The most significant etiological factor in Alzheimer's disease (AD) is age. But how does age contribute to the cellular and molecular pathology of AD? It is hypothesized that hippocampal neurons from aged animals are more susceptible to Abeta than younger neurons due to a decreased ability to generate the energy needed to control ion fluxes in this region of the AD brain. Novel techniques for the culture of aged neurons in serum-free medium have been developed recently by the PI, enabling examination of age-related cellular responses. New data have been obtained that subtoxic levels of lactate acidosis alter APP processing resulting in deposition of more amyloidogenic fragments. Also, neurons from aged rats are more susceptible to Abeta, lactate acidosis, and glutamate toxicity and fail to increase ATP levels to meet demands of increased ionic fluxes. Using neurons cultured from adult and aged rats, the first aim is to compare responses to fibrillar Abeta in terms of intracellular calcium, pH, and viability. Also regional AD pathology will be examined by comparing responses to Abeta in hippocampal with cerebellar granule neurons.
The second aim examines the impact of glutamate and lactate acidosis on Abeta toxicity.
The third aim examines whether age-related changes in susceptibility to Abeta are accounted for by declines in energy production, free radical damage, or induction of apoptosis. These studies hope to provide a better understanding of the age-related responses of cultured neurons to stressors thought to be important in the AD brain.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
3R01AG013435-03S1
Application #
6051450
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1997-04-01
Project End
2001-03-31
Budget Start
1999-04-15
Budget End
2000-03-31
Support Year
3
Fiscal Year
1999
Total Cost
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
Walker, Michael P; LaFerla, Frank M; Oddo, Salvador S et al. (2013) Reversible epigenetic histone modifications and Bdnf expression in neurons with aging and from a mouse model of Alzheimer's disease. Age (Dordr) 35:519-31
Ghosh, Debolina; LeVault, Kelsey R; Barnett, Aaron J et al. (2012) A reversible early oxidized redox state that precedes macromolecular ROS damage in aging nontransgenic and 3xTg-AD mouse neurons. J Neurosci 32:5821-32
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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