The primary goals of this project are to determine the pathways involved in neuron death following insults implicated in aging and late-onset neurodegenerative disorders including Alzheimer's disease; to test the hypothesis that these pathways are, in part, Ca/2+ dependent; to assess the relative involvement calpain- and caspase-mediated proteolysis in the neuron death and cytoskeletal disruption; and to determine if an age-related increase in sensitivity to insults reflects increase propensity for apoptotic or necrotic neuron death. The mitochondrial toxin 3-nitropropionic acid (3NP, an irreversible inhibitor of succinate dehydrogenase) will be utilized extensively in these studies. 3NP-induced metabolic impairment can lead to neuron death via indirect excitotoxic insult resulting in necrotic death or via apoptotic mechanisms where the role of Ca/2+ and Ca/2+-dependent proteases is poorly understood. 3NP can be utilized in vitro and in vivo. The first specific aim will examine the hypothesis that following metabolic impairment induced by 3NP, apoptotic neuron death can occur via both Ca/2+-dependent and -independent mechanisms.
The second aim will examine the relative contributions of Ca/2+-activated proteases (calpains) and cysteinyl aspartate-specific proteases (caspases) to the necrotic and apoptotic death. Distinct profiles of cytoskeletal disruption are predicated to be associated with necrosis, Ca/2+- dependent apoptosis, and Ca/2+-independent apoptosis.
The third aim i s to produce and characterize antibodies specific for caspase-mediated cleavage of cytoskeletal proteins.
The third aim i s to produce and characterize antibodies specific for caspase-mediated cleavage of cytoskeletal proteins. These antibodies will be utilized in aims four and five, along with biochemical and morphologic criteria, to characterize neuron death in vivo following metabolic impairment; to examine the hypothesis that blockade of excitotoxic death may unmask apoptotic mechanisms; to assess the age-related increase in vulnerability to metabolic impairment; and to evaluate the contributions of necrosis, Ca/2+-dependent-apoptosis and Ca/2+-independent apoptosis to the cytoskeletal disruption evident in Alzheimer's disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Butterfield, D Allan; Palmieri, Erika M; Castegna, Alessandra (2016) Clinical implications from proteomic studies in neurodegenerative diseases: lessons from mitochondrial proteins. Expert Rev Proteomics 13:259-74
Chen, Chun-Hau; Li, Wenzong; Sultana, Rukhsana et al. (2015) Pin1 cysteine-113 oxidation inhibits its catalytic activity and cellular function in Alzheimer's disease. Neurobiol Dis 76:13-23
Cenini, Giovanna; Fiorini, Ada; Sultana, Rukhsana et al. (2014) An investigation of the molecular mechanisms engaged before and after the development of Alzheimer disease neuropathology in Down syndrome: a proteomics approach. Free Radic Biol Med 76:89-95
Barone, Eugenio; Di Domenico, Fabio; Mancuso, Cesare et al. (2014) The Janus face of the heme oxygenase/biliverdin reductase system in Alzheimer disease: it's time for reconciliation. Neurobiol Dis 62:144-59
Förster, Sarah; Welleford, Andrew S; Triplett, Judy C et al. (2014) Increased O-GlcNAc levels correlate with decreased O-GlcNAcase levels in Alzheimer disease brain. Biochim Biophys Acta 1842:1333-9
Swomley, Aaron M; Förster, Sarah; Keeney, Jierel T et al. (2014) Abeta, oxidative stress in Alzheimer disease: evidence based on proteomics studies. Biochim Biophys Acta 1842:1248-57
Latimer, Caitlin S; Brewer, Lawrence D; Searcy, James L et al. (2014) Vitamin D prevents cognitive decline and enhances hippocampal synaptic function in aging rats. Proc Natl Acad Sci U S A 111:E4359-66
Butterfield, D Allan; Di Domenico, Fabio; Barone, Eugenio (2014) Elevated risk of type 2 diabetes for development of Alzheimer disease: a key role for oxidative stress in brain. Biochim Biophys Acta 1842:1693-706
Perluigi, Marzia; Di Domenico, Fabio; Buttterfield, D Allan (2014) Unraveling the complexity of neurodegeneration in brains of subjects with Down syndrome: insights from proteomics. Proteomics Clin Appl 8:73-85
Farr, Susan A; Ripley, Jessica L; Sultana, Rukhsana et al. (2014) Antisense oligonucleotide against GSK-3? in brain of SAMP8 mice improves learning and memory and decreases oxidative stress: Involvement of transcription factor Nrf2 and implications for Alzheimer disease. Free Radic Biol Med 67:387-95

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