Age-Dependent Response of Hippocampal Neurons to Stress Age remains the most significant unexplained etiologic factor in common neurodegenerative diseases. To explore the basis of age-related sensitivity to common stressors, Ab and glutamate, we have developed novel techniques for isolation and culture of hippocampal rat neurons of any age (Brewer, 1997). Compared to embryonic and middle age neurons, we find that old neurons are more sensitive to glutamate and Ab toxicity (Brewer, 1998). Part of the mechanism involves age-related increases in apoptosis, indicated by more condensed nuclei and higher levels of caspase-3 activation. Here, we will test the hypothesis that age-related functional deficits in hippocampal mitochondria are responsible for age-related neurotoxicity of Ab and glutamate.
Our aims will continue to use hippocampal neurons isolated from rat brains of three ages embryonic, middle and old age) to compare single cell function under uniform culture conditions: 1) Are age related functional deficits of mitochondria responsible for the age-related increase in susceptibility to glutamate and A-beta stressors? Mitochondrial deficits will be measured as respiration, steps in oxidative phosphorylation, preconditioning, release of cytochrome C and oxyradical products. 2) Can multiple inhibitor: better protect against age-related stressor toxicity than either alone? 3) Are there age-related deficits in mitochondrial DNA of mice transgenic for mutant human APP in situ hybridization with probes for common deletions? 4) Can neuron multiplication select for wild-type mitochondrial DNA and thereby restore normal function including response to stressors? These studies are likely to reveal mechanistic insights into age related neurotoxicity and suggest new targets for therapeutic intervention at both preventative and restorative levels of neurodegeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
2R01AG013435-05A2
Application #
6541636
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (01))
Program Officer
Wise, Bradley C
Project Start
1997-04-01
Project End
2007-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
5
Fiscal Year
2002
Total Cost
$292,983
Indirect Cost
Name
Southern Illinois University School of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Springfield
State
IL
Country
United States
Zip Code
62794
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Brewer, Gregory J; Torricelli, John R; Lindsey, Amanda L et al. (2010) Age-related toxicity of amyloid-beta associated with increased pERK and pCREB in primary hippocampal neurons: reversal by blueberry extract. J Nutr Biochem 21:991-8
Yang, Dianer; Wang, Man-Tzu; Tang, Yong et al. (2010) Impairment of mitochondrial respiration in mouse fibroblasts by oncogenic H-RAS(Q61L). Cancer Biol Ther 9:122-33
Jones, Torrie T; Brewer, Gregory J (2010) Age-related deficiencies in complex I endogenous substrate availability and reserve capacity of complex IV in cortical neuron electron transport. Biochim Biophys Acta 1797:167-76
Brewer, Gregory J (2010) Epigenetic oxidative redox shift (EORS) theory of aging unifies the free radical and insulin signaling theories. Exp Gerontol 45:173-9
Jones, Torrie T; Brewer, Gregory J (2009) Critical age-related loss of cofactors of neuron cytochrome C oxidase reversed by estrogen. Exp Neurol 215:212-9
Patel, Jigisha R; Brewer, Gregory J (2008) Age-related differences in NFkappaB translocation and Bcl-2/Bax ratio caused by TNFalpha and Abeta42 promote survival in middle-age neurons and death in old neurons. Exp Neurol 213:93-100
Brewer, Gregory J; Boehler, Michael D; Jones, Torrie T et al. (2008) NbActiv4 medium improvement to Neurobasal/B27 increases neuron synapse densities and network spike rates on multielectrode arrays. J Neurosci Methods 170:181-7
Patel, Jigisha R; Brewer, Gregory J (2008) Age-related changes to tumor necrosis factor receptors affect neuron survival in the presence of beta-amyloid. J Neurosci Res 86:2303-13

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