We hypothesize that altered protein phosphorylation reactions are deleterious to neurons and might be involved in neurodegeneration in Alzheimer's disease (AD). It is now well recognized that protein phosphorylation is a key biochemical reaction required for the regulation of cell growth and cell survival. Thus, it is possible that aberrant phosphorylation reactions play an important role in the neuronal degeneration. There are age-associated declines of some protein kinases. Therefore, it is possible that the neurodegeneration observed in AD which is an age-associated disease, might be at least partly explained by the altered protein phosphorylation reactions. In affected neurons, there are neurofibrially tangles composed of cytoskeletal proteins, ubiquitin, and still unknown molecules. Immunohistochemical studies have revealed that the constituents of tangles as well as proteins in neurons at risk are excessively phosphorylated. Our in vitro phosphorylation study has supported the notion that the phosphorylation cascade reactions are aberrant in AD. We have identified protein kinase C (PKC), casein kinase II (CK-ll), and protein tyrosine kinase (PTK) as altered in AD. Interestingly, PKC alteration might be associated with neuritic plaque pathology in AD and CK-ll alteration with neurofibrillary tangle pathology. In the current proposal, we extend this study to their substrate proteins employing biochemical and immunohistochemical techniques. Furthermore, we attempt to identify an unknown protein kinase, the activity of which, measured with exogenous histone lll-S, is increased in AD, and a phosphoprotein, P60, which was found by in vitro phosphorylation of AD cytosol. In addition, possible phosphorylation of t, a tangle constituent, by CK-ll and other kinases will be studied. The purpose of the project is to pull all the altered molecules of protein phosphorylation into a cohesive cascade of AD pathology. To this end, we will study the localization of various components of protein phosphorylation.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Neurological Sciences Subcommittee 1 (NLS)
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University of California San Diego
Schools of Medicine
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Saitoh, T; Kang, D; Mallory, M et al. (1997) Glial cells in Alzheimer's disease: preferential effect of APOE risk on scattered microglia. Gerontology 43:109-18
Conrad, C; Andreadis, A; Trojanowski, J Q et al. (1997) Genetic evidence for the involvement of tau in progressive supranuclear palsy. Ann Neurol 41:277-81
Kang, D E; Saitoh, T; Chen, X et al. (1997) Genetic association of the low-density lipoprotein receptor-related protein gene (LRP), an apolipoprotein E receptor, with late-onset Alzheimer's disease. Neurology 49:56-61
Jin, L W; Masliah, E; Iimoto, D et al. (1996) Neurofibrillary tangle-associated alteration of stathmin in Alzheimer's disease. Neurobiol Aging 17:331-41
Chen, X; Xia, Y; Gresham, L S et al. (1996) ApoE and CYP2D6 polymorphism with and without parkinsonism-dementia complex in the people of Chamorro, guam. Neurology 47:779-84
Samuel, W; Galasko, D; Masliah, E et al. (1996) Neocortical lewy body counts correlate with dementia in the Lewy body variant of Alzheimer's disease. J Neuropathol Exp Neurol 55:44-52
Baum, L; Seger, R; Woodgett, J R et al. (1995) Overexpressed tau protein in cultured cells is phosphorylated without formation of PHF: implication of phosphoprotein phosphatase involvement. Brain Res Mol Brain Res 34:1-17
Jin, L W; Saitoh, T (1995) Changes in protein kinases in brain aging and Alzheimer's disease. Implications for drug therapy. Drugs Aging 6:136-49
Okazaki, T; Wang, H; Masliah, E et al. (1995) SCG10, a neuron-specific growth-associated protein in Alzheimer's disease. Neurobiol Aging 16:883-94
Chen, X; Xia, Y; Alford, M et al. (1995) The CYP2D6B allele is associated with a milder synaptic pathology in Alzheimer's disease. Ann Neurol 38:653-8

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