheimer's disease may be determined and further support of the altered energy metabolism hypothesis of AD may be provided. Investigation of oxidatively modified glycolytic proteins in this novel DS model may also create a new focal point for potential biomarkers in AD and potential therapeutics. Down syndrome is a genetic disease in which persons have reduced mental capacity. Persons with DS have a trisomy at chromosome 21, the location of amyloid precursor protein. This trisomy causes A? overproduction, which could possibly be a correlate to the early development of AD in persons with DS. Enzymatic cleavage by ?-secretase and ?-secretase forms the toxic p3 fragment, A?(17-42), which is the major form of A? peptide in Down syndrome. No correlation has yet been made between the p3 fragment and AD pathogenesis. Glycolysis is a metabolic pathway that converts glucose to pyruvate and generates 2 ATP molecules in the process. Many key glycolytic enzymes such as ?-enolase, ?-enolase, glyceraldehyde 3-phosphate, phosphoglycerate mutase and triosephosphate isomerase are oxidized in AD brain confirming the inability to effectively metabolize glucose, the brain's principal source of energy. In the three progressive stages of Alzheimer's disease, MCI, EAD, and late-stage AD, 70% of glycolytic enzymes undergo oxidative modification, which can greatly affect their enzyme activity and subsequent protein function. All enzymes affected react after the production of fructose 1,6-bisphosphate (FBP). If oxidatively modified pre-FBP proteins are observed in DS, this will provide further support for the altered energy metabolism of AD.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Exploratory Grants (P20)
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Special Emphasis Panel (ZRR1-RI-4 (01))
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University of Louisville
Anatomy/Cell Biology
Schools of Medicine
United States
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Stenslik, M J; Evans, A; Pomerleau, F et al. (2018) Methodology and effects of repeated intranasal delivery of DNSP-11 in awake Rhesus macaques. J Neurosci Methods 303:30-40
Green, Kimberly A; Becker, Yvonne; Fitzsimons, Helen L et al. (2016) An Epichloƫ festucae homologue of MOB3, a component of the STRIPAK complex, is required for the establishment of a mutualistic symbiotic interaction with Lolium perenne. Mol Plant Pathol 17:1480-1492
Rouchka, Eric C; Flight, Robert M; Fasciotto, Brigitte H et al. (2016) Transcriptional profile of immediate response to ionizing radiation exposure. Genom Data 7:82-5
Saikkonen, Kari; Young, Carolyn A; Helander, Marjo et al. (2016) Endophytic Epichloƫ species and their grass hosts: from evolution to applications. Plant Mol Biol 90:665-75
Smith, Michael E; Monroe, J David (2016) Causes and Consequences of Sensory Hair Cell Damage and Recovery in Fishes. Adv Exp Med Biol 877:393-417
Witkowski, Travis A; Grice, Alison N; Stinnett, DeAnna B et al. (2016) UmuDAb: An Error-Prone Polymerase Accessory Homolog Whose N-Terminal Domain Is Required for Repression of DNA Damage Inducible Gene Expression in Acinetobacter baylyi. PLoS One 11:e0152013
Hofmann, Emily; Webster, Jonathan; Do, Thuy et al. (2016) Hydroxylated chalcones with dual properties: Xanthine oxidase inhibitors and radical scavengers. Bioorg Med Chem 24:578-87
Harrison, Benjamin J; Venkat, Gayathri; Lamb, James L et al. (2016) The Adaptor Protein CD2AP Is a Coordinator of Neurotrophin Signaling-Mediated Axon Arbor Plasticity. J Neurosci 36:4259-75
Rau, Kristofer K; Hill, Caitlin E; Harrison, Benjamin J et al. (2016) Cutaneous tissue damage induces long-lasting nociceptive sensitization and regulation of cellular stress- and nerve injury-associated genes in sensory neurons. Exp Neurol 283:413-27
Gemmell, Amber P; Marcus, Jeffrey M (2015) A tale of two haplotype groups: Evaluating the New World Junonia ring species hypothesis using the distribution of divergent COI haplotypes. Syst Entomol 40:532-546

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