Although with the cloning of the cDNA for the amyloid precursor protein (APP) in late 1986 the sequences and identification of APP have been possible, the importance of APP in the pathogenesis of Alzheimer Disease (AD) is essentially unknown. During the previous funding period, several immunochemical and biochemical probes were produced and used by this laboratory to conclude that neurons are the major source of APP in the senile plaque, the site of the amyloid deposition. They suggest these findings are directly relevant to their original hypothesis: that the intraneuronal cytoskeletal changes of AD, neurofibrillary pathology (NFP), is a direct result of the interaction of APP with the cytoskelton. The finding that NFP contains abundant heparin sulfate proteoglycans (HSPG) gave them a chemical basis for this binding, since APP is an ASPG binding protein. In binding studies, they found that many NFP components specifically associate with APP accumulations. Support was therefore found for the hypothesis that NFP components are incorporated through reciprocal binding. In the present proposal, they will extend these studies through the following aims: (1) Binding studies that will define NFP's biochemistry in situ as well as traditional biochemical properties; (2) determine whether HSPG's are associated with the NFP's of other diseases; (3) determine the relationship of neuritic change to amyloid deposition in AD and control brains; (4) study the effect of APP gradients in the brain through brain implants of APP and B-protein; (5) physical mapping of NFP epitopes.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
2R01AG007552-04
Application #
3118671
Study Section
Neurology A Study Section (NEUA)
Project Start
1988-04-01
Project End
1994-03-31
Budget Start
1991-04-01
Budget End
1992-03-31
Support Year
4
Fiscal Year
1991
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; 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
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
Shimohama, S; Perry, G; Richey, P et al. (1995) Characterization of the association of phospholipase C-delta with Alzheimer neurofibrillary tangles. Brain Res 669:217-24
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

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