application): Diminished brain metabolism and oxidative stress are characteristic features of AD. The mechanisms underlying these changes are as yet poorly defined. The recent studies indicate that a marker of mitochondrial damage, the cc-ketoglutarate dehydrogenase complex (KGDHC), correlates at least as well with clinical disability as do plaque and tangle counts. KGDHC and several other mitochondrial enzymes are known to be sensitive to reactive oxygen species (ROS). The studies in this proposal will test the hypothesis that impairment or select mitochondrial enzymes by ROS is an important component of the cascade or events that leads to diminished metabolism and to the cognitive deficits in AD. This hypothesis will be tested on human autopsy brains collected by the investigators collaborators at the Mt Sinai (NY) ADRC, who have collected several hundred samples of brain from patients whose pre-terminal neuropsychological status has been determined using the Clinical Dementia Rating (CDR). Quantitative markers of oxidative stress and activities of specific mitochondrial enzymes will be compared to clinical status (CDR) and to markers of AD pathology including plaque and tangle counts, by refined statistical methods described in the proposal. Tissue culture models will also be used, so as to do mechanistic experiments on the effects of specific ROS on the activities of the same mitochondrial enzymes examined in the necessarily correlational studies of human autopsied brain. The models will be: (1) cultured fibroblasts from AD patients, to test the effects of ROS on cells which have the same genetic background as that in which the disease is expressed; (2) culture models of neurons, the most vulnerable cell type in AD brains. These models will also provide systems to test the efficacy of approaches to limit or reverse the changes in mitochondria.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG019589-04
Application #
6644763
Study Section
Special Emphasis Panel (ZAG1-PKN-7 (J1))
Program Officer
Snyder, Stephen D
Project Start
2000-09-30
Project End
2005-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
4
Fiscal Year
2003
Total Cost
$190,125
Indirect Cost
Name
Winifred Masterson Burke Med Research Institute
Department
Type
DUNS #
780676131
City
White Plains
State
NY
Country
United States
Zip Code
10605
Huang, Hsueh-Meei; Chen, Huan-Lian; Gibson, Gary E (2014) Interactions of endoplasmic reticulum and mitochondria Ca(2+) stores with capacitative calcium entry. Metab Brain Dis 29:1083-93
Bunik, Victoria I; Schloss, John V; Pinto, John T et al. (2011) A survey of oxidative paracatalytic reactions catalyzed by enzymes that generate carbanionic intermediates: implications for ROS production, cancer etiology, and neurodegenerative diseases. Adv Enzymol Relat Areas Mol Biol 77:307-60
Gibson, Gary E; Starkov, Anatoly; Blass, John P et al. (2010) Cause and consequence: mitochondrial dysfunction initiates and propagates neuronal dysfunction, neuronal death and behavioral abnormalities in age-associated neurodegenerative diseases. Biochim Biophys Acta 1802:122-34
Huang, Hsueh-Meei; Chen, Huan-Lian; Gibson, Gary E (2010) Thiamine and oxidants interact to modify cellular calcium stores. Neurochem Res 35:2107-16
Krasnikov, Boris F; Nostramo, Regina; Pinto, John T et al. (2009) Assay and purification of omega-amidase/Nit2, a ubiquitously expressed putative tumor suppressor, that catalyzes the deamidation of the alpha-keto acid analogues of glutamine and asparagine. Anal Biochem 391:144-50
Gibson, Gary E; Karuppagounder, Saravanan S; Shi, Qingli (2008) Oxidant-induced changes in mitochondria and calcium dynamics in the pathophysiology of Alzheimer's disease. Ann N Y Acad Sci 1147:221-32
Shi, Q; Karuppagounder, S S; Xu, H et al. (2007) Responses of the mitochondrial alpha-ketoglutarate dehydrogenase complex to thiamine deficiency may contribute to regional selective vulnerability. Neurochem Int 50:921-31
Shi, Qingli; Gibson, Gary E (2007) Oxidative stress and transcriptional regulation in Alzheimer disease. Alzheimer Dis Assoc Disord 21:276-91
Bunik, Victoria I; Schloss, John V; Pinto, John T et al. (2007) Enzyme-catalyzed side reactions with molecular oxygen may contribute to cell signaling and neurodegenerative diseases. Neurochem Res 32:871-91
Kim, Soo-Youl; Marekov, Lyuben; Bubber, Parvesh et al. (2005) Mitochondrial aconitase is a transglutaminase 2 substrate: transglutamination is a probable mechanism contributing to high-molecular-weight aggregates of aconitase and loss of aconitase activity in Huntington disease brain. Neurochem Res 30:1245-55

Showing the most recent 10 out of 25 publications