The major barrier in preventing or treating Alzheimer's disease (AD) is its unknown pathogenesis/etiology. The basic hypothesis of this proposal is that an elevation of brain Zn and alterations of Zn transporter protein levels disrupts the delicate balance of brain Zn in AD and may play a role in the pathogenesis of neuron degeneration. The investigators' previous studies showed significant increases in total Zn in AD brain and a significant elevation of Zn in AD senile plaques using micro-PIXE. Preliminary micro-PIXE studies of flash-frozen AD hippocampus demonstrate pronounced differences in Zn with neurofibrillary tangle (NFT)-bearing neurons demonstrating elevations of Zn, while NFT-free neurons demonstrate depletions of Zn. Preliminary studies of Zn transporter protein levels show significant alterations in proteins responsible for Zn efflux and sequestration. Preliminary analyses of brain from presenilin 1 (PS-1) knockin mice demonstrate elevations of bulk Zn and alterations in Zn transporters similar to those observed in AD brain. The proposed studies will enhance our understanding of zinc's role in AD by a) quantitating levels of Zn in NFT-bearing, NFT-free and control neurons and neuropil in sections of flash-frozen AD and control brain and in neurons and neuropil from PS- 1 mutant and wildtype (WT) mice using micro-PIXE; b) measuring levels of Zn transporter proteins (ZnT-1 and ZnT-3) in multiple AD and control brain regions and in PS-1 mutant and WT mice using immuno-chemistry; c) determining the impact of elevated Zn and altered Zn transporters in PC-12 cells expressing ; S-1 mutations and in PC-12 cells overexpressing ZnT-1 in the absence of the PS-1 mutation; and d) determining the effects of chronic prolonged Zn exposure on cellular function including the effects on Na+/K+ ATPase activity, glutamate and glucose uptake and the induction of genes associated with Zn regulation or cell death including ZnT-l, ZnT-3 metallothionein, and c-jun in primary rat neuron cultures.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG016269-01A2
Application #
6193642
Study Section
Special Emphasis Panel (ZRG1-BDCN-4 (01))
Program Officer
Snyder, D Stephen
Project Start
2000-09-16
Project End
2005-08-31
Budget Start
2000-09-16
Budget End
2001-08-31
Support Year
1
Fiscal Year
2000
Total Cost
$181,208
Indirect Cost
Name
University of Kentucky
Department
Other Health Professions
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
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