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)
Project #
Application #
Study Section
Special Emphasis Panel (ZRR1-RI-4 (01))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Louisville
Anatomy/Cell Biology
Schools of Medicine
United States
Zip Code
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
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
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
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
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
Saikkonen, Kari; Young, Carolyn A; Helander, Marjo et al. (2016) Endophytic Epichloë species and their grass hosts: from evolution to applications. Plant Mol Biol 90:665-75
Hestand, Matthew S; Kalbfleisch, Theodore S; Coleman, Stephen J et al. (2015) Annotation of the Protein Coding Regions of the Equine Genome. PLoS One 10:e0124375
Young, Carolyn A; Schardl, Christopher L; Panaccione, Daniel G et al. (2015) Genetics, genomics and evolution of ergot alkaloid diversity. Toxins (Basel) 7:1273-302
Harrison, Benjamin J; Venkat, Gayathri; Hutson, Thomas et al. (2015) Transcriptional changes in sensory ganglia associated with primary afferent axon collateral sprouting in spared dermatome model. Genom Data 6:249-52
Stenslik, Mallory J; Potts, Lisa F; Sonne, James W H et al. (2015) Methodology and effects of repeated intranasal delivery of DNSP-11 in a rat model of Parkinson's disease. J Neurosci Methods 251:120-9

Showing the most recent 10 out of 239 publications