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The Role of β-Amyloid in the Development of Alzheimer’s Disease

Drugs & Aging volume 7, pages 97–109 (1995)Cite this article

Summary

Recent molecular biological, biochemical and immunohistochemical studies have revealed various novel facts about β-amyloidosis including its role in the pathogenesis of Alzheimer’s disease (AD). Such discoveries include the finding that β/A4-amyloid protein (β-AP) is the major component of the amyloid found in senile plaques (SPs) and amyloid angiopathy, the elucidation of the molecular structures of β-AP and β-amyloid protein precursor (APP), the finding that point mutations of APP are involved in some cases of familial AD (FAD), the location of genes for FAD, APP and Down’s syndrome on chromosome 21, and of other genes relating to AD on chromosomes 19, 14 and 6, and the successful development of Alzheimer-type neuropathology in transgenic mice overexpressing V717F APP, a mutation of APP

Furthermore, the involvement of various proteases and their inhibitors in metabolism of β-AP have been suggested by: the presence of Kunitz class serine protease and metalloprotease inhibitor domains on some APP, the presence of various proteases and inhibitors in SPs and neurofibrillary tangles (NFTs), the involvement of various proteases in the secretory and endosome/lysosome pathways of APP processing, mutation of the APP gene in hereditary cerebral haemorrhage with amyloidosis, Dutch type (HCHWA-D), mutation of the cysteine proteinase inhibitor cystatin C gene in HCHWA-I (Iceland type), and abnormal increases of some proteases or the inhibitors in dystrophic neuntes of SP, amyloid of SP, and NFTs.

Judging from these reports, dysfunction or deregulation of proteolytic systems may play an important role in β-amyloid formation. Recent studies of β-amyloid and various proteases and inhibitors in disorders associated with β-amyloid formation are reviewed including our ‘overload hypothesis’ as an underlying event in the dysfunction of proteolytic systems.

This information should be helpful to identify targets in the development of drugs for the treatment of AD or other age-related disorders.

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References

  1. Ashall F, Goate AM. Role of the β-amyloid precursor protein in Alzheimer’s disease. Trends Biochem Sci 1994; 19: 42–6

    PubMed  CAS  Google Scholar 

  2. Hauw JJ, Duykaerts C, Delaere P. Alzheimer’s disease. In: Duckett S, editor. The pathology of the aging human nervous system. Philadelphia: Lea & Febiger, 1991: 113–47

    Google Scholar 

  3. Lishman WA. Organic psychiatry consequences of cerebral disorder. 2nd ed. Oxford: Blackwell, 1987

    Google Scholar 

  4. Tomlinson BE. Ageing and the dementias. In: Adams JH, Duchen LW, editors. Greenfield’s neuropathology. 5th ed. New York: Oxford University Press, 1992: 1284–410

    Google Scholar 

  5. Nitsch RM, Growdon JH, Corkin S, et al., editors. Alzheimer’s disease. Amyloid precursor proteins, signal transduction, neuronal transplantation. Part V: approaches to pharmacology. Ann NY Acad Sci 1993; 695: 300–36

    Google Scholar 

  6. Growdon JH, Corkin S, Ritter-Walker E, et al., editors. Aging and Alzheimer’s disease. Sensory systems, neuronal growth and neuronal metabolism. Part VIII: human pharmacology. Ann NY Acad Sci 1991; 640: 228–83

    Google Scholar 

  7. Glenner GG, Wong CN. Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984; 120: 885–90

    PubMed  CAS  Google Scholar 

  8. Glenner GG, Wong CW. Alzheimer’s disease and Down syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun 1984; 122: 1131–5

    PubMed  CAS  Google Scholar 

  9. Masters CL, Simms G, Weinman NA, et al. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA 1985; 82: 4245–9

    PubMed  CAS  Google Scholar 

  10. Pash J, Posescu N, Matosha M, et al. Chromosomal protein HMG-14 gene maps to the Down syndrome region of human chromosome 21 and is overexpressed in mouse trisomy 16. Proc Natl Acad Sci USA 1990; 87: 3836–40

    PubMed  CAS  Google Scholar 

  11. Peterson MB, Adelsberger PA, Schinzel AA, et al. Down syndrome due to de novo Robertsonian translocation t (14q: 21 q): DNA polymorphism analysis suggests that the origin of the extra 21q is maternal. Am J Hum Genet 1991; 49: 529–36

    Google Scholar 

  12. Potter H. Review and hypothesis: Alzheimer disease and Down syndrome — chromosome 21 nonjunction may underlie both disorders. Am J Hum Genet 1991; 48: 1192–200

    PubMed  CAS  Google Scholar 

  13. Korenberg JR, Bradley C, Disteche CM. Down syndrome: molecular mapping of the congenital heart disease and duodenal stenosis. Am J Hum Genet 1992; 50: 294–302

    PubMed  CAS  Google Scholar 

  14. Goldgaber D, Schmechel DE. Expression of the amyloid β-protein precursor gene. In: Wurtman RJ, Corkin S, Growdon JH, et al., editors. Advances in neurology: Alzheimer’s disease. New York: Raven Press, 1990; 51: 163–9

    Google Scholar 

  15. Cytogenetics and cell genetics. Human gene mapping 10. New Haven Conference 1989. 10th International Workshop on Human Gene Mapping; Karger, Switzerland, 1989

  16. Schellenberg GD, Bird TD, Wizsman EM, et al. Genetic linkage evidence for a familial Alzheimer’s disease locus on chromosome 14. Science 1992; 258: 668–71

    PubMed  CAS  Google Scholar 

  17. St George-Hyslop PH, Haines J, Rogaev E, et al. Genetic evidence for a novel Alzheimer’s disease locus on chromosome 14. Nature Genet 1992; 2: 330–4

    PubMed  CAS  Google Scholar 

  18. Van Broekhoven C, Backhovens H, Cruts M, et al. Mapping of a gene predisposing to early-onset Alzheimer’s disease to chromosome 14q24.3. Nature Genet 1992; 2: 335–9

    Google Scholar 

  19. Wasco W, Peppercorn J, Tanji RE. Search for the genes responsible for familial Alzheimer disease. In: Nitsch RM, Growdon JH, Corkins S, et al., editors. Alzheimer’s disease. Amyloid precursor proteins, signal transduction, neuronal translocation. Ann NY Acad Sci 1993; 695: 203–8

    CAS  Google Scholar 

  20. Wong L, Liang Y, Jiang L, et al. Mutation of gene for the human lysosomal serine protease cathepsin G is not the cause of aberrant APP processing in familial Alzheimer disease. Neurosci Lett 1993; 152: 96–8

    PubMed  CAS  Google Scholar 

  21. Namba Y, Tomonaga M, Kawasaki H, et al. Apolipoprotein E immunohistochemistry in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer’s disease and Kuru plaque amyloid in Creutzfeld-Jakob disease. Brain Res 1991; 541: 163–6

    PubMed  CAS  Google Scholar 

  22. Strittmatter WJ, Saunders AM, Schmechel D, et al. Apolipoprotein E: high-avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer’s disease. Proc Natl Acad Sci USA 1993; 90: 1977–81

    PubMed  CAS  Google Scholar 

  23. Pericak-Vance MA, Bebout JL, Gaskell Jr PC, et al. Linkage studies in familial Alzheimer’s disease: evidence for chromosome 19 linkage. Am J Hum Genet 1991; 48: 1034–50

    PubMed  CAS  Google Scholar 

  24. Weitkamp LR, Nee L, Keats B, et al. Alzheimer’s disease: evidence for susceptibility loci on chromosomes 6 and 14. Am J Hum Genet 1983; 35: 443–53

    PubMed  CAS  Google Scholar 

  25. St George-Hyslop PH. Recent advances in the molecular genetics of Alzheimer’s disease. In: Perry G, editor. Alzheimer’s disease. Clin Neurosci 1993; 1: 171–5

    Google Scholar 

  26. Wisniewski KE, Wisniewski HM, Wen GY. Occurrence of neurological changes and dementia of Alzheimer’s disease in Down’s syndrome. Ann Neurol 1985; 17: 278–82

    PubMed  CAS  Google Scholar 

  27. Nitsch RM, Slack BE, Wurtman RJ, et al. Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science 1992; 258: 304–7

    PubMed  CAS  Google Scholar 

  28. Shoji M, Golde TE, Ghiso J, et al. Production of the Alzheimer amyloid β-protein by normal proteolytic processing. Science 1992; 258: 126–9

    PubMed  CAS  Google Scholar 

  29. Beyreuther K, Masters CL. Amyloid genes and neuronal dysfunction, p.86–88. In: Gajdusek C, Beyreuther K, Brown P, et al., (FENS group). Regulation and genetic control of brain amyloid. Brain Res Rev 1991; 16: 83–114

    Google Scholar 

  30. Estus S, Golde TE, Kunishita T, et al. Potentially amyloidogenic, carboxy-terminal derivatives of the amyloid protein precursor. Science 1992: 255: 726–8

    PubMed  CAS  Google Scholar 

  31. Kang J, Lemaire H, Unterbeck A, et al. The precursor of Alzheimer’s disease amyloid A4 protein resembling a cell-surface receptor. Nature 1987; 325: 733–6

    PubMed  CAS  Google Scholar 

  32. Ponte P, Gonzalez-DeWhitt P, Schilling J, et al. A new A4 amyloid mRNA contains a domain homologous to serine protease inhibitors. Nature 1988; 331: 525–7

    PubMed  CAS  Google Scholar 

  33. Tanzi RE, McClathy AI, Lamperti ED, et al. Protease inhibitor damain encoded by an amyloid protein precursor mRNA associated with Alzheimer’s disease. Nature 1988; 331: 528–30

    PubMed  CAS  Google Scholar 

  34. Kitaguchi N, Yakahashi Y, Tokushima Y, et al. Precursor of Alzheimer’s disease amyloid protein shows protease inhibitory activity. Nature 1988; 231: 530–2

    Google Scholar 

  35. de Sauvage F, Octave J-N. A novel mRNA of the A4 amyloid precursor gene coding for a possibly secreted protein. Science 1989; 245: 651–3

    PubMed  Google Scholar 

  36. Neve RL, Roger J, Higgins GA. The amyloid precursor-related transcript lacking the beta/A4 sequences is specifically increased in Alzheimer’s disease brain. Neuron 1990; 5: 329–38

    PubMed  CAS  Google Scholar 

  37. Golde TE, Estus S, Youkin LH, et al. Processing of the amyloid protein in precursor to potentially amyloidogenic derivatives. Science 1992; 255: 728–30

    PubMed  CAS  Google Scholar 

  38. Tanaka S, Shiojiri S, Takahashi Y, et al. Tissue specific expression of three types of β-protein precursor mRNA: enhancement of protease inhibitor-haboring types in Alzheimer’s disease brain. Biochem Biophys Res Commun 1989; 165: 1406–14

    PubMed  CAS  Google Scholar 

  39. Beyreuther K, Buch AI, Dyrks T, et al. Mechanism of amyloid deposition in Alzheimer’s disease. In: Growdon JH, Corkin S, Ritter-Walker E, et al., editors. Aging and Alzheimer’s disease. Ann NY Acad Sci 1991; 640: 129–59

    CAS  Google Scholar 

  40. Palmert MR, Podlinsky MB, Witker DS, et al. The β-amyloid protein precursor of Alzheimer’s disease has soluble derivatives found in human brain and cerebrospinal fluid. Proc Natl Acd Sci USA 1989; 86: 6338–42

    CAS  Google Scholar 

  41. Kitaguchi N, Tokushima Y, Oishi K, et al. Determination of amyloid β-protein precursor harboring active form of proteinase inhibitor domains in cerbrospinal fluid of Alzheimer’s disease patients by trypsin-antibody sandwich ELISA. Biochem Biophys Res Commun 1990; 166: 1453–9

    PubMed  CAS  Google Scholar 

  42. Goate AM, Chartier-Harlin M-C, Mullan M, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 1991; 349: 704–6

    PubMed  CAS  Google Scholar 

  43. Naruse S, Igarashi S, Kobayashi H, et al. Missense mutation Val-Ile in exon 17 of amyloid precursor protein gene in Japanese familial Alzheimer’s disease. Lancet 1991; 337: 978–9

    PubMed  CAS  Google Scholar 

  44. Yoshioka K, Miki T, Katsuya T, et al. The 717Val-Ile substitution in amyloid precursor protein is associated with familial Alzheimer’s disease regardless of ethnic groups. Biochem Biophys Res Commun 1991; 178: 1141–6

    PubMed  CAS  Google Scholar 

  45. Murrell J, Farlow M, Ghetti B, et al. A mutation in the amyloid precursor protein associated with hereditary Alzheimer’s disease. Science 1991; 254: 97–9

    PubMed  CAS  Google Scholar 

  46. Chartier-Harlin M-C, Grawford F, Houlden H, et al. Early-onset Alzheimer’s disease caused by mutation at codon 717 of the β-amyloid precursor protein gene. Nature 1991; 353: 844–6

    PubMed  CAS  Google Scholar 

  47. Kennedy AM, Newman S, McCaddon A, et al. Familial Alzheimer’s disease. Brain 1993; 116: 309–24

    PubMed  Google Scholar 

  48. Mullan M, Crawford F, Axelman K, et al. A pathogenic mutation for probable Alzheimer’s disease in the APP gene at the N-terminus of β-amyloid. Nature Genet 1992; 1: 345–7

    PubMed  CAS  Google Scholar 

  49. Hendriks L, van Duijn CM, Grap P, et al. Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the β-amyloid precursor protein gene. Nature Genet 1992; 1: 218–21

    PubMed  CAS  Google Scholar 

  50. Citron M, Oltersdolf T, Hasss C, et al. Mutation of β-amyloid precursor protein in familial Alzheimer’s disease increases protein production. Nature 1992; 360: 672–4

    PubMed  CAS  Google Scholar 

  51. Levy E, Carman MD, Fernavdez-Madrid IJ, et al. Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral haemorrhage, Dutch type. Science 1990; 248: 1124–6

    PubMed  CAS  Google Scholar 

  52. Jones CT, Morris S, Yetes CM, et al. Mutation in codon 713 of the β-amyloid precursor protein gene presenting with schizophrenia. Nature Genet 1992; 1: 306–9

    PubMed  CAS  Google Scholar 

  53. Haas C, Koo EH, Mellon A, et al. Targeting of cell-surface β-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments. Nature 1992; 357: 500–2

    Google Scholar 

  54. Hyman BT, Tanzi RE, Marzloff BA, et al. Kunitz protease inhibitor containing amyloid β-protein precursor immunoreactivity in Alzheimer’s disease. J Neuropathol Exp Neurol 1992; 51: 76–83

    PubMed  CAS  Google Scholar 

  55. Rosemullar JM, Ahbink JJ, Kamp AM, et al. Distribution pattern and functional state of α1-antichymotrypsin in plaques and vascular amyloid in Alzheimer’s disease. An immuno-histochemical study with monoclonal antibodies against native and inactivated α-1 antichymotrypsin. Acta Neuropathol 1991; 82: 200–7

    Google Scholar 

  56. Miyazaki K, Hasegawa M, Funahashi K, et al. A metallo-proteinase inhibitor domain in Alzheimer amyloid protein precursor. Nature 1993; 362: 839–41

    PubMed  CAS  Google Scholar 

  57. Perry G, Smith MA. Senile plaques and neurofibrillary tangles: what role do they play in Alzheimer’s disease? Clinical Neurosci 1993; 1: 199–203

    Google Scholar 

  58. Trojanowski JQ, Lee VM-Y. Phosphorylation of neuronal cytoskelstal proteins in Alzheimer’s disease and Lewy body dementias. In: Disterhoft JF, Gispen WH, Traber J, et al., editors. Calcium hypothesis of aging and dementia. Ann NY Acad Sci 1994; 747: 92–109

    Google Scholar 

  59. Grundke-Iqubal I, Iqubal K, Tung Y-C, et al. Abnormal phosphorylation of the microtubule-associated protein τ (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 1986; 83: 4913–7

    Google Scholar 

  60. Ihara Y, Nukina N, Miura R, et al. Phosphorylated tau is integrated into paired helical filaments in Alzheimer’s disease. J Biochem (Tokyo) 1986; 99: 1807–10

    CAS  Google Scholar 

  61. Perry G, Friedman R, Shaw G, et al. Ubiquitin is detected in neurofibrillary tangles and senile plaque neurites of Alzheimer’s disease brains. Proc Natl Acad Sci USA 1987; 84: 3033–6

    PubMed  CAS  Google Scholar 

  62. Dickson DW, Crystal H, Mattiace LA, et al. Diffuse Lewy body disease: light and electron microscopic immunocytochemistry of senile plaques. Acta Neuropathol (Berl) 1989; 78: 572–84

    CAS  Google Scholar 

  63. Mori H, Kondo J, Ihara Y. Ubiquitin is a component of paired helical filaments in Alzheimer’s disease. Science 1987; 235: 1641–4

    PubMed  CAS  Google Scholar 

  64. Ito H, Goto S, Hirano A, et al. Immunocytochemical study on the hippocampus in Parkinsonism-dementia complex on Guam. J Geriatr Psychiatry Neurol 1991; 4: 134–42

    PubMed  CAS  Google Scholar 

  65. Hyman BT, Hosgen GW, van Damasio AR, et al. A4 amyloid protein immunoreactivity is present in Alzheimer’s disease neurofibrillary tangles. Neurosci Lett 1989; 101: 352–5

    PubMed  CAS  Google Scholar 

  66. Coria F, Castro E, Prelli F, et al. Isolation and characterization of amyloid P component from Alzheimer’s disease and other types of cerebral amyloidosis. Lab Invest 1988; 58: 454–8

    PubMed  CAS  Google Scholar 

  67. Selkoe DJ, Abraham CR, Podlisny MB, et al. Isolation of low molecular weight protein from amyloid plaque fibers in Alzheimer’s disease. J Neurochem 1986; 46: 1820–34

    PubMed  CAS  Google Scholar 

  68. Yamaguchi H, Ishiguro K, Shoji M, et al. Amyloid β/A4 protein precursor is bound to neurofibrillary tangles in Alzheimer type dementia. Brain Res 1990; 537: 318–22

    PubMed  CAS  Google Scholar 

  69. Splantini MG, Goedert M, Jakes R, et al. Different configurational states of β-amyloid and their distributions relative to plaques and tangles in Alzheimer’s disease. Proc Natl Acad Sci USA 1990; 87: 3947–51

    Google Scholar 

  70. Splantini MG, Goedert M, Jakes R, et al. Topographical relationship between β-amyloid and tau protein epitopes in tangle-bearing cells in Alzheimer’s disease. Proc Natl Acad Sci USA 1990; 87: 3952–6

    Google Scholar 

  71. Abraham CR, Selkoe DJ, Potter H. Immunohistochemical identification of the serine protease inhibitor α1-antichymotrypsin inhibitor in the brain amyloid deposits of Alzheimer’s disease. Cell 1988; 52: 487–501

    PubMed  CAS  Google Scholar 

  72. Gollin PA, Kalaria RN, Eikelenboom P, et al. α1-Antitrypsin and 4 antichymotrypsin are in the lesions of Alzheimer’s disease. Neuroreport 1992; 3: 201–3

    PubMed  CAS  Google Scholar 

  73. Kalaria RN, Galloway PG, Perry G. Widespread serum amyloid P immunoreactivity in cortical amyloid deposits and the neurofibrillary pathology of Alzheimer’s disease and other degenerative disorders. Neuropathol Appl Neurobiol 1991; 17: 189–201

    PubMed  CAS  Google Scholar 

  74. Kalaria RN, Golde T, Kroon SN, et al. Senile protease inhibitor anti-thrombin III and its messenger RNA in the pathogenesis of Alzheimer’s disease. Am J Pathol 1993; 143: 886–93

    PubMed  CAS  Google Scholar 

  75. Kalaria R. Cerebral microvasculature and immunological factors in Alzheimer’s disease. In: Perry G, editor. Alzheimer’s disease. Clin Neurosci 1993; 1: 204–11

    Google Scholar 

  76. Ii K, Ito H, Kominami E, et al. Abnormal distribution of cathepsin proteases and endogenos inhibitors (cystatins) in the hippocampus of patients with Alzheimer’s diasease, parkinsonism-dementia complex on Guam and senile dementia and in the aged. Virchows Arch A Pathol Anat Histopathol 1993; 423: 185–94

    PubMed  CAS  Google Scholar 

  77. Armstrong RA. The spacial patterns of β/A4 deposit subtypes in Down’s syndrome. Acta Neuropathol (Berl) 1994; 88: 353–8

    CAS  Google Scholar 

  78. Bugiani O, Tagliavini F, Giaccone G. Preamyloid deposits, amyloid deposits, and senile plaques in Alzheimer’s disease, Down Syndrome, and aging. In: Growdon JH, Corkin S, Ritter-Walker E, et al., editors. Aging and Alzheimer’s disease. Sensory systems, neuronal growth, and neuronal metabolism. Ann NY Acad Sci 1991; 640: 122–8

    Google Scholar 

  79. Nixon RA, Marotta CA. Degradation of neurofilament proteins by purified human cathepsin D. J Neurochem 1984; 43: 507–16

    PubMed  CAS  Google Scholar 

  80. Suzuki DH, Tanaka M, Kato Y, et al. Cathepsin D activities in dementia brains and the degeneration of neurofilament proteins with cathepsin D [abstract]. Neurochem Res 1988; 13: 265

    Google Scholar 

  81. Suzuki H, Takeda M, Nakamura Y, et al. Activation of lysosomal enzymes in rat brain with experimental neurofibrillary changes. Neurosci Lett 1988; 89: 234–9

    PubMed  CAS  Google Scholar 

  82. Bernstein H-G, Briszis S, Schmidt S, et al. Immunodetection of cathepsin D in neuritic plaques formed in brains of patients with dementia of Alzheimer type. J Hirnforsch 1989; 30: 613–8

    PubMed  CAS  Google Scholar 

  83. Cataldo AM, Thayer CY, Bird ED, et al. Lysosomal proteinase antigens are prominently localized within senile plaques of Alzheimer’s disease: evidence for a neuronal origin. Brain Res 1990; 513: 181–92

    PubMed  CAS  Google Scholar 

  84. Cataldo AM, Nixon PA. Enzymologically active lysosomal proteases are associated with amyloid deposits in Alzheimer’s brain. Proc Natl Acad Sci USA 1990; 87: 3861–5

    PubMed  CAS  Google Scholar 

  85. Bernstein H-G, Kirschke H, Wiederanders B, et al. Antigenic expression of cathepsin B in aged human brain. Brain Res Bullet 1990; 24: 543–9

    CAS  Google Scholar 

  86. Cataldo AM, Paskevich PA, Rominami E, et al. Lysosomal hydrolases of different classes are abnormally distributed in brains of patients with Alzheimer’s disease. Proc Natl Acad Sci USA 1991; 88: 10998–1002

    PubMed  CAS  Google Scholar 

  87. Nakamura Y, Masatoshi T, Suzuki H, et al. Abnormal distribution of cathepsins in the brains of patients with Alzheimer’s disease. Neurosci Lett 1991; 130: 195–8

    PubMed  CAS  Google Scholar 

  88. Ii K, Hirano A, Ito H, et al. Lysosomal and non-lysosomal proteases are increased in lesions in Alzheimer disease and parkinsonism-dementia complex on Guam. An immunohistochemical study of the hippocampus [abstract]. J Neuropathol Exp Neurol 1991; 50: 360

    Google Scholar 

  89. Nixon RA, Cataldo AM, Pakevich PA, et al. The lysosomal system in neurons: involvement at multiple stages of Alzheimer’s disease pathogenesis. Ann NY Acad Sci 1992; 674: 65–88

    PubMed  CAS  Google Scholar 

  90. Smith MA, Kalaira RN, Perry G. α1-trypsin immunreactivity in Alzheimer disease. Biochem Biophys Res Commun 1993; 193: 579–84

    PubMed  CAS  Google Scholar 

  91. Osmar R, Papolla M, Argani I, et al. Acid phosphatase activity in senile plaques and cerebrospinal fluid of patients with Alzheimer’s disease. Arch Pathol Lab Med 1993; 117: 166–9

    Google Scholar 

  92. Matus A, Green GDL. Age-related increase in a cathepsin D-like protease that degrade brain microtubule-associated proteins. Biochemistry 1987; 26: 8083–6

    PubMed  CAS  Google Scholar 

  93. Wiederanders B, Oelke B. Accumulation of inactive cathepsin D in old rats. Mech Ageing Dev 1984; 24: 265–77

    PubMed  CAS  Google Scholar 

  94. Benowitz LI, Rodriguez W, Pakevich P, et al. The amyloid precursor protein is concentrated in neuronal lysosomes in normal and Alzheimer disease subjects. Exp Neurol 1989; 106: 237–50

    PubMed  CAS  Google Scholar 

  95. Hardy J, Mullan M. Alzheimer’s disease in search of the soluble. Nature 1992; 359: 268–9

    PubMed  CAS  Google Scholar 

  96. Ishiura S, Tsukahara T, Tabira T, et al. Putative N-terminal splitting enzyme of amyloid A4 peptide is the multicatalytic protease, ingensin, which is widely distributed in mammalian cells. FEBS Lett 1989; 257: 388–92

    PubMed  CAS  Google Scholar 

  97. Ishiura S, Tsukahara T, Tabira T, et al. Identification of a putative amyloid A4-generating enzyme as a propyl endopeptidase. FEBS Lett 1990; 260: 131–4

    CAS  Google Scholar 

  98. Tagawa R, Kinoshita T, Maruyama K, et al. Alzheimer’s disease amyloid β-clipping enzyme (APP secretase): identification, purification and characterization of the enzyme. Biochem Biophys Res Commun 1991; 177: 377–87

    PubMed  CAS  Google Scholar 

  99. Cataldo MA, Hamilton DJ, Nixon RA. Lysosomal abnormalities in degenerating neurons link neuronal compromise to senile plaque development in Alzheimer’s disease. Brain Res 1994; 640: 68–80

    PubMed  CAS  Google Scholar 

  100. Smith MA, Kalaria R, Perry G. 4-Trypsin immunoreactivity in Alzheimer disease. Biochem Biophys Res Commun 1993; 193: 579–84

    PubMed  CAS  Google Scholar 

  101. Nelson RS, Siman R. Clipsin, a chymotrypsin-like protease in rat brain which is irreversively inhibited by α1-antichymo-trypsin. J Biol Chem 1990; 265: 3836–43

    PubMed  CAS  Google Scholar 

  102. Anderson JM, Hubbard BM, Cogill G. Amyloid P components in plaque and tangles of Alzheimer’s disease. Neurosci Lett Suppl 1987; 29: 78

    Google Scholar 

  103. Coria F, Castano E, Prelli F, et al. Isolation and characterization of amyloid P-component from Alzheimer’s disease and other cerebral amyloidosis. Lab Invest 1988; 58: 454–8

    PubMed  CAS  Google Scholar 

  104. Rosemullar JM, Eikelenboom P, Stam FC, et al. A4 protein in Alzheimer’s disease: primary and secondary cellular events in extracelluar amyloid deposition. J Neuropathol Exp Neurol 1989; 48: 647–63

    Google Scholar 

  105. Wagner SL, Geddes JW, Cotman CW, et al. Protease nexin-1, antithrombin with neurite outgrowth activity, is reduced in Alzheimer’s disease. Proc Natl Acad Sci USA 1989; 86: 8284–8

    PubMed  CAS  Google Scholar 

  106. Van Nostrand WE, Wagner SL, Suzuki M, et al. Protease nexin-II, a potent antichymotrypsin, shows identity to amyloid β-protein precursor. Nature 1989; 341: 546–9

    PubMed  Google Scholar 

  107. Cunningham DD, Van Nostrand WE. Protease nexin 2/amyloid β-protein precursor may function in wound repair. In: Gajdusek DC, Beyreuther K, Brown P, et al., editors. Regulation and genetic control of brain amyloid. Brain Res Rev 1991; 16: 95–6

    Google Scholar 

  108. Ghiso J, Jenson O, Fragione S. Amyloid fibrils in hereditary cerebral haemorrhage with amylodosis of Iceland type is a variant of γ-trace basic protein (cystatin C). Proc Natl Acad Sci USA 1986; 83: 2974–8

    PubMed  CAS  Google Scholar 

  109. Levy E, Lopez-Otin C, Ghiso J, et al. Stroke in Icelandic patients with hereditary amyloid angiopathy is related to a mutation in the cystatin C gene, an inhibitor of cysteine proteases. J Exp Med 1989; 169: 1171–8

    Google Scholar 

  110. Bernstein H-G, Rinne R, Kirschke H, et al. Cystatin A-like immunoreactivity is widely distributed in human brain and accumulates in neurotic plaques of Alzheimer’s disease subjects. Brain Res Bullet 1994; 33: 477–81

    CAS  Google Scholar 

  111. Tanaka K, Ii K, Ichihara A. A high molecular weight protease in cytosol of rat liver. I. Purification, enzymological properties and tissue distribution. J Biol Chem 1986; 261: 15197–203

    PubMed  CAS  Google Scholar 

  112. Tanaka K, Kumatori A, Ii K, et al. Direct evidence for nuclear and cytoplasmic colocalization of proteasomes (multiprotease complexes) in liver. J Cell Phys 1989; 139: 34–41

    CAS  Google Scholar 

  113. Tanaka K, Tamura T, Yoshimura T, et al. Proteasomes: protein and gene structures. New Biologist 1992; 4: 173–87

    PubMed  CAS  Google Scholar 

  114. Goldberg AL. The mechanism and functioning of ATP-dependent protease in bacterial and animal cells. Eur J Biochem 1992; 204: 9–23

    Google Scholar 

  115. Hershko A, Chiechianover A. The ubiquitin system for protein degradation. Ann Rev Biochem 1992; 61: 761–807

    PubMed  CAS  Google Scholar 

  116. Ugai S, Tamura T, Tanahashi N, et al. Purification of 26S protease complex catalyzing ATP-dependent breakdown of ubiquitin-ligated proteins from rat liver. J Biochem 1993; 113: 754–68

    PubMed  CAS  Google Scholar 

  117. Lowe J, Blanchard A, Morrell K, et al. Ubiquitin is a common factor in intermediate filament inclusion bodies of diverse type in man, including those of Parkinson’s disease, Pick’s disease, and Alzheimer’s disease, as well as Rosenthal fibers in cerebellar astrocytomic, cytoplasmic bodies in muscle, and Mallory bodies in alcoholic liver disease. J Pathol 1988; 155: 9–15

    PubMed  CAS  Google Scholar 

  118. Lowe J, Mayer RJ, Landon M. Ubiquitin in neurodegenerative diseases. Brain Pathol 1993; 3: 58–65

    Google Scholar 

  119. Eytan E, Ganoth D, Armon T, et al. ATP-dependent incorporation of 20S protease into the 26S complex that degrades proteins conjugated to ubiquitin. Proc Natl Acad Sci USA 1986: 7751–5

    Google Scholar 

  120. Ciechanover A: The ubiquitin-mediated proteolytic pathway. Brain Pathol 1993; 3: 67–75

    PubMed  CAS  Google Scholar 

  121. Doherty FJ, Osborn NU, Wassel JA, et al. Ubiquitin protein conjugates accumulate in the lysosomal system of fibroblasts treated with cysteine proteinase inhibitors. Biochem J 1989; 263: 47–5

    PubMed  CAS  Google Scholar 

  122. Ito H, Ii K, Hirano A, et al. Immunohistochemical identification of the proteasome in ubiquitin reactive abnormal structures of the nervous system [abstract]. J Neuropathol Exp Neurol 1991; 50: 360

    Google Scholar 

  123. Rock K, Gramm C, Rothstein L, et al. Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides on MHC-Class I molecules. Cell 1994; 78: 761–71

    PubMed  CAS  Google Scholar 

  124. Palombella VS, Rando W, Goldberg AL, et al. Ubiquitin and the proteasome are required for processing the NFkB1 (p105) precursor and the activation of NF-kB. Cell 1994; 78: 773–85

    PubMed  CAS  Google Scholar 

  125. Laszlo L, Doherty, Osborn NU, Mayer et al. Ubiquitinated protein conjugates are specially enriched in the lysosomal system of fibroblasts. FEBS Lett 1990; 261: 365–8

    PubMed  CAS  Google Scholar 

  126. Marrotta CA, Chou W-G, Majocha RE, et al. Overexpression of amyloid precursor protein A4 (β-amyloid) immunoreactivity in genetically transformed cells: implications for a cellular model of Alzheimer amyloidosis. Proc Natl Acad Sci USA 1989; 86: 337–41

    Google Scholar 

  127. Maruyama K, Terakado K, Usami M, et al. Formation of amyloid-like fibrils in C-OS cells overexpressing part of the Alzheimer amyloid protein precursor. Nature 1990; 347: 566–9

    PubMed  CAS  Google Scholar 

  128. Kawabata S, Higgins GA, Gordon JW. Amyloid plaques, neurofibrillary tangles and neuronal loss in brains of transgenic mice overexpressing a C-terminal fragment of human amyloid precursor protein. Nature 1991; 354: 476–8

    PubMed  CAS  Google Scholar 

  129. Quon D, Wang Y, Catalano R, et al. Formation of β-amyloid protein deposit in brains of transgenic mice. Nature 1991; 352: 239–41

    PubMed  CAS  Google Scholar 

  130. Wirak DO, Bayney R, Ramabhadran TV, et al. Deposit of amyloid protein in the central nervous system of transgenic mice. Science 1991; 253: 323–5

    PubMed  CAS  Google Scholar 

  131. Marx J. Major setback for Alzheimer’s models. Science 1992; 255: 1200–2

    PubMed  CAS  Google Scholar 

  132. Robertson M. Alzheimer’s disease and amyloid. Nature 1992; 356: 103

    PubMed  CAS  Google Scholar 

  133. Games D, Adams D, Alessandrini R, et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature 1995; 373: 523–7

    PubMed  CAS  Google Scholar 

  134. Doi A, Fujimoto K, Yoshida M, et al. Alzheimer’s disease in identical twin brothers — investigation of their family history and of clinical development of the disease. Psychiatr Neurol Jpn 1984; 86: 417–47

    CAS  Google Scholar 

  135. Kudo E, Ii K, Iwahana H, et al. PCR-SSCP screening of β-amyloid precursor protein mutations in two Japanese pedigree with familial early onset Alzheimer’s disease. Biomed Res 1993; 14: 223–31

    CAS  Google Scholar 

  136. Fitch N, Becker R, Heller A, et al. The inheritance of familial Alzheimer’s disease. A new interpretation. Ann Neurol 1988; 23: 14–9

    PubMed  CAS  Google Scholar 

  137. Duara R, Lopez-Alberola RF, Barker WW, et al. A comparison of familial and sporadic Alzheimer’s disease. Neurology 1993; 43: 1377–84

    PubMed  CAS  Google Scholar 

  138. Tanzi RE, Vaula G, Romand DM, et al. Assessment of amyloid β-protein precursor gene mutations in a large set of familial and sporaic Alzheimer disease cases. Am J Hum Genet 1992; 51: 273–82

    PubMed  CAS  Google Scholar 

  139. Selkoe DJ. Aging, amyloid, and Alzheimer’s disease. N Engl J Med 1989; 320: 1484–7

    PubMed  CAS  Google Scholar 

  140. Dickson DW, Crystal A, Mattiace LA, et al. Identification of normal and pathological aging in prospectively studied non-demented elderly humans. Neurobiol Aging 1991; 13: 179–89

    Google Scholar 

  141. Uno H, Walker LC. The age of biosenescence and the incidence of cerebral β-amyloidosis in aged captive rhesus monkeys. In: Nitsch RM, Growdon JH, Corkin S, et al. Alzheimer’s disease. Amyloid precursor proteins, Signal transduction, Neuronal trans-plantation. Ann NY Acad Sci 1993; 695: 232–5

    Google Scholar 

  142. Un F, Lin R, Wisniewski HM, et al. Detection of point mutations in codon 331 of mitochondrial NADH dehygrogenase subunit 2 in Alzheimer’s brain. Biochem Biophys Res Commun 1992; 182: 238–348

    Google Scholar 

  143. Nakamura Y, Masatoshi T, Suzuki H, et al. Lysosome instability in aged rat brain. Neurosci Lett 1989; 97: 215–20

    PubMed  CAS  Google Scholar 

  144. Ivy GO, Schottler F. Inhibitors of lysosomal enzymes: accumulation of lipofuscin-like dense bodies in rat brain. Science 1984; 226: 985–7

    PubMed  CAS  Google Scholar 

  145. Nunomura A, Miyagishi T. Ultrastructural observations on neuronal lipofuscin (age related) and dense bodies induced by a proteinase inhibitor, leupeptin, in rat hippocampus. Acta Neuropathol 1993; 86: 319–28

    PubMed  CAS  Google Scholar 

  146. Hajidohammadreza I, Anderson VER, Cavanagh JB, et al. β-Amyloid precursor protein fragment and lysosomal dense bodies are found in rat brain neurons after ventricular infusion of leupeptin. Brain Res 1994; 640: 25–32

    Google Scholar 

  147. Takauchi S, Miyoshi K. Degeneration of neuronal processes in rats induced by a protease inhibitor, leupeptin. Acta Neuropathol (Berl) 1989; 78: 380–7

    CAS  Google Scholar 

  148. Umezawa H, Aoyagi T. Activities of proteinase inhibitors of microbial origin. In: Barret AJ, editor. Proteinases in mammalian cells and tissues. Amsterdam: Elsevier/North-Holland, 1977: 637–62

    Google Scholar 

  149. Marx J. Alzheimer’s debate boils over. Science 1992; 257: 1336–8

    PubMed  CAS  Google Scholar 

  150. Oyama Y, Chikahisa L, Ueha T, et al. Changes in membrane permeability induced by amyloid b protein fragment 25–35 in brain neurons dissociated from the rats. Jpn J Pharmacol 1995; 86: 77–83

    Google Scholar 

  151. Wisniewski T, Frangione B. Apolipoprotein E: a pathological chaperone protein in patients with cerabral and systemic amyloid. Neurosci Lett 1992; 135: 235–8

    PubMed  CAS  Google Scholar 

  152. Yamaguchi H, Hirai S, Moromatsu M, et al. Diffuse type of senile plaques in the brains of Alzheimer-type dementia. Acta Neuropathol (Berl) 1988; 77: 113–9

    CAS  Google Scholar 

  153. Wisniewski T, Bancher C, Barcikowska M, et al. Spectrum of morphological appearance of amyloid deposits in Alzheimer’s disease. Acta Neuropathol 1989; 78: 337–47

    PubMed  CAS  Google Scholar 

  154. Ogomori K, Kitamoto T, Tateishi J, et al. β-Protein amyloid is widely distributed in the central nervous system of patients with Alzheimer’s disease. Am J Pathol 1989; 134: 243–51

    PubMed  CAS  Google Scholar 

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    Kunio Ii

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Ii, K. The Role of β-Amyloid in the Development of Alzheimer’s Disease. Drugs & Aging 7, 97–109 (1995). https://doi.org/10.2165/00002512-199507020-00004

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Keywords

  • Adis International Limited
  • Down Syndrome
  • Amyloid Precursor Protein
  • Senile Plaque
  • Amyloid Formation