Studies from our laboratory have established that oxidative stress and oxidative protein modification are salient features of the lesions of Alzheimer disease (AD). These studies are a direct outcome of the aims of the funding period in which we determined that neurofibrillary tangles (NFT) share the same solubility properties of proteins in aged individuals, which are crosslinked by advanced glycation endproducts (AGE). We then demonstrated antibodies to AGE recognize NFT and senile plaques (SP). When AGE modified-t was introduced to neuroblastoma cells, lipid peroxidation was increased and a strong oxidative stress response by heme oxygenase-1 (HO-1) and NFkb was noted. HO-1 immunoreactivity is also increased in NFT-containing neurons, but is absent in brains of control cases. Direct oxidation of protein was also found in NFT as well as neuronal cytoplasm and nuclei of glia and neurons of AD cases but not age matched control brains indicating oxidative damage is not restricted to the lesions and that oxidative stress likely precedes the formation of NFT and SP. Further suggestions of this come from monoclonal antibodies raised to NFT which recognize AGE adducts of neurofilament proteins as well as t. The latter, Alz50, which recognizes a reducible (i.e., early) glycation modification of t, is the earliest marker of cytoskeletal alteration of AD. We now propose to determine three features of the AGE modification that will be essential to understanding their role in AD pathogenesis. First, determine which proteins are modified and when they become modified during lesion formation. Second, assess the effect of AGE modification of NFT and SP on resistance to proteolysis and phagocytosis. Third, evaluate the oxidative stress response of various brain cell types to AGE modified proteins. These studies will address whether AGE modification is a specific and early modification of the neuronal cytoskeleton, its role in lesion persistence and the differential response of cells to AGE.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
2R01AG009287-06A2
Application #
2001336
Study Section
Special Emphasis Panel (ZRG1-NLS-3 (01))
Program Officer
Oliver, Eugene J
Project Start
1990-09-01
Project End
1999-11-30
Budget Start
1996-12-15
Budget End
1997-11-30
Support Year
6
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Pathology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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