The major histological lesions consistently found in the brains of Alzheimer patients are neurofibrillary tangles (NFT) and senile plaques (SF). Although NFT are also found in other neurodegenerative conditions, recent results obtained using molecular biological approaches suggest that understanding the NFT and SP may provide an important insight into the etiology of Alzheimer disease (AD). These studies have demonstrated that the gene coding for the protein precursor of amyloid, the major component of SP, is located in the same region of chromosome 21 that is altered in familial AD and duplicate in sporadic AD. The building block of amyloid, a breakdown product of the amyloid precursor protein, possibly results from the ubiquitin-directed proteolytic system. Recent studies have demonstrated that ubiquitin conjugates are present in NFT. The nature and function of the amyloid precursor in normal cell physiology has not been determined. Since the amino acid sequence of the amyloid precursor is published, antibodies to synthetic peptides can be produced. These antibodies will be used to identify which cells produce amyloid precursor and whether it is ubiquitinated. Although NFT and SP share epitopes, the sequences of amyloid precursor found is PHF may not be identical to those found in SP. Amyloid precursor is a membrane receptor protein. Physiologically, proteins of this class interact with the cytoskeleton. The presence of cytoskeletal elements in NFT may be a direct result of the presence of sequences from the intracellular domain of the amyloid precursor. Therefore, it will be important to know whether antibodies to the intracellular domain stain NFT and if cytoskeletal elements bind to these sequences. The finding of a common mechanism of formation of both NFT and SP would advance substantially the understanding of the pathogenesis of AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG007552-03
Application #
3118674
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1988-04-01
Project End
1991-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
3
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Smith, M A; Perry, G (1996) Alzheimer disease: protein-protein interaction and oxidative stress. Bol Estud Med Biol 44:5-10
Praprotnik, D; Smith, M A; Richey, P L et al. (1996) Plasma membrane fragility in dystrophic neurites in senile plaques of Alzheimer's disease: an index of oxidative stress. Acta Neuropathol (Berl) 91:1-5
Smith, M A; Dunbar, C E; Miller, E J et al. (1996) Trypsin interaction with the senile plaques of Alzheimer disease is mediated by beta-protein precursor. Mol Chem Neuropathol 27:145-54
Praprotnik, D; Smith, M A; Richey, P L et al. (1996) Filament heterogeneity within the dystrophic neurites of senile plaques suggests blockage of fast axonal transport in Alzheimer's disease. Acta Neuropathol (Berl) 91:226-35
Smith, M A; Siedlak, S L; Richey, P L et al. (1996) Quantitative solubilization and analysis of insoluble paired helical filaments from Alzheimer disease. Brain Res 717:99-108
Premkumar, D R; Smith, M A; Richey, P L et al. (1995) Induction of heme oxygenase-1 mRNA and protein in neocortex and cerebral vessels in Alzheimer's disease. J Neurochem 65:1399-402
Smith, M A; Rudnicka-Nawrot, M; Richey, P L et al. (1995) Carbonyl-related posttranslational modification of neurofilament protein in the neurofibrillary pathology of Alzheimer's disease. J Neurochem 64:2660-6
Smith, M A; Perry, G (1995) Free radical damage, iron, and Alzheimer's disease. J Neurol Sci 134 Suppl:92-4
Castellani, R; Smith, M A; Richey, P L et al. (1995) Evidence for oxidative stress in Pick disease and corticobasal degeneration. Brain Res 696:268-71
Shimohama, S; Fujimoto, S; Matsushima, H et al. (1995) Alteration of phospholipase C-delta protein level and specific activity in Alzheimer's disease. J Neurochem 64:2629-34

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