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Alzheimer's Amyloid-β as a Preventive Antioxidant for Brain Lipoproteins

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Abstract

1. Increased production of Aβ in a form of lipoprotein antioxidant under the action of increased oxidative stress in aging with subsequent chelation of transition metal ions by Aβ, accumulation of toxic Aβ–metal lipoprotein complexes, production of reactive oxygen species, and neurotoxicity are reviewed and postulated to form the temporal sequence of events in the development of Alzheimer's disease (AD).

2. Since (i) Aβ binds copper stronger than iron and other transition metals, and (ii) copper is a more efficient catalyst of oxidation than other transition metals, chelation of copper by Aβ is proposed to be a most important part of this pathway.

3. Whereas this amyloid-binds-copper (ABC) model does not remove Aβ peptide from its central place in our current thinking of AD, it places additional factors in the center of discussion.

4. Most importantly, they embrace pathological mechanisms known to develop in aging (which is the most important risk factor for AD), such as increased production of reactive oxygen species by mitochondria, that can be positioned upstream relative to the generation of Aβ.

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REFERENCES

  • Andreasen, N., Minthon, L., Davidsson, P., Vanmechelen, E., Vanderstichele, H., Winblad, B., and Blennow, K. (2001). Evaluation of CSF-tau and CSF-Abeta42 as diagnostic markers for Alzheimer disease in clinical practice. Arch. Neurol. 58:373-379.

    Google Scholar 

  • Arlt, S., Finckh, B., Beisiegel, U., and Kontush, A. (2000). Time-course of oxidation of lipids in human cerebrospinal fluid in vitro. Free Radic. Res. 32:103-114.

    Google Scholar 

  • Atwood, C. S., Moir, R. D., Huang, X., Scarpa, R. C., Bacarra, N. M., Romano, D. M., Hartshorn, M. A., Tanzi, R. E., and Bush, A. I. (1998). Dramatic aggregation of Alzheimer Abeta by Cu(II) is induced by conditions representing physiological acidosis. J. Biol. Chem. 273:12817-12826.

    Google Scholar 

  • Atwood, C. S., Scarpa, R. C., Huang, X., Moir, R. D., Jones, W. D., Fairlie, D. P., Tanzi, R. E., and Bush, A. I. (2000). Characterization of copper interactions with Alzheimer amyloid beta peptides: Identification of an attomolar-affinity copper binding site on amyloid beta 1–42. J. Neurochem. 75:1219-1233.

    Google Scholar 

  • Behl, C., Davis, J. B., Lesley, R., and Schubert, D. (1994). Hydrogen peroxide mediates amyloid beta protein toxicity. Cell 77:817-827.

    Google Scholar 

  • Berndt, C., Kontush, A., and Beisiegel, U. (1998). Neuronal cell cultures protect low density lipoprotein from oxidation. Neurobiol. Aging 19:S284.

    Google Scholar 

  • Berthon, G. (1993). Is copper pro-or anti-inflammatory? A reconciling view and a novel approach for the use of copper in the control of inflammation. Agents Actions 39:210-217.

    Google Scholar 

  • Berthon, G. (2000). Does human betaA4 exert a protective function against oxidative stress in Alzheimer's disease? Med. Hypotheses 54:672-677.

    Google Scholar 

  • Bondy, S. C., Guo-Ross, S. X., and Truong, A. T. (1998). Promotion of transition metal-induced reactive oxygen species formation by beta-amyloid. Brain Res. 799:91-96.

    Google Scholar 

  • Bonilla, E., Tanji, K., Hirano, M., Vu, T. H., Dimauro, S., and Schon, E. A. (1999). Mitochondrial involvement in Alzheimer's disease. Biochem. Biophys. Acta 1410:171-182.

    Google Scholar 

  • Brasseur, R., Pillot, T., Lins, L., Vandekerckhove, J., and Rosseneu, M. (1997). Peptides in membranes: Tipping the balance of membrane stability. Trends Biochem. Sci. 22:167-171.

    Google Scholar 

  • Brown, M. S., Ye, J., Rawson, R. B., and Goldstein, J. L. (2000). Regulated intramembrane proteolysis: A control mechanism conserved from bacteria to humans. Cell 100:391-398.

    Google Scholar 

  • Busciglio, J., Gabuzda, D. H., Matsudaira, P., and Yankner, B. A. (1993). Generation of beta-amyloid in the secretory pathway in neuronal and nonneuronal cells. Proc. Natl. Acad. Sci. U.S.A. 90:2092-2096.

    Google Scholar 

  • Bush, A. I. (2000). Metals and neuroscience. Curr. Opin. Chem. Biol. 4:184-191.

    Google Scholar 

  • Bush, A. I., Atwood, C. S., Cherny, R. A., McLean, C., Fraser, F., Goldstein, L. E., Moir, R. D., Gray, D., Zheng, H., Tanzi, R. E., and Masters, C. L. (2000). In vivo inhibition of A-beta amyloid formation in a transgenic mouse model for Alzheimer's disease following oral treatment with a copper/zinc chelator. World Alzheimer Meeting 2000. Abstract.

  • Bush, A. I., Pettingell, W. H., Multhaup, G., Paradis, M., Vonsattel, J. P., Gusella, J. F., Beyreuther, K., Masters, C. L., and Tanzi, R. E. (1994). Rapid induction of Alzheimer A beta amyloid formation by zinc. Science 265:1464-1467.

    Google Scholar 

  • Butterfield, D. A., Hensley, K., Harris, M., Mattson, M., and Carney, J. (1994). Beta-Amyloid peptide free radical fragments initiate synaptosomal lipoperoxidation in a sequence-specific fashion: Implications to Alzheimer's disease. Biochem. Biophys. Res. Commun. 200:710-715.

    Google Scholar 

  • Cadenas, E., and Davies, K. J. (2000). Mitochondrial free radical generation, oxidative stress, and aging. Free Radic. Biol. Med. 29:222-230.

    Google Scholar 

  • Chandrasekaran, K., Stoll, J., Giordano, T., Atack, J. R., Matocha, M. F., Brady, D. R., and Rapoport, S. I. (1992). Differential expression of cytochrome oxidase (COX) genes in different regions of monkey brain. J. Neurosci. Res. 32:415-423.

    Google Scholar 

  • Chen, M., Inestrosa, N. C., Ross, G. S., and Fernandez, H. L. (1995). Platelets are the primary source of amyloid beta-peptide in human blood. Biochem. Biophys. Res. Commun. 213:96-103.

    Google Scholar 

  • Cherny, R. A., Legg, J. T., McLean, C. A., Fairlie, D. P., Huang, X., Atwood, C. S., Beyreuther, K., Tanzi, R. E., Masters, C. L., and Bush, A. I. (1999). Aqueous dissolution of Alzheimer's disease Abeta amyloid deposits by biometal depletion. J. Biol. Chem. 274:23223-23228.

    Google Scholar 

  • Chisolm, G. M., Hazen, S. L., Fox, P. L., and Cathcart, M. K. (1999). The oxidation of lipoproteins by monocytes-macrophages. Biochemical and biological mechanisms. J. Biol. Chem. 274:25959-25962.

    Google Scholar 

  • Cuajungco, M. P., Goldstein, L. E., Nunomura, A., Smith, M. A., Lim, J. T., Atwood, C. S., Huang X., Farrag, Y. W., Perry, G., and Bush, A. I. (2000). Evidence that the beta-amyloid plaques of Alzheimer's disease represent the redox-silencing and entombment of Abeta by zinc. J. Biol. Chem. 275:19439-19442.

    Google Scholar 

  • Frears, E. R., Stephens, D. J., Walters, C. E., Davies, H., and Austen, B. M. (1999). The role of cholesterol in the biosynthesis of beta-amyloid. Neuroreport 10:1699-1705.

    Google Scholar 

  • Frederikse, P. H., Garland, D., Zigler, J. S., Jr., and Piatigorsky, J. (1996). Oxidative stress increases production of beta-amyloid precursor protein and beta-amyloid (Abeta) in mammalian lenses, and Abeta has toxic effects on lens epithelial cells. J. Biol. Chem. 271:10169-10174.

    Google Scholar 

  • Gabuzda, D., Busciglio, J., Chen, L. B., Matsudaira, P., and Yankner, B. A. (1994). Inhibition of energy metabolism alters the processing of amyloid precursor protein and induces a potentially amyloidogenic derivative. J. Biol. Chem. 269:13623-13628.

    Google Scholar 

  • Gentleman, S. M., Greenberg, B. D., Savage, M. J., Noori, M., Newman, S. J., Roberts, G. W., Griffin, W. S., and Graham, D. I. (1997). A beta 42 is the predominant form of amyloid beta-protein in the brains of short-term survivors of head injury. Neuroreport 8:1519-1522.

    Google Scholar 

  • Ghiso, J., Matsubara, E., Koudinov, A., Choi Miura, N. H., Tomita, M., Wisniewski, T., and Frangione, B. (1993). The cerebrospinal-fluid soluble form of Alzheimer's amyloid beta is complexed to SP-40,40 (apolipoprotein J), an inhibitor of the complement membrane-attack complex. Biochem. J. 293:27-30.

    Google Scholar 

  • Haass, C., Schlossmacher, M. G., Hung, A. Y., Vigo-Pelfrey, C., Mellon, A., Ostaszewski, B. L., Lieberburg, I., Koo, E. H., Schenk, D., and Teplow, D. B. (1992). Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature 359:322-325.

    Google Scholar 

  • Halliwell, B., and Gutteridge, J. M. (1989). Free Radicals in Biology and Medicine, 2nd edn., Clarendon Press, Oxford.

    Google Scholar 

  • Han, S. H., Hulette, C., Saunders, A. M., Einstein, G., Pericak-Vance, M., Strittmatter, W. J., Roses, A. D., and Schmechel, D. E. (1994). Apolipoprotein E is present in hippocampal neurons without neurofibrillary tangles in Alzheimer's disease and in age-matched controls. Exp. Neurol. 128:13-26.

    Google Scholar 

  • Hardy, J. (1997). Amyloid, the presenilins and Alzheimer's disease. Trends. Neurosci. 20:154-159.

    Google Scholar 

  • Huang, X., Atwood, C. S., Hartshorn, M. A., Multhaup, G., Goldstein, L. E., Scarpa, R. C., Cuajungco, M. P., Gray, D. N., Lim, J., Moir, R. D., Tanzi, R. E., and Bush, A. I. (1999a). The Abeta peptide of Alzheimer's disease directly produces hydrogen peroxide through metal ion reduction. Biochemistry 38:7609-7616.

    Google Scholar 

  • Huang, X., Cuajungco, M. P., Atwood, C. S., Hartshorn, M. A., Tyndall, J. D., Hanson, G. R., Stokes, K. C., Leopold, M., Multhaup, G., Goldstein, L. E., Scarpa, R. C., Saunders, A. J., Lim, J., Moir, R. D., Glabe, C., Bowden, E. F., Masters, C. L., Fairlie, D. P., Tanzi, R. E., and Bush, A. I. (1999b). Cu(II) potentiation of Alzheimer Abeta neurotoxicity. Correlation with cell-free hydrogen peroxide production and metal reduction. J. Biol. Chem. 274:37111-37116.

    Google Scholar 

  • Irizarry, M. C., Soriano, F., McNamara, M., Page, K. J., Schenk, D., Games, D., and Hyman, B. T. (1997). Abeta deposition is associated with neuropil changes, but not with overt neuronal loss in the human amyloid precursor protein V717F (PDAPP) transgenic mouse. J. Neurosci. 17:7053-7059.

    Google Scholar 

  • Iversen, L. L., Mortishire-Smith, R. J., Pollack, S. J., and Shearman, M. S. (1995). The toxicity in vitro of beta-amyloid protein. Biochem. J. 311:1-16.

    Google Scholar 

  • Iwata, N., Tsubuki, S., Takaki, Y., Watanabe, K., Sekiguchi, M., Hosoki, E., Kawashima-Morishima, M., Lee, H. J., Hama, E., Sekine-Aizawa, Y., and Saido, T. C. (2000). Identification of the major Abetal-42-degrading catabolic pathway in brain parenchyma: Suppression leads to biochemical and pathological deposition. Nat. Med. 6:143-150.

    Google Scholar 

  • Janus, C., Pearson, J., McLaurin, J., Mathews, P. M., Jiang, Y., Schmidt, S. D., Chishti, M. A., Horne, P., Heslin, D., French, J., Mount, H. T., Nixon, R. A., Mercken, M., Bergeron, C., Fraser, P. E., George-Hyslop, P., and Westaway, D. (2000). A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature 408:979-982.

    Google Scholar 

  • Jarrett, J. T., and Lansbury, P. T. (1993). Seeding “one-dimensional crystallization” of amyloid: A pathogenic mechanism in Alzheimer's disease and scrapie? Cell 73:1055-1058.

    Google Scholar 

  • Jendroska, K., Poewe, W., Daniel, S. E., Pluess, J., Iwerssen-Schmidt, H., Paulsen, J., Barthel, S., Schelosky, L., Cervos-Navarro, J., and DeArmond, S. J. (1995). Ischemic stress induces deposition of amyloid beta immunoreactivity in human brain. Acta Neuropathol. (Berl.) 90:461-466.

    Google Scholar 

  • Jick, H., Zornberg, G. L., Jick, S. S., Seshadri, S., and Drachman, D. A. (2000). Statins and the risk of dementia. Lancet 356:1627-1631.

    Google Scholar 

  • Kardos, J., Kovacs, I., Hajos, F., Kalman, M., and Simonyi, M. (1989). Nerve endings from rat brain tissue release copper upon depolarization. A possible role in regulating neuronal excitability. Neurosci. Lett. 103:139-144.

    Google Scholar 

  • Klein, W. L., Krafft, G. A., and Finch, C. E. (2001). Targeting small Abeta oligomers: The solution to an Alzheimer's disease conundrum? Trends Neurosci. 24:219-224.

    Google Scholar 

  • Koch, S., and Beisiegel, U. (2000). Lipoproteins in the brain: A new frontier? In Betteridge, D. J. (ed.), Lipids and Vascular Disease, Martin Dunitz, London, pp. 51-64.

    Google Scholar 

  • Kontush, A., Berndt, C., Weber, W., Akopyan, V., Arlt, S., Schippling, S., and Beisiegel, U. (2001a). Amyloid-beta is an antioxidant for lipoproteins in cerebrospinal fluid and plasma. Free Radic. Biol. Med. 30:119-128.

    Google Scholar 

  • Kontush, A., Donarski, N., and Beisiegel, U. (in press). Resistance of human cerebrospinal fluid to in vitro oxidation is directly related to its amyloid-beta content. Free Radic. Res.

  • Koudinov, A., Matsubara, E., Frangione, B., and Ghiso, J. (1994). The soluble form of Alzheimer's amyloid beta protein is complexed to high density lipoprotein 3 and very high density lipoprotein in normal human plasma. Biochem. Biophys. Res. Commun. 205:1164-1171.

    Google Scholar 

  • Koudinov, A. R., and Koudinova, N. V. (1997). Alzheimer's soluble amyloid beta protein is secreted by HepG2 cells as an apolipoprotein. Cell Biol. Int. 21:265-271.

    Google Scholar 

  • Koudinov, A. R., Koudinova, N. V., Kumar, A., Beavis, R. C., and Ghiso, J. (1996). Biochemical characterization of Alzheimer's soluble amyloid beta protein in human cerebrospinal fluid: Association with high density lipoproteins. Biochem. Biophys. Res. Commun. 223:592-597.

    Google Scholar 

  • Lai, J. C., and Cooper, A. J. (1986). Brain alpha-ketoglutarate dehydrogenase complex: Kinetic properties, regional distribution, and effects of inhibitors. J. Neurochem. 47:1376-1386.

    Google Scholar 

  • LeBlanc, A. (1995). Increased production of 4kDa amyloid beta peptide in serum deprived human primary neuron cultures: Possible involvement of apoptosis. J. Neurosci. 15:7837-7846.

    Google Scholar 

  • Liu, S. T., Howlett, G., and Barrow, C. J. (1999). Histidine-13 is a crucial residue in the zinc ion-induced aggregation of the A beta peptide of Alzheimer's disease. Biochemistry 38:9373-9378.

    Google Scholar 

  • Loeffler, D. A., LeWitt, P. A., Juneau, P. L., Sima, A. A., Nguyen, H. U., DeMaggio, A. J., Brickman, C. M., Brewer, G. J., Dick, R. D., Troyer, M. D., and Kanaley, L. (1996). Increased regional brain concentrations of ceruloplasmin in neurodegenerative disorders. Brain Res. 738:265-274.

    Google Scholar 

  • Lonnrot, K., Metsa, K. T., Molnar, G., Ahonen, J. P., Latvala, M., Peltola, J., Pietila, T., and Alho, H. (1996). The effect of ascorbate and ubiquinone supplementation on plasma and CSF total antioxidant capacity. Free Radic. Biol. Med. 21:211-217.

    Google Scholar 

  • Lovell, M. A., Robertson, J. D., Teesdale, W. J., Campbell, J. L., and Markesbery, W. R. (1998). Copper, iron and zinc in Alzheimer's disease senile plaques. J. Neurol. Sci. 158:47-52.

    Google Scholar 

  • Lovstad, R. A. (1987). Copper catalyzed oxidation of ascorbate (vitamin C). Inhibitory effect of catalase, superoxide dismutase, serum proteins (ceruloplasmin, albumin, apotransferrin) and amino acids. Int. J. Biochem. 19:309-313.

    Google Scholar 

  • Lynch, S. M., and Frei, B. (1997). Physiological thiol compounds exert pro-and anti-oxidant effects, respectively, on iron-and copper-dependent oxidation of human low-density lipoprotein. Biochem. Biophys. Acta 1345:215-221.

    Google Scholar 

  • Mann, D. M., and Esiri, M. M. (1989). The pattern of acquisition of plaques and tangles in the brains of patients under 50 years of age with Down's syndrome. J. Neurol. Sci. 89:169-179.

    Google Scholar 

  • Mantyh, P. W., Ghilardi, J. R., Rogers, S., DeMaster, E., Allen, C. J., Stimson, E. R., and Maggio, J. E. (1993). Aluminum, iron, and zinc ions promote aggregation of physiological concentrations of beta-amyloid peptide. J. Neurochem. 61:1171-1174.

    Google Scholar 

  • Mark, R. J., Blanc, E. M., and Mattson, M. P. (1996). Amyloid beta-peptide and oxidative cellular injury in Alzheimer's disease. Mol. Neurobiol. 12:211-224.

    Google Scholar 

  • Mark, R. J., Lovell, M. A., Markesbery, W. R., Uchida, K., and Mattson, M. P. (1997b). A role for 4-hydroxynonenal, an aldehydic product of lipid peroxidation, in disruption of ion homeostasis and neuronal death induced by amyloid beta-peptide. J. Neurochem. 68:255-264.

    Google Scholar 

  • Mark, R. J., Pang, Z., Geddes, J. W., Uchida, K., and Mattson, M. P. (1997a). Amyloid beta-peptide impairs glucose transport in hippocampal and cortical neurons: Involvement of membrane lipid peroxidation. J. Neurosci. 17:1046-1054.

    Google Scholar 

  • Markesbery, W. R. (1997). Oxidative stress hypothesis in Alzheimer's disease. Free Radic. Biol. Med. 23:134-147.

    Google Scholar 

  • Mason, R. P., Jacob, R. F., Walter, M. F., Mason, P. E., Avdulov, N. A., Chochina, S. V., Igbavboa, U., and Wood, W. G. (1999). Distribution and fluidizing action of soluble and aggregated amyloid beta-peptide in rat synaptic plasma membranes. J. Biol. Chem. 274:18801-18807.

    Google Scholar 

  • May, P. M., Linder, P. W., and Williams, D. R. (1976). Ambivalent effect of protein binding on computed distributions of metal ions complexed by ligands in blood plasma. Experientia 32:1492-1494.

    Google Scholar 

  • McLachlan, D. R., Dalton, A. J., Kruck, T. P., Bell, M. Y., Smith, W. L., Kalow, W., and Andrews, D. F. (1991). Intramuscular desferrioxamine in patients with Alzheimer's disease. Lancet 337:1304-1308.

    Google Scholar 

  • McRae, A., Dahlstrom, A., and Ling, E. A. (1997). Microglial in neurodegenerative disorders: Emphasis on Alzheimer's disease. Gerontology 43:95-108.

    Google Scholar 

  • Mielke, R., Kessler, J., Szelies, B., Herholz, K., Wienhard, K., and Heiss, W. D. (1998). Normal and pathological aging: Findings of positron-emission-tomography. J. Neural Transm. 105:821-837.

    Google Scholar 

  • Misonou, H., Morishima-Kawashima, M., and Ihara, Y. (2000). Oxidative stress induces intracellular accumulation of amyloid beta-protein (Abeta) in human neuroblastoma cells. Biochemistry 39:6951-6959.

    Google Scholar 

  • Miura, T., Suzuki, K., Kohata, N., and Takeuchi, H. (2000). Metal binding modes of Alzheimer's amyloid beta-peptide in insoluble aggregates and soluble complexes. Biochemistry 39:7024-7031.

    Google Scholar 

  • Miyata, M., and Smith, J. D. (1996). Apolipoprotein E allele-specific antioxidant activity and effects on cytotoxicity by oxidative insults and beta-amyloid peptides. Nat. Genet. 14:55-61.

    Google Scholar 

  • Moir, R. D., Atwood, C. S., Romano, D. M., Laurans, M. H., Huang, X., Bush, A. I., Smith, J. D., and Tanzi, R. E. (1999). Differential effects of apolipoprotein E isoforms on metal-induced aggregation of A beta using physiological concentrations. Biochemistry 38:4595-4603.

    Google Scholar 

  • Motter, R., Vigo-Pelfrey, C., Kholodenko, D., Barbour, R., Johnson-Wood, K., Galasko, D., Chang, L., Miller, B., Clark, C., and Green, R. (1995). Reduction of beta-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer's disease. Ann. Neurol. 38:643-648.

    Google Scholar 

  • Nunomura, A., Perry, G., Pappolla, M. A., Friedland, R. P., Hirai, K., Chiba, S., and Smith, M. A. (2000). Neuronal oxidative stress precedes amyloid-beta deposition in Down syndrome. J. Neuropathol. Exp. Neurol. 59:1011-1017.

    Google Scholar 

  • Nunomura, A., Perry, G., Zhang, J., Montine, T., Takeda, A., Chiba, S., and Smith, M. A. (1999). RNA oxidation in Alzheimer and Parkinson diseases. J. Anti-Aging Med. 2:227-230.

    Google Scholar 

  • Olivieri, G., Baysang, G., Meier, F., Muller-Spahn, F., Stahelin, H. B., Brockhaus, M., and Brack, C. (2001). N-acetyl-L-cysteine protects SHSY5Y neuroblastoma cells from oxidative stress and cell cytotoxicity: Effects on beta-amyloid secretion and tau phosphorylation. J. Neurochem. 76:224-233.

    Google Scholar 

  • Olivieri, G., Brack, C., Muller-Spahn, F., Stahelin, H. B., Herrmann, M., Renard, P., Brockhaus, M., and Hock, C. (2000). Mercury induces cell cytotoxicity and oxidative stress and increases beta-amyloid secretion and tau phosphorylation in SHSY5Y neuroblastoma cells. J. Neurochem. 74:231-236.

    Google Scholar 

  • Perry, G., Castellani, R., Hirai, K., and Smith, M. A. (1998). Reactive oxygen species mediate cellular damage in Alzheimer's disease. J. Alzheimer Dis. 1:45-55.

    Google Scholar 

  • Perry, G., Nunomura, A., Hirai, K., Zhu, X., Perez, M., Avila, J., Castellani, R., Aliev, G., Takeda, A., and Smith, M. A. (in press). Is oxidative damage the common mechanism of neurodegenerative diseases? Neuromusc. Dis. Aging.

  • Pirttila, T., Kim, K. S., Mehta, P. D., Frey, H., and Wisniewski, H. M. (1994). Soluble amyloid beta-protein in the cerebrospinal fluid from patients with Alzheimer's disease, vascular dementia and controls. J. Neurol. Sci. 127:90-95.

    Google Scholar 

  • Pitas, R. E., Boyles, J. K., Lee, S. H., Hui, D., and Weisgraber, K. H. (1987). Lipoproteins and their receptors in the central nervous system. J. Biol. Chem. 262:14352-14360.

    Google Scholar 

  • Raby, C. A., Morganti-Kossmann, M. C., Kossmann, T., Stahel, P. F., Watson, M. D., Evans, L. M., Mehta, P. D., Spiegel, K., Kuo, Y. M., Roher, A. E., and Emmerling, M. R. (1998). Traumatic brain injury increases beta-amyloid peptide 1–42 in cerebrospinal fluid. J. Neurochem. 71:2505-2509.

    Google Scholar 

  • Rae, T. D., Schmidt, P. J., Pufahl, R. A., Culotta, V. C., and O'Halloran, T. V. (1999). Undetectable intracellular free copper: The requirement of a copper chaperone for superoxide dismutase. Science 284:805-808.

    Google Scholar 

  • Refolo, L. M., Pappolla, M. A., Malester, B., LaFrancois, J., Bryant-Thomas, T., Wang, R., Tint, G. S., Sambamurti, K., and Duff, K. (2000). Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model. Neurobiol. Dis. 7:321-331.

    Google Scholar 

  • Rottkamp, C. A., Raina, A. K., Zhu, X., Gaier, E., Bush, A. I., Atwood, C. S., Chevion, M., Perry, G., and Smith, M. A. (2001). Redox-active iron mediates amyloid-beta toxicity. Free Radic. Biol. Med. 30:447-450.

    Google Scholar 

  • Sayre, L. M., Perry, G., Harris, P. L., Liu, Y., Schubert, K. A., and Smith, M. A. (2000). In situ oxidative catalysis by neurofibrillary tangles and senile plaques in Alzheimer's disease: A central role for bound transition metals. J. Neurochem. 74:270-279.

    Google Scholar 

  • Schippling, S., Kontush, A., Arlt, S., Buhmann, C., Sturenburg, H., Mann, U., Muller-Thomsen, T., and Beisiegel, U. (2000). Increased lipoprotein oxidation in Alzheimer's disease. Free Radic. Biol. Med. 28:351-360.

    Google Scholar 

  • Schubert, D., and Chevion, M. (1995). The role of iron in beta amyloid toxicity. Biochem. Biophys. Res. Commun. 216:702-707.

    Google Scholar 

  • Selkoe, D. J. (2001). Alzheimer's disease: Genes, proteins, and therapy. Physiol. Rev. 81:741-766.

    Google Scholar 

  • Shigenaga, M. K., Hagen, T. M., and Ames, B. N. (1994). Oxidative damage and mitochondrial decay in aging. Proc. Natl. Acad. Sci. U.S.A. 91:10771-10778.

    Google Scholar 

  • Simons, M., Keller, P., De, S. B., Beyreuther, K., Dotti, C. G., and Simons, K. (1998). Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. Proc. Natl. Acad. Sci. U.S.A. 95:6460-6464.

    Google Scholar 

  • Smith, J. D. (2000). Apolipoprotein E4: An allele associated with many diseases. Ann. Med. 32:118-127.

    Google Scholar 

  • Smith, M. A., Joseph, J. A., and Perry, G. (2000c). Arson: Tracking the culprit in Alzheimer's disease. Ann. N.Y. Acad. Sci. 924:35-38.

    Google Scholar 

  • Smith, M. A., Nunomura, A., Zhu, X., Takeda, A., and Perry, G. (2000b). Metabolic, metallic, and mitotic sources of oxidative stress in Alzheimer disease. Antioxid. Redox Signal. 2:413-420.

    Google Scholar 

  • Smith, M. A., and Perry, G. (1998). What are the facts and artifacts of the pathogenesis and etiology of Alzheimer disease? J. Chem. Neuroanat. 16:35-41.

    Google Scholar 

  • Smith, M. A., and Perry, G. (2000). Molecular and cellular aspects of oxidative damage in Alzheimer's disease. In Poli, G., Cadenas, E., and Packer, L. (ed.), Free Radicals in Brain Pathophysiology, Marcel Dekker, New York, pp. 313-321.

    Google Scholar 

  • Smith, M. A., Rottkamp, C. A., Nunomura, A., Raina, A. K., and Perry, G. (2000a). Oxidative stress in Alzheimer's disease. Biochim. Biophys. Acta 1502:139-144.

    Google Scholar 

  • Soriani, M., Pietraforte, D., and Minetti, M. (1994). Antioxidant potential of anaerobic human plasma: Role of serum albumin and thiols as scavengers of carbon radicals. Arch. Biochem. Biophys. 312:180-188.

    Google Scholar 

  • Sparks, D. L., Scheff, S. W., Hunsaker, J. C., Liu, H., Landers, T., and Gross, D. R. (1994). Induction of Alzheimer-like beta-amyloid immunoreactivity in the brains of rabbits with dietary cholesterol. Exp. Neurol. 126:88-94.

    Google Scholar 

  • Stocker, R. (1994). Lipoprotein oxidation: Mechanistic aspects, methodological approaches and clinical relevance. Curr. Opin. Lipidol. 5:422-433.

    Google Scholar 

  • Tienari, P. J., Ida, N., Ikonen, E., Simons, M., Weidemann, A., Multhaup, G., Masters, C. L., Dotti, C. G., and Beyreuther, K. (1997). Intracellular and secreted Alzheimer beta-amyloid species are generated by distinct mechanisms in cultured hippocampal neurons. Proc. Natl. Acad. Sci. U.S.A. 94:4125-4130.

    Google Scholar 

  • Tokuda, T., Calero, M., Matsubara, E., Vidal, R., Kumar, A., Permanne, B., Zlokovic, B., Smith, J. D., LaDu, M. J., Rostagno, A., Frangione, B., and Ghiso, J. (2000). Lipidation of apolipoprotein E influences its isoform-specific interaction with Alzheimer's amyloid beta peptides. Biochem. J. 348:359-365.

    Google Scholar 

  • Turner, R. S., Suzuki, N., Chyung, A. S., Younkin, S. G., and Lee, V. M. (1996). Amyloids beta40 and beta42 are generated intracellularly in cultured human neurons and their secretion increases with maturation. J. Biol. Chem. 271:8966-8970.

    Google Scholar 

  • Varadarajan, S., Yatin, S., Aksenova, M., and Butterfield, D. A. (2000). Review: Alzheimer's amyloid beta-peptide-associated free radical oxidative stress and neurotoxicity. J. Struct. Biol. 130:184-208.

    Google Scholar 

  • Walter, M. F., Mason, P. E., and Mason, R. P. (1997). Alzheimer's disease amyloid beta peptide 25–35 inhibits lipid peroxidation as a result of its membrane interactions. Biochem. Biophys. Res. Commun. 233:760-764.

    Google Scholar 

  • Whitson, J. S., Selkoe, D. J., and Cotman, C. W. (1989). Amyloid beta protein enhances the survival of hippocampal neurons in vitro. Science 243:1488-1490.

    Google Scholar 

  • Wisniewski, T., and Frangione, B. (1992). Apolipoprotein E: A pathological chaperone protein in patients with cerebral and systemic amyloid. Neurosci. Lett. 135:235-238.

    Google Scholar 

  • Wisniewski, H. M., and Wen, G. Y. (1992). Aluminium and Alzheimer's disease. Ciba Found. Symp. 169:142-154.

    Google Scholar 

  • Wolozin, B., Kellman, W., Ruosseau, P., Celesia, G. G., and Siegel, G. (2000). Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch. Neurol. 57:1439-1443.

    Google Scholar 

  • Xu, J., Chen, S., Ahmed, S. H., Chen, H., Ku, G., Goldberg, M. P., and Hsu, C. Y. (2001). Amyloid-beta peptides are cytotoxic to oligodendrocytes. J. Neurosci. 21:RC118.

    Google Scholar 

  • Yan, S. D., Yan, S. F., Chen, X., Fu, J., Chen, M., Kuppusamy, P., Smith, M. A., Perry, G., Godman, G. C., Nawroth, P. (1995). Non-enzymatically glycated tau in Alzheimer's disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid beta-peptide. Nat. Med. 1:693-699.

    Google Scholar 

  • Yankner, B. A. (1996). Mechanisms of neuronal degeneration in Alzheimer's disease. Neuron 16:921-932.

    Google Scholar 

  • Zhang, L., Zhao, B., Yew, D. T., Kusiak, J. W., and Roth, G. S. (1997). Processing of Alzheimer's amyloid precursor protein during H2O2-induced apoptosis in human neuronal cells. Biochem. Biophys. Res. Commun. 235:845-848.

    Google Scholar 

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Kontush, A. Alzheimer's Amyloid-β as a Preventive Antioxidant for Brain Lipoproteins. Cell Mol Neurobiol 21, 299–315 (2001). https://doi.org/10.1023/A:1012629603390

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