A basic knowledge of how we age is essential for our understanding of age-related impairments in brain function that lead to major personal and economic problems for older citizens. In addition, changes in the brain considered part of normal aging may contribute to the onset and progression of age-related neurodegenerative diseases of the central nervous system (CNS), the classic examples of which are Alzheimer's, Huntington's and Parkinson's diseases. However, while many of the neurodegenerative diseases of the CNS have a characteristic age of onset after midlife, it is unclear what role age-related changes in the morphological, biochemical and electrophysiological properties of CNS neurons play in the onset and progression of a disease process. The proposed program project targets this gap in our knowledge of the aging brain by testing hypotheses about mechanisms of age-related changes in brain function. We propose an integrated program of basic research to examine the cellular and molecular mechanisms involved in brain aging, with particular emphasis on the substantia nigra and striatum, structures especially vulnerable in Parkinson's and Huntington's diseases. The study of reactive synaptogenesis, neuron death and functional adaptability to aging and injury represent the main areas of focus on our renewal application. Furthermore, we propose to manipulate age-related changes in dopaminergic function using chronic dietary restriction or treatment with the dopamine agonist pergolide. These studies will investigate the cellular and molecular events associated with oxidative stress in aging, with an emphasis on GFAP expression and other glial responses that we have documented in response to neurodegeneration. In addition, we will analyze the expression of several recently discovered genes, including apoJ, SCG-10, BDNF, GDNF, which seem to play key roles in processes determining cell survival and plasticity. The proposed experiments will help to understand the cellular and molecular mechanisms that lead to cell death in some regions of the aged brain and will provide the basis for the development of future therapeutic strategies aimed at the treatment of age-related neurodegenerative diseases of the CNS.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG009793-10
Application #
6168091
Study Section
Neuroscience, Behavior and Sociology of Aging Review Committee (NBSA)
Program Officer
Wise, Bradley C
Project Start
1991-06-01
Project End
2003-05-31
Budget Start
2000-06-01
Budget End
2003-05-31
Support Year
10
Fiscal Year
2000
Total Cost
$1,106,483
Indirect Cost
Name
University of Southern California
Department
Type
Organized Research Units
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Chinta, S J; Lieu, C A; Demaria, M et al. (2013) Environmental stress, ageing and glial cell senescence: a novel mechanistic link to Parkinson's disease? J Intern Med 273:429-36
Vali, Shireen; Chinta, Shankar J; Peng, Jun et al. (2008) Insights into the effects of alpha-synuclein expression and proteasome inhibition on glutathione metabolism through a dynamic in silico model of Parkinson's disease: validation by cell culture data. Free Radic Biol Med 45:1290-301
Jakowec, Michael W; Nixon, Kerry; Hogg, Elizabeth et al. (2004) Tyrosine hydroxylase and dopamine transporter expression following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurodegeneration of the mouse nigrostriatal pathway. J Neurosci Res 76:539-50
Finch, Caleb E (2003) Neurons, glia, and plasticity in normal brain aging. Neurobiol Aging 24 Suppl 1:S123-7; discussion S131
McNeill, Thomas H; Brown, Sally A; Hogg, Elizabeth et al. (2003) Synapse replacement in the striatum of the adult rat following unilateral cortex ablation. J Comp Neurol 467:32-43
Robinson, Siobhan; Freeman, Pierre; Moore, Cynthia et al. (2003) Acute and subchronic MPTP administration differentially affects striatal glutamate synaptic function. Exp Neurol 180:74-87
Jha, Nandita; Kumar, M Jyothi; Boonplueang, Rapee et al. (2002) Glutathione decreases in dopaminergic PC12 cells interfere with the ubiquitin protein degradation pathway: relevance for Parkinson's disease? J Neurochem 80:555-61
Rozovsky, Irina; Hoving, Saske; Anderson, Christopher P et al. (2002) Equine estrogens induce apolipoprotein E and glial fibrillary acidic protein in mixed glial cultures. Neurosci Lett 323:191-4
Finch, C E (2002) Neurons, glia, and plasticity in normal brain aging. Adv Gerontol 10:35-9
Jiang, D; Jha, N; Boonplueang, R et al. (2001) Caspase 3 inhibition attenuates hydrogen peroxide-induced DNA fragmentation but not cell death in neuronal PC12 cells. J Neurochem 76:1745-55

Showing the most recent 10 out of 87 publications