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Free radical theory of aging: A hypothesis on pathogenesis of senile dementia of the Alzheimer’s type

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Abstract

Senile dementia of the Alzheimer’s type (SDAT) is the major cause of dementia. It is a spontaneous, i.e. sporadic, systemic disorder whose major manifestations are in the brain. It is hypothesized that SDAT may be the result of one of a number of potential mutations in a mitochondrial DNA molecule, early in development and after germ cell segregation, that impairs oxidative phosphorylation and increases production of \(O\mathop \cdot \limits_2^ -\) and H2O2. Replicative segregation distributes the mutated mtDNA to the cells of the developing organism in such a manner that with advancing age cellular dysfunction occurs first in areas of the brain associated with Alzheimer’s disease. Cell damage and death is attributed to random free radical damage secondary to falling ATP production and increasing formation of \(O\mathop \cdot \limits_2^ -\) and H2O2 due to aging of the normal and defective mitochondria. The increasing oxidative stress contributes to cell damage and eventual death in part by impairing cellular control of Ca2+ concentration; sustained increases in cellular Ca2+ disrupts the cytoskeleton and activates calcium dependent catabolic enzymes.

SDAT is essentially due to acceleration of normal neuronal aging. The amyloid associated with SDAT is apparently a consequence of normal neuronal metabolism and of the changes associated with normal neuronal death.

The incidence of SDAT may be decreased by efforts to prevent mutation of a mtDNA molecule early in development, for example, possibly by decreasing maternal deleterious free radical reactions by dietary modulation and/or antioxidant supplements. Similar efforts by the general population may also decrease the incidence by disproportionately slowing the rate of production of free radical damage in those individuals destined to develop Alzheimer’s disease owing to their higher rate of initiation of deleterious free radical reactions. The function of SDAT patients may be temporarily improved by “ rescuing” some impaired neurons, and the underlying mitochondrial decline slowed, by measures similar to those employed with other mitochondrial disorders.

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References

  1. Katzman, R.: Alzheimer’s disease. New Eng. J. Med., 314: 964–973, 1986.

    Article  CAS  PubMed  Google Scholar 

  2. Breitner, J.C.S., Murphy, E.A., Silverman, J.M., Mohs, R.C., and Davis, K.L.: Age-dependent expression of familial risk in Alzheimer’s disease. Amer. J. Epidemiology, 128: 536–548, 1988.

    CAS  Google Scholar 

  3. Nalbantoglu, J., Lacoste-Royal, G., and Gauvreau, D.: Genetic factors in Alzheimer’s disease. J. Amer. Geriat. Soc., 38: 564–568, 1990.

    CAS  PubMed  Google Scholar 

  4. Kosik, K.S.: Alzheimer’s disease: A cell biological perspective. Science, 256: 780–783, 1992.

    CAS  PubMed  Google Scholar 

  5. St. George-Hyslop, P.H., Tanzi, R.E., Polinsky, R.J., et al.: The genetic defect causing familial Alzheimer’s disease maps on chromosome 21. Science, 235: 885–890, 1987.

    CAS  PubMed  Google Scholar 

  6. Murrell, J., Farlow, M., Ghetti, B., and Benson, M.D.: A mutation in the amyloid precursor protein associated with hereditary Alzheimer’s disease. Science, 254: 97–99, 1991.

    CAS  PubMed  Google Scholar 

  7. Goate, A., Chartier-Harlin, M.-C., and Mullan, M., et al.: Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature, 349: 704–706, 1991.

    Article  CAS  PubMed  Google Scholar 

  8. Katzman, R., and Saitoh, T.: Advances in Alzheimer’s disease. FASEB J., 5: 278–286, 1991.

    CAS  PubMed  Google Scholar 

  9. Hafner, H.: Epidemiology of Alzheimer’s disease, in Alzheimer’s Disease: Epidemiology, Neuropathology, Neurochemistry, and Clinics, edited by Maurer, K., Riederer, P., and Beckmann, H., New York, Springer-Verlag, 1990, pp. 23–39.

    Google Scholar 

  10. Peterson, C., and Goldman, J.E.: Alterations in calcium content and biochemical processes in cultured skin fibroblasts from aged and Alzheimer’s donors. Proc. Natl. Acad. Sci., USA, 83: 2758–2762, 1986.

    CAS  PubMed  Google Scholar 

  11. Nitsch, R.M., Blusztajn, J.K., Pittas, A.G., Slack, B.E., Growdon, J.H., and Wurtman, R.J.: Evidence for a membrane defect in Alzheimer’s disease brain. Proc. Natl. Acad. Sci., USA, 89: 1671–1675, 1992.

    CAS  PubMed  Google Scholar 

  12. Bossman, G.J.C.G.M., Bartholomeus, I.G.P., and de Grip, W.J.: Alzheimer’s disease and cellular aging: Membrane-related events as clues to primary mechanisms. Gerontol., 37: 95–112, 1991.

    Article  Google Scholar 

  13. Parker, Jr., W.D., Filley, C.M., and Parks, J.K.: Cytochrome oxidase deficiency in Alzheimer’s disease. Neurol., 40: 1302–1303, 1990.

    Google Scholar 

  14. Katzman, R., and Jackson, J.E.: Alzheimer disease: Basic and clinical advances. J. Amer. Geriat. Soc., 39: 516–525, 1991.

    CAS  PubMed  Google Scholar 

  15. McKee, A.C., Kosik, K.S., and Kowall, N.W.: Neuritic pathology and dementia in Alzheimer’s disease. Ann. Neurol., 30: 156–165, 1991.

    Article  CAS  PubMed  Google Scholar 

  16. Terry, R.D.: Ultrastructural alterations in senile dementia, in Alzheimer’s Disease: Senile Dementia and Related Disorders, edited by Katzman, R., Terry, R.D., and Bick, K.L., New York, Raven Press, 1978, pp. 375–382.

    Google Scholar 

  17. Wisniewski, H.M., and Merz, G.S.: Neuropathology of the aging brain and dementia of the Alzheimer type, in Aging 2000: Our Health Care Destiny, Vol. 1: Biomedical issues, edited by Gaitz, C.M., and Samorajski, T., New York, Springer-Verlag, 1983, pp. 231–243.

    Google Scholar 

  18. Wisniewski, H.M., and Terry, R.D.: Morphology of the aging brain, human and animal. Progr. Brain Res., 40: 167–186, 1973.

    CAS  Google Scholar 

  19. Crystal, H., Dickson, D., Fuld, P., et al.: Clinicopathologic studies in dementia: Nondemented subjects with pathologically confirmed Alzheimer’s disease. Neurol., 38: 1682–1687, 1988.

    CAS  Google Scholar 

  20. Braak, H., and Braak, E.: Morphology of the cerebral cortex in relation to Alzheimer’s dementia, in Alzheimer’s Disease: Epidemiology, Neuropathology, Neurochemistry, and Clinics, edited by Maurer, K., Riederer, P., and Beckmann, H., New York, Springer-Verlag, 1990, pp. 85–91.

    Google Scholar 

  21. Pearson, R.C.A., Esiri, M.M., Hiorns, R.W., Wilcock, G.K., and Powell, T.P.S.: Anatomical correlates of the distribution of the pathological changes in the neocortex in Alzheimer’s disease. Proc. Natl. Acad. Sci., USA, 82: 4531–4534, 1985.

    CAS  PubMed  Google Scholar 

  22. Arendt, T., Bigl, V., Tennsted, A., and Arendt, A.: Neuronal loss in different parts of the nucleus basalis is related to neuritic plaque formation in cortical target areas in Alzheimer’s disease. Neurosci., 14: 1–14, 1985.

    Article  CAS  Google Scholar 

  23. Cataldo, A.M., and Nixon, R.A.: Enzymatically active lysosomal proteases are associated with amyloid deposits in Alzheimer brain. Proc. Natl. Acad. Sci., USA, 87: 3861–3865, 1990.

    CAS  PubMed  Google Scholar 

  24. Cataldo, A.M., Paskevich, P.A., Kominami, E., and Nixon, R.A.: Lysosomal hydrolases of different classes are abnormally distributed in brains of patients with Alzheimer’s disease. Proc. Natl. Acad. Sci., USA, 88: 10998–11002, 1991.

    Google Scholar 

  25. Masliah, E., Terry, R.D., DeTeresa, R.M., and Hansen, L.A.: Immunohistochemical quantification of the synapse-related protein synaptophysin in Alzheimers disease. Neurosci. Lett., 103: 234–239, 1989.

    Article  CAS  PubMed  Google Scholar 

  26. DeKosky, S.T., and Scheff, S.W.: Synapse loss in frontal cortex biopsies in Alzheimer’s disease: Correlation with cognitive severity. Ann. Neurol., 27: 457–464, 1990.

    Article  CAS  PubMed  Google Scholar 

  27. Hyman, B.T., Van Hoesen, G.W., Damasio, A.R., and Barnes, C.L.: Alzheimer’s disease: Cell-specific pathology isolates the hippocampal formation. Science, 225: 1168–1170, 1984.

    CAS  PubMed  Google Scholar 

  28. Ball, M.J., Hachinski, V., Fox, A., Kirshen, A.J., Fisman, M., Blume, W., Kral, V.A., and Fox, H.: A new definition of Alzheimer’s disease: A hippocampal dementia. Lancet, 1: 14–16, 1985.

    Article  CAS  PubMed  Google Scholar 

  29. Braak, H., and Braak, E.: Entorhinal lesions in dementia, in Alzheimer’s Disease: Basic Mechanisms, Diagnosis and Therapeutic Strategies, edited by Iqbal, K., McLachlan, D.R.C., Winblad, B., and Wisniewski, H.M., New York, John Wiley, 1990, pp. 91–97.

    Google Scholar 

  30. Mann, D.M.A.: The neuropathology of Alzheimer’s disease: A review with pathogenic, aetiological and therapeutic considerations. Mech. Ageing Dev., 31: 213–255, 1985.

    Article  CAS  PubMed  Google Scholar 

  31. Friede, R.L.: The relation of the formation of lipofuscin to the distribution of oxidative enzymes in the human brain. Acta Neuropathol., 2: 113–125, 1962.

    Article  CAS  Google Scholar 

  32. Harman, D.: Lipofuscin and ceroid formation: The cellular recycling system, in Lipofuscin and Ceroid Pigments, edited by Porta, E.A., New York, Plenum Press, 1990, pp. 3–15.

    Google Scholar 

  33. Brizzee, K.R., Eddy, D.E., Harman, D., and Ordy, J.M.: Free radical theory of aging: Effect of dietary lipids on lipofuscin accumulation in the hippocampus of rats. Age, 7: 9–15, 1984.

    Article  CAS  Google Scholar 

  34. Eddy, D.E., and Harman, D.: Rat brain fatty acid composition: Effect of dietary fat and age. J. Gerontol. 30: 647–654, 1975.

    CAS  PubMed  Google Scholar 

  35. Crawford, M.A., and Sinclair, A.J.: Nutritional influences in the evolution of mammalian brain, in Lipids, Malnutrition & the Developing Brain, edited by Elliott, K., and Knight, J., Amsterdam, Elsevier/Excerpta/North-Holland, 1972, pp. 267–287.

    Google Scholar 

  36. Eddy, D.E., and Harman, D.: Free radical theory of aging: Effect of age, sex and dietary precursors on rat brain docosahexanoic acid. J. Amer. Geriat. Soc., 25: 220–229, 1977.

    CAS  PubMed  Google Scholar 

  37. Tinoco, J., Williams, M.A., Hincenbergs, I., and Lyman, R.L.: Evidence for nonessentiality of linolenic acid in the diet of the rat. J. Nutr., 101: 937–946, 1971.

    CAS  PubMed  Google Scholar 

  38. Walker, R.L.: Maternal diet and brain fatty acids in young rats. Lipids, 2: 497–500, 1967.

    CAS  PubMed  Google Scholar 

  39. Tamai, Y., Matsukawa, S., and Satake, M.: Lipid composition of nerve cell perikarya. Brain Res., 26: 149–157, 1971.

    Article  CAS  Google Scholar 

  40. Cotman, C., Blank, M.L., Moehl, A., and Snyder, F.: Lipid composition of synaptic plasma membranes isolated from rat brain by zonal centrifugation. Biochem., 8: 4606–4612, 1969.

    Article  CAS  Google Scholar 

  41. Hubbard, B.M., and Anderson, J.M.: Sex difference in age-related brain atrophy. Lancet 1: 1447–1448, 1983.

    Article  CAS  PubMed  Google Scholar 

  42. Mayer, R.J., Landon, M., Lazlo, L., Lennox, G., and Lowe, J.: Protein processing in lysosomes: The new therapeutic target in neurodegenerative disease. Lancet, 340: 156–159, 1992.

    Article  CAS  PubMed  Google Scholar 

  43. Stadtman, E.R.: Oxidation of protein by mixed-function oxidation systems: Implication in protein tumover, ageing and neutrophil function. Trends Biochem. Sci., 11: 11–12, 1986.

    Article  CAS  Google Scholar 

  44. Stadtman, E.R.: Biochemical markers of ageing. Exper. Gerontol., 23: 327–347, 1988.

    Article  CAS  Google Scholar 

  45. Stadtman, E.R.: Covalent modification reactions are marking steps in protein turnover. Biochem., 29: 6323–6331, 1990.

    Article  CAS  Google Scholar 

  46. Stadtman, E.R.: Metal ion-catalyzed oxidation of proteins: Biochemical mechanisms and biological consequences. Free Radical Biol. Med., 9: 315–325, 1990.

    Article  CAS  Google Scholar 

  47. Stadtman, E.R.: Protein oxidation and aging. Science, 257: 1220–1224, 1992.

    CAS  PubMed  Google Scholar 

  48. Davies, K.J.A.: Protein damage and degradation by oxygen radicals. J. Biol. Chem., 262: 9895–9901, 1987.

    CAS  PubMed  Google Scholar 

  49. Stadtman, E.R., and Oliver, C.N.: Minireview: Metal-catalyzed oxidation of proteins. J. Biol. Chem., 266: 2005–2008, 1991.

    CAS  PubMed  Google Scholar 

  50. Rivett, A.J., and Hare, J.F.: Mixed function oxidation of glutamine synthetase leads to its rapid degradation in vitro and after fusion-mediated injection into hepatoma cells. Biochem. Soc. Trans., 14: 643–644, 1986.

    CAS  Google Scholar 

  51. Starke-Reed, P.E., and Oliver, C.N.: Protein oxidation and proteolysis during aging and oxidative stress. Arch. Biochem. Biophys., 275: 559–567, 1989.

    Article  CAS  PubMed  Google Scholar 

  52. Roots, B.I.: Neurofilament accumulation induced in synapses by leupeptin. Science, 224: 971–972, 1983.

    Google Scholar 

  53. Ivy, G.O., Schottler, F., Wenzel, J., Baudry, M., and Lynch, G.: Inhibitors of lysosomal enzymes: Accumulation of lipofuscin-like dense bodies in brain. Science, 226: 985–987, 1984.

    CAS  PubMed  Google Scholar 

  54. Takauchi, S., and Miyoski, K.: Degeneration of neuronal processes in rats induced by a protease inhibitor, leupeptin. Acta Neuropathol., 78: 380–387, 1989.

    Article  CAS  PubMed  Google Scholar 

  55. Harman, D.: Free radical theory of aging: Role of free radicals in the origination and evolution of life, aging, and disease processes, in Free Radicals, Aging, and Degenerative Diseases, edited by Johnson, Jr., J.E., Walford, R., Harman, D., and Miquel, J., New York, Alan R. Liss, 1986, pp. 3–49.

    Google Scholar 

  56. Harman, D.: Free radical theory of aging. Mutation Res., 275: 257–266, 1992.

    Article  CAS  PubMed  Google Scholar 

  57. Sagai, M., and Ichinose, T.: Age-related changes in lipid peroxidation as measured by ethane, ethylene, butane and pentane in respired gases by rats. Life Sci., 27: 731–738, 1980.

    Article  CAS  PubMed  Google Scholar 

  58. Linnane, A.W., Marzuki, S., Ozawa, T., and Tanaka, M.: Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet, 1: 642–645, 1989.

    Article  CAS  PubMed  Google Scholar 

  59. Yen, T.-C., Chen, Y.-S., King, K.-L., Yeh, S.-H., and Wei, Y.-H.: Liver mitochondrial respiratory functions decline with age. Biochem. Biophys. Res. Comm., 165: 994–1003, 1989.

    Article  Google Scholar 

  60. Zaman, Z., Roche, S., Fielden, P., Frost, P.G., Niriella, D.C., and Cayley, A.C.D.: Plasma concentrations of vitamins A and E and carotenoids in Alzheimer’s disease. Age and Ageing, 21: 91–94, 1992.

    CAS  PubMed  Google Scholar 

  61. Simms, N.R., Bowen, D.M., Neary, D., and Davison, A.N.: Metabolic processes in Alzheimer’s disease: Adenine nucleotide content and production of 14CO2 from (U-14C)glucose in vitro in human neocortex. J. Neurochem., 41: 1329–1334, 1983.

    Google Scholar 

  62. Sims, N.R., Finegan, J.M., and Blass, J.P.: Altered glucose metabolism in fibroblasts from patients with Alzheimer’s disease. New Engl. J. Med., 313: 638–639, 1985.

    Article  CAS  PubMed  Google Scholar 

  63. Khansari, N., Whitten, H.D., Chou, Y.K., and Fudenberg, H.H.: Immunological dysfunction in Alzheimer’s disease. J. Neuroimmunol., 7: 279–285, 1985.

    Article  CAS  PubMed  Google Scholar 

  64. Martins, R.N., Harper, C.G., Stokes, G.B., and Masters, C.L.: Increased cerebral glucose-6-phosphate dehydrogenase activity in Alzheimer’s disease may reflect oxidative stress. J. Neurochem., 46: 1042–1045, 1986.

    CAS  PubMed  Google Scholar 

  65. Orrenius, S., McConkey, D.S., Bellomo, G., and Nicotera, P.: Role of Ca2+ in toxic cell killing. Trends Pharmacol. Sci., 10: 281–285, 1989.

    Article  CAS  PubMed  Google Scholar 

  66. Orrenius, S., McConkey, D.J., and Nicotera, P.: Role of calcium in toxic and programmed cell death. Adv. Exper. Med. Biol., 283: 419–425, 1991.

    CAS  Google Scholar 

  67. Mirabelli, F., Salis, A., Vairetti, M., Bellomo, G., Thor, H., and Orrenius, S.: Cytoskeletal alterations in human platelets exposed to oxidative stress are mediated by oxidative and Ca2+-dependent mechanisms. Arch. Biochem. Biophy., 270: 478–489, 1989.

    Article  CAS  Google Scholar 

  68. Nicotera, P., Bellomo, G., and Orrenius, S.: The role of Ca2+ in cell killing. Chem. Res. Toxicol., 3: 484–494, 1990.

    Article  CAS  PubMed  Google Scholar 

  69. Boobis, A.R., Fawthrop, D.J., and Davies, P.S.: Mechanisms of cell death. Trends Pharmacol. Sci., 10: 275–280, 1989.

    Article  CAS  PubMed  Google Scholar 

  70. Mattson, M.D., Rychlik, B., and Engle, M.G.: Possible involvement of calcium and inositol phospholipid signaling pathays in neurofibrillary degeneration, in Alzheimer’s Disease: Basic Mechanisms, Diagnosis and Therapeutic Strategies, edited by Iqbal, K., McLachlan, D.R.C., Winblad, B., and Wisniewski, H.M., New York, John Wiley & Sons, 1990, pp. 191–198.

    Google Scholar 

  71. Montejo de Garcini, E., Carrascosa, J.L., Correas, I., Nieto, A., and Avila, J.: Tau factor polymers are similar to paired helical filaments of Alzheimer’s disease. FEBS Lett., 236: 150–154, 1988.

    Article  CAS  PubMed  Google Scholar 

  72. Bancher, C., Brunner, C., Lassmann, H., Budka, H., Jellinger, K., Wiche, G., Seitelberger, F., Grundke-Iqbal, I., Iqbal, K., and Wisniewski, H.M.: Accumulation of abnormally phosphorylated τ precedes the formation of neurofibrillary tangles in Alzheimer’s disease. Brain Res., 477: 90–99, 1989.

    Article  CAS  PubMed  Google Scholar 

  73. Biernat, J., Mandelkow, E.-M., Schroter, C., Lichtenberg-Kraag, B., Steiner, B., Berling, B., Meyer, H., Mercken, M., Vandermeeren, A., Goedert, M., and Mandelkow, E.: The switch of tau protein to an Alzheimer-like state includes the phosphorylation of two serine-proline motifs upstream of the microtubule binding region. EMBO J., 11: 1593–1597, 1992.

    CAS  PubMed  Google Scholar 

  74. Vogelsang, G.D., Zemlan, F.P., and Dean, G.E.: Hyperpurification of paired helical filaments reveals elevations in hydroxyproline content and a core structure related peptide fragment. Prog. Clin. Biol. Res., 317: 791–800, 1989.

    CAS  PubMed  Google Scholar 

  75. Love, S., Saitok, T., Quijada, S., Cole, G.M., Terry, R.D.: Alz-50, ubiquitin and tau immunoreactivity of neurofibrillary tangles, Pick bodies and Lewy bodies. J. Neuropath. Exper. Neurol., 47: 393–405, 1988.

    Article  CAS  Google Scholar 

  76. Dean, R.T.: A mechanism for accelerated degradation of intracellular proteins after limited damage by free radicals. FEBS Lett., 220: 278–282, 1987.

    Article  CAS  PubMed  Google Scholar 

  77. Goedert, M., Spillantini, M.G., Cairns, N.J., and Crowther, R.A.: Tau proteins of Alzheimer paired helical filaments: Abnormal phosphorylation of all six brain isoforms. Neuron., 8: 159–168, 1992.

    Article  CAS  PubMed  Google Scholar 

  78. Haass, C., Schlossmacher, M.G., Hung, A.Y., et al.: Amyloid β-peptide is produced by cultured cells during normal metabolism. Nature, 359: 322–325, 1992.

    Article  CAS  PubMed  Google Scholar 

  79. Seubert, P., Vigo-Pelfrey, C., Esch, F., Lee, M., et al.: Isolation and quantification of soluble Alzheimer’s β-peptide from biological fluids. Nature, 359: 325–327, 1992.

    Article  CAS  PubMed  Google Scholar 

  80. Shoji, M., Golde, T.E., and Ghiso, J., et al.: Production of the Alzheimer amyloid β-protein by normal proteolytic processing. Science, 258: 126–129, 1992.

    CAS  PubMed  Google Scholar 

  81. Golde, T.E., Estus, S., Younkin, L.H., Selkoe, D.J., and Younkin, S.G.: Processing of the amyloid protein precursor to potentially amyloidgenic derivatives. Science, 255: 728–730, 1992.

    CAS  PubMed  Google Scholar 

  82. Haass, C., Koo, E.H., Mellon, A., Hung, A.Y., and Selkoe, D.J.: Targeting of cell-surface β-amyloid precursor protein to lysosomes: Alternative processing into amyloid-bearing fragments. Nature, 357: 500–503, 1992.

    Article  CAS  PubMed  Google Scholar 

  83. Isenman, L.D., and Dice, J.F.: Secretion of intact proteins and peptide fragments by lysosomal pathways of protein degradation. J. Biol. Chem., 264: 21591–21596, 1989.

    Google Scholar 

  84. Buktenica, S., Olenick, S.J., Salgia, R., and Frankfater, A.: Degradation and regurgitation of extracellular proteins by cultured mouse peritoneal macrophages and baby hamster kidney fibroblasts. J. Biol. Chem., 262: 9469–9476, 1987.

    CAS  PubMed  Google Scholar 

  85. Harman, D.: Free radical theory of aging: Effect of free radical inhibitors on the mortality rate of male LAF1 mice. J. Gerontol., 23: 476–482, 1968.

    CAS  PubMed  Google Scholar 

  86. Harman, D.: Free radical theory of aging: Inhibition of amyloidosis in mice by antioxidants; possible mechanism. J. Amer. Geriat. Soc., 24: 203–210, 1976.

    CAS  PubMed  Google Scholar 

  87. Yamada, T., Sasaki, H., Furuya, H., et al.: Complimentary DNA for the mouse homolog of the human amyloid beta protein precursor. Biochem. Biophys. Res. Comm., 149: 665–671, 1987.

    Article  CAS  PubMed  Google Scholar 

  88. Yamada, T., Sasaki, H., Dohura, K., Goto, I., and Sakaki, Y.: Structure and expression of the alternatively-spliced forms of mRNA for the mouse homolog of Alzheimer’s disease amyloid beta protein precursor. Biochem. Biophys. Res. Comm., 158: 906–912, 1989.

    Article  CAS  PubMed  Google Scholar 

  89. Fukuchi, K., Kamino, K., Deeb, S.S., et al.: Overexpression of amyloid precursor protein alters its normal processing and is associated with neurotoxicity. Biochem. Biophys. Res. Comm., 182: 165–173, 1992.

    Article  CAS  PubMed  Google Scholar 

  90. Johnstone, E.M., Chaney, M.O., Norris, F.H., Pasgual, R., and Little, S.P.: Conservation of the sequence of Alzheimer’s disease amyloid peptide in dog, polar bear and five other mammals by cross-species polymerase chain reaction analysis. Mol. Brain Res., 10: 299–305, 1991.

    Article  CAS  PubMed  Google Scholar 

  91. Kawai, M., Cras, P., Richey, P., Tabaton, M., Lowery, D.E., Gonzalez-DeWhitt, P.A., Greenberg, B.D., Gambetti, P., and Perry, G.: Subcellular localization of amyloid precursor protein in senile plaques of Alzheimer’s disease. Amer. J. Pathol., 140: 947–958, 1992.

    CAS  Google Scholar 

  92. Barrows, C.J., and Zagorski, M.G.: Solution structure of β peptide and its constituent fragments: Relation to amyloid deposition. Science, 253: 179–182, 1991.

    Google Scholar 

  93. Burdick, D., Soreghan, B., Kwon, M., et al.: Assembly and aggregation properties of synthetic Alzheimer’s A4/β amyloid peptide analogs. J. Biol. Chem., 267: 546–554, 1992.

    CAS  PubMed  Google Scholar 

  94. Hilbich, C., Kisters-Wolke, B., Reed, J., Masters, C.L., and Beyreuther, K.: Aggregation and secondary structure of synthetic amyloid βA4 peptides of Alzheimer’s disease. J. Mol. Biol., 218: 149–163, 1991.

    Article  CAS  PubMed  Google Scholar 

  95. Kirschner, D.A., Inouge, H., Duffy, L.K., et al.: Synthetic peptide homologous to β-protein from Alzheimer’s disease forms amyloid-like fibrils in vitro. Proc. Natl. Acad. Sci., USA, 84: 6953–6957, 1987.

    CAS  PubMed  Google Scholar 

  96. Kowall, N.W., Beal, M.F., Busciglio, J., Duffy, L.K., and Yankner, B.A.: An in vivo model for the neurodegenerative effects of β-amyloid and protection by substance P. Proc. Natl. Acad. Sci., USA, 88: 7247–7251, 1991.

    CAS  PubMed  Google Scholar 

  97. Selkoe, D.J.: Amyloid protein and Alzheimer’s disease. Scientif. Amer., 265: No. 5, 68–78, 1991.

    Article  CAS  Google Scholar 

  98. Yankner, B.A., and Mesulam, M.-M.: β-amyloid and the pathogenesis of Alzheimer’s disease. New Engl. J. Med., 325: 1849–1857, 1991.

    Article  CAS  PubMed  Google Scholar 

  99. Hardy, J.A., and Higgins, G.A.: Alzheimer’s disease: The amyloid cascade hypothesis. Science, 256: 184–185, 1992.

    CAS  PubMed  Google Scholar 

  100. Regland, B., and Gottfries, C.-G.: The role of amyloid β-protein in Alzheimer’s disease. Lancet, 340: 467–469, 1992.

    Article  CAS  PubMed  Google Scholar 

  101. Yoshikawa, K., Aizawa, T., and Hayashi, T.: Degeneration in vitro of post-mitotic neurons overexpressing the Alzheimer amyloid protein precursor. Nature, 359: 64–67, 1992.

    Article  CAS  PubMed  Google Scholar 

  102. Tanzi, R.E., and Hyman, B.T.: Alzheimer’s mutation. Nature, 350: 564, 1991.

    Article  CAS  PubMed  Google Scholar 

  103. Bugiani, O., Giaccone, G., Frangione, B., Ghetti, B., and Tagliavini, F.: Alzheimer patients: Preamyloid deposits are more widely distributed than senile plaques throughout the central nervous system. Neurosci. Lett., 103: 263–268, 1989.

    Article  CAS  PubMed  Google Scholar 

  104. Mann, D.M.A., and Esiri, M.M.: 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, 1989.

    Article  CAS  PubMed  Google Scholar 

  105. Bandy, B., and Davison, A.J.: Mitochondrial mutations may increase oxidative stress: Implications for carcinogenesis and aging? Free Radical Biol. Med., 8: 523–539, 1990.

    Article  CAS  Google Scholar 

  106. Lin, F.-H., Lin, R., Wisniewski, H.M., Hwang, Y.-W., Grundke-Iqbal, F., Healy-Louie, G., and Iqbal, K.: Detection of point mutations in codon 331 of mitochondrial NADH dehydrogenase subunit 2 in Alzheimer’s brains. Biochem. Biophys. Res. Commun., 182: 238–246, 1992.

    Article  CAS  PubMed  Google Scholar 

  107. Wallace, D.C.: Mitochondrial genetics: A paradigm for aging and degenerative diseases? Science, 256: 628–632, 1992.

    CAS  PubMed  Google Scholar 

  108. Shoffner, J.M., and Wallace, D.C.: Oxidative phosphorylation diseases: Disorders of two genomes. Adv. Hum. Genet., 19: 267–330, 1990.

    CAS  PubMed  Google Scholar 

  109. Grossman, L.I.: Invited editorial: Mitochondrial DNA in sickness and in health. Am. J. Hum. Genet., 46: 415–417, 1990.

    CAS  PubMed  Google Scholar 

  110. Shoffner, J.M., Lott, M.T., Voljavec, A.S., Soueidan, S.A., Costigan, D.A., and Wallace, D.C.: Spontaneous Kearns-Sayre/chronic external ophthalmoplegia plus syndrome associated with a mitochondrial DNA deletion: A slip-replication model and metabolic therapy. Proc. Natl. Acad. Sci., USA, 86: 7952–7956, 1989.

    CAS  PubMed  Google Scholar 

  111. Shoffner, J.M., and Wallace, D.C.: Heart disease and mitochondrial DNA mutations. Heart Disease and Stroke, 1: 235–241, 1992.

    CAS  PubMed  Google Scholar 

  112. Holt, I.J., Harding, A.E., Cooper, J.M., Schapira, A.H.V., Toscano, A., Clark, J.B., and Morgan-Hughes, J.A.: Mitochondrial myopathics: Clinical and biochemical features of 30 patients with major deletions of muscle mitochondrial DNA. Ann. Neurol., 26: 699–708, 1989.

    Article  CAS  PubMed  Google Scholar 

  113. Elroy-Stein, D., and Groner, Y.: Impaired neurotransmitter uptake in PC12 cells overexpressing human Cu/Zn superoxide dismutase — implications for gene dosage effects in Down syndrome. Cell, 52: 259–267, 1988.

    Article  CAS  PubMed  Google Scholar 

  114. Zemlan, F.P., Thienhaus, O.J., and Bosmann, H.B.: Superoxide dismutase activity in Alzheimer’s disease: Possible mechanism for paired helical filament formation. Brain Res., 476: 160–162, 1989.

    Article  CAS  PubMed  Google Scholar 

  115. Sinet, P.-M., Lejeune, J., and Jerome, H.: Trisomy 21 (Down’s syndrome): Glutathione peroxidase, hexose monophosphate shunt and I.Q. Life Sci., 24: 29–34, 1979.

    Article  CAS  PubMed  Google Scholar 

  116. Parker, Jr., W.D., Boysen, S.J., and Parks, J.K.: Abnormalities of the electron transport chain in idiopathic Parkinson’s disease. Ann. Neurol., 26: 719–723, 1989.

    Article  PubMed  Google Scholar 

  117. Schapira, A.H.V., Cooper, J.M., Dexter, D., Clark, J.B., Jenner, P., and Marsden, C.D.: Mitochondrial Complex I deficiency in Parkinson’s disease.. J. Neurochem., 54: 823–827, 1990.

    CAS  PubMed  Google Scholar 

  118. Agid, Y.: Parkinson’s disease: Pathophysiology. Lancet, 337: 1321–1327, 1991.

    Article  CAS  PubMed  Google Scholar 

  119. Braak, H., and Braak, E.: Cognitive impairment in Parkinson’s disease: Amyloid plaques, neurofibrillary tangles, and neuropil threads in the cerebral cortex. J. Neural Transm. (P-D Sect), 2: 45–57, 1990.

    Article  CAS  Google Scholar 

  120. Lennox, G., Lowe, J.S., Godwin-Austen, R.B., Landon, M., and Mayer, R.J.: Diffuse Lewy body disease: An important differential diagnosis in dementia with extrapyramidal features. Prog. Clin. Biol. Res., 317: 121–130, 1989.

    CAS  PubMed  Google Scholar 

  121. Arts. W.F.M., Scholte, H.R., Bogaard, J.M., Kerrebijn, K.F., and Luyt-Houwen, I.E.M.: NADH-CoQ reductase deficient myopathy: Successful treatment with riboflavin. Lancet, 2: 581–582, 1983.

    Article  CAS  PubMed  Google Scholar 

  122. Eleff, S., Kennaway, N.G., Buist, N.R.M., Darley-Usmar, V.M., Capaldi, R.A., Bank, W.J., and Chance, B.: 31P NMR study of improvement in oxidative phosphorylation by vitamin K3 and C in a patient with a defect in electron transport at complex III in skeletal nuscle. Proc. Natl. Acad. Sci., USA, 81: 3529–3533, 1984.

    CAS  PubMed  Google Scholar 

  123. Ogasahura, S., Nishikawa, Y., Yorifuji, S., et al.: Treatment of Kearns-Sayre syndrome with coenzyme Q10. Neurol., 36: 45–53, 1986.

    Article  Google Scholar 

  124. Imagawa, M., Naruse, S., Tsuji, S., Fujioka, A., and Yamaguchi, H.: Coenzyme Q10, iron, and vitamin B6 in genetically-confirmed Alzheimer’s disease. Lancet, 340: 671–672, 1992.

    Article  CAS  PubMed  Google Scholar 

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  1. University of Nebraska Medical Center, College of Medicine, 600 South 42nd St., Omaha, NE, 68198-4635

    Denham Harman

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Harman, D. Free radical theory of aging: A hypothesis on pathogenesis of senile dementia of the Alzheimer’s type. AGE 16, 23–30 (1993). https://doi.org/10.1007/BF02436127

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