Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG009287-08
Application #
2837311
Study Section
Special Emphasis Panel (ZRG1-NLS-3 (01))
Program Officer
Heemskerk, Jill E
Project Start
1990-09-01
Project End
2000-11-30
Budget Start
1998-12-01
Budget End
2000-11-30
Support Year
8
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Case Western Reserve University
Department
Pathology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106

  Publications

Wataya, Takafumi; Nunomura, Akihiko; Smith, Mark A et al. (2002) High molecular weight neurofilament proteins are physiological substrates of adduction by the lipid peroxidation product hydroxynonenal. J Biol Chem 277:4644-8
Zhang, J; Montine, T J; Smith, M A et al. (2002) The mitochondrial common deletion in Parkinson's disease and related movement disorders. Parkinsonism Relat Disord 8:165-70
Nunomura, A; Perry, G; Aliev, G et al. (2001) Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 60:759-67
Hirai, K; Aliev, G; Nunomura, A et al. (2001) Mitochondrial abnormalities in Alzheimer's disease. J Neurosci 21:3017-23
Cuajungco, M P; Goldstein, L E; Nunomura, A et al. (2000) Evidence that the beta-amyloid plaques of Alzheimer's disease represent the redox-silencing and entombment of abeta by zinc. J Biol Chem 275:19439-42
Castellani, R J; Harris, P L; Lecroisey, A et al. (2000) Evidence for a novel heme-binding protein, HasAh, in Alzheimer disease. Antioxid Redox Signal 2:137-42
Nunomura, A; Perry, G; Pappolla, M A et al. (2000) Neuronal oxidative stress precedes amyloid-beta deposition in Down syndrome. J Neuropathol Exp Neurol 59:1011-7
Kim, H T; Russell, R L; Raina, A K et al. (2000) Protein disulfide isomerase in Alzheimer disease. Antioxid Redox Signal 2:485-9
Takeda, A; Smith, M A; Avila, J et al. (2000) In Alzheimer's disease, heme oxygenase is coincident with Alz50, an epitope of tau induced by 4-hydroxy-2-nonenal modification. J Neurochem 75:1234-41
Zhu, X; Rottkamp, C A; Boux, H et al. (2000) Activation of p38 kinase links tau phosphorylation, oxidative stress, and cell cycle-related events in Alzheimer disease. J Neuropathol Exp Neurol 59:880-8

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