Abstract
In 1907, Alois Alzheimer published an account (1) of a 51-year-old female patient, Auguste D., who suffered from strong feelings of jealousy towards her husband, increased memory impairment, disorientation, hallucinations, and often loud and aggressive behavior. After four and a half years of rapidly deteriorating mental illness, Auguste D died in a completely demented state. Postmortem histological analysis of her brain using the Bielschowsky silver technique revealed dense bundles of unusual fibrils within nerve cells (neurofibrillary tangles or NFTs) and numerous focal lesions within the cerebral cortex, subsequently named “senile plaques” by Simchowicz (2) Fig. 1). This combination of progressive presenile dementia with senile plaques and neurofibrillary tangles came to be known as Alzheimer’s disease (AD), a term that was later broadened to include senile forms of dementia with similar neuropathological findings. It was Divry (3) who first demonstrated the presence of amyloid at the center of the senile plaque, by means of Congo red staining. All amyloid deposits were originally thought to be starch-like in nature (hence the name), but it is now apparent that they are formed from a variety of different peptides and proteins (the latest count being 18). All amyloid share the property of a characteristic birefringence under polarized light after staining with Congo red dye, which is due to the presence of well-ordered 10 nm fibrils. The underlying protein component of these fibrils invariably adopts predominantly an antiparallel β-pleated sheet configuration. Ultrastructural observations have confirmed that the core of the senile plaque consists of large numbers of closely-packed, radiating fibrils, similar in appearance to those seen in other forms of amyloidosis (4,5), and have also revealed the presence of paired helical filaments (PHFs) within the NFTs (6). However, it took more than 50 yr from Divry’s original observation to determine the precise chemical nature of the senile plaque amyloid. Many neuropathologists have regarded this amyloid as a “tombstone” (an inert bystander) of AD. However, the advent of molecular genetics has finally and firmly established the central role of amyloid in the pathogenesis of the disease, although this is still disputed by some workers in the field. This introductory chapter is written in support of what has become known as the “amyloid cascade” hypothesis.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Alzheimer, A. (1907) Uber eine eigenartige Erkankung der Hirnrinde. Allg. Zschr. f Psychiatr. Psychisch-Gerichtl. Mediz. 64, 146–148.
Simchowicz, T. (1911) Histologische Studien uber der senile Demenz. NisslAlzheimer Histologische histopathologische. Arbeiten 4/2, 267–444.
Divry, P. (1927) Etude histochemique des plaques seniles. J. Neurol. Psychiatry 27, 643–657.
Kidd, M. (1964) Alzheimer’s disease: an electron microscopical study. Brain 87, 307–320.
Terry, R. D., Gonatas, H. K., and Weiss, M. (1964) Ultrastructural studies in Alzheimer’s presenile dementia. Am. J. Pathol. 44, 269–297.
Kidd, M. (1963) Paired helical filaments in electron microscopy of Alzheimer’s disease. Nature 97, 192–193.
Allsop, D., Landon, M., and Kidd, M. (1983) The isolation and amino acid composition of senile plaque core amyloid. Brain Res. 259, 348–352.
Selkoe, D. J., Ihara, Y., and Salazar, F. J. (1982) Alzheimer’s disease: insolubility of partially purified paired helical filaments in sodium dodecyl sulphate and urea. Science 215, 1243–1245.
Glenner, G. G. and Wong, C. W. (1984) Alzheimer’s disease: initial report of the purification and characterisation of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun. 120, 885–890.
Wong, C. W., Quaranta, V., and Glenner, G. G. (1985) Neuritic plaques and cerebrovascular amyloid in Alzheimer’s disease are antigenically related. Proc. Natl. Acad. Sci. USA 82, 8729–8732.
Allsop, D., Landon, M., Kidd, M., Lowe, J. S., Reynolds G. P., and Gardner, A. (1986) Monoclonal antibodies raised against a subsequence of senile plaque core protein react with plaque cores, plaque periphery and cerebrovascular amyloid in Alzheimer’s disease. Neurosci. Lett. 68, 252–256.
Ikeda, S. I., Wong, C. W., Allsop, D., Landon, M., Kidd, M., and Glenner, G. G. (1987) Immunogold labeling of cerebrovascular and neuritic plaque amyloid fibrils in Alzheimer’s disease with an anti-β protein monoclonal antibody. Lab. Invest. 57, 446–449.
Kirschner, D. A., Inouye, H., Duffy, L. K., Sinclair, A., Lind, M., and Selkoe, D. J. (1987) Synthetic peptide homologous to β protein from Alzheimer disease forms amyloid-like fibrils in vitro. Proc. Natl. Acad. Sci. USA 84, 6953–6957.
Grundke-Iqbal, I., Iqbal, K., Tung, Y. C., Quinlan, M., Wisniewski, H. M., and Binder, L. I. (1986) Abnormal phosphorylation of the microtubule-associated protein tau in Alzheimer cytoskeletal pathology. Proc. Natl. Acad. Sci. USA 83, 4913–4917.
Kosik, K. S., Joachim, C. L., and Selkoe, D. J. (1986) Microtubule-associated protein tau is a major antigenic component of paired helical filaments in Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 83, 4044–4048.
Lee, V. M.-Y., Balin, B. J., Otvos, L., and Trojanowski, J. Q. (1991) A68, a major subunit of paired helical filaments and derivatized froms of normal tau. Science 251, 675–678.
Wischik, C. M., Novak, M., Thogersen, H. C., Edwards, P. C., Runswick, M. J., Jakes, R., et al. (1988) Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc. Natl. Acad. Sci. USA 85, 4506–4510.
Goedert, M., Jakes, R., Spillantini, M. G., Hasegawa, M., Smith, M. J., and Crowther, R. A. (1996) Assembly of microtubule-associated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans. Nature 383, 550–553.
Goedert, M., Spillantini, M. G., Cairns, N. J., and Crowther, R. A. (1992) Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 8, 159–168.
Goedert, M. (1996) Tau protein and the neurofibrillary pathology of Alzheimer’s disease. Ann. NY Acad. Sci. 777, 121–131
Matsuo, E. S., Shin, R.-W., Billingsley, M. L., Van de Voorde, A., O′Connor, M., Trojanowski, J. Q., et al. (1994) Biopsy-derived adult human brain tau is phosphorylated at many of the same sites as Alzheimer’s disease paired helical filament tau. Neuron 13, 989–1002.
Consensus report of the Working Group on: “Molecular and Biochemical Markers of Alzheimer’s Disease”; (1998) Neurobiol. Aging 19.
Kang, J., Lemaire, H. G., Unterbeck, A., Salbaum, J. M., Masters, C. L., Grzeschik, K. H., et al. (1987) The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 325, 733–736.
Ponte, P., Gonzalez-DeWhitt, P., Schilling, J., Miller, J., Hsu, D., Greenberg B., et al. (1988) A new A4 amyloid mRNA contains a domain homologous to serine proteinase inhibitors. Nature 331, 525–527.
Kitaguchi, N., Takahashi, Y., Tokushima, Y., Shiojiri, S., and Ito, H. (1988) Novel precursor of Alzheimer’s disease amyloid protein shows protease inhibitory activity. Nature 331, 530–532.
Sandbrink R., Masters, C. L., and Beyreuther, K. (1994) βA4-amyloid protein precursor mRNA isoforms without exon 15 are ubiquitously expressed in rat tissues including brain, but not in neurons. J. Biol. Chem. 269, 1510–1517.
deSauvage, F. and Octave, J. N. (1989) A novel mRNA of the A4 amyloid precursor gene coding for a possibly secreted protein. Science 245, 651–653.
Esch, F. S., Keim, P. S., Beattie, E. C., Blacher, R. W., Culwell, A. R., Olersdorf, T., et al. (1990) Cleavage of amyloid β peptide during constitutive processing of its precursor. Science 248, 1122–1124.
Anderson, J. P., Esch, F. S., Keim, P. S., Sambamurti, K., Lieberberg, I., and Robakis N. K. (1991) Exact cleavage site of Alzheimer amyloid precursor in neuronal PC-12 cells. Neurosci. Lett. 128, 126–128.
Palmert, M. R., Siedlak, S. L., Podlisny, M. B., Greenberg, B., Shelton, E. R., Chan, H. W., et al. (1989) Soluble derivatives of the β amyloid protein precursor of Alzheimer’s disease are labeled by antisera to the β amyloid protein. Biochem. Biophys. Res. Commun. 165, 182–188.
Kennedy, H. E., Kametani, F., and Allsop D. (1992) Only kunitz-inhibitor-containing isoforms of secreted Alzheimer amyloid precursor protein show amyloid immunoreactivity in normal cerebrospinal fluid. Neurodegeneration. 1, 59–64.
Seubert, P., Oltersdorf, T., Lee, M. G., Barbour, R., Blomquist, C., Davis, D. L., et al. (1993) Secretion of beta-amyloid precursor protein cleaved at the amino terminus of the β-amyloid peptide. Nature 361, 260–263.
Estus, S., Golde, T. E., Kunishita, T., Blades, D., Lowery, D., Eisen, M., et al. (1992) Potentially amyloidogenic, carboxyl-terminal derivatives of the amyloid protein precursor. Science 255, 726–728.
Haass, C., Schlossmacher, M. G., Hung, A. Y., Vigo-Pelfrey, C., Mellon, A., Ostaszewski, B. L., et al. (1992) Amyloid β-peptide is produced by cultured cells during normal metabolism. Nature 359, 322–325.
Shoji, M., Golde, T. E., Ghiso, J., Cheung, T. T., Estus, S., Shaffer, L. M., et al. (1992) Production of the Alzheimer amyloid β protein by normal proteolytic processing. Science 1992 258, 126–129.
Seubert, P., Vigo-Pelfrey, C., Esch, F., Lee, M., Dovey, H., Davis, D., et al. (1992) Isolation and quantification of soluble Alzheimer’s β-peptide from biological fluids. Nature 359, 325–327.
Ghiso, J., Calero, M., Matsubara, E., Governale, S., Chuba, J., Beavis R., et al. (1997) Alzheimer’s soluble amyloid β is a normal component of human urine. FEBSLett. 408, 105–108.
Asami-Odaka, A., Ishibashi, Y., Kikuchi, T., Kitada, C., and Suzuki, N. (1995) Long amyloid β-protein secreted from wild-type human neuroblastoma IMR-32 cells. Biochemistry 34, 10,272–10,278.
Parvathy, S., Hussain, I., Karran, E. H., Turner, A. J., and Hooper, N. M. (1998) Alzheimer’s amyloid precursor protein α-secretase is inhibited by hydroxamic acid-based zinc metalloprotease inhibitors: similarities to the angiotensin converting enzyme secretase. Biochemistry 37, 1680–1685.
Ishiura, S., Tsukahara, T., Tabira, T., and Sugita, H. (1989) Putative N-terminal splitting enzyme of amyloid A4 peptides is the multicatalytic proteinase, ingensin, which is widely distributed in mammalian cells. FEBS Lett. 257, 388–392.
Nelson, R. B., Siman, R., Iqbal, M. A., and Potter, H. (1993) Identification of a chymotrypsin-like mast cell protease in rat brain capable of generating the N-terminus of the Alzheimer amyloid β-protein. J. Neurochem. 61, 567–577.
Sahasrabudhe, S. R., Brown, A. M., Hulmes, J. D., Jacobsen, J. S., Vitek, M. P., Blume, A. J., and Sonnenberg, J. L. (1993) Enzymatic generation of the amino terminus of the β-amyloid peptide. J. Biol. Chem. 268, 16699–16705.
Savage, M. J., Iqbal, M., Loh, T., Trusko, S. P., Scott, R., and Siman, R. (1994) Cathepsin G: localization in human cerebral cortex and generation of amyloidogenic fragments from the β-amyloid precursor protein. Neuroscience 60, 607–619.
McDermott, J. R., Biggins, J. A. and Gibson, A. M. (1992) Human brain peptidase activity with the specificity to generate the N-terminus of the Alzheimer β-amyloid protein from its precursor. Biochem. Biophys. Res. Commun. 185, 746–752.
Chevallier, N., Jiracek, J., Vincent, B., Baur, C. P., Spillantini, M. G., Goedert, M., et al. (1997) Examination of the role of endopeptidase 3.4.24. 15 in Aβ secretion by human transfected cells. Br. J. Pharmacol. 121, 556–562.
Ladror, U. S., Snyder, S. W., Wang, G. T., Holzman, T. F., and Krafft, G. A. (1994) Cleavage at the amino and carboxyl termini of Alzheimer’s amyloid-β by cathepsin D. J. Biol. Chem. 269, 18,422–18,428.
Saftig, P., Peters, C., Von Figura, K., Craessaerts, K., Van Leuven, F., and De Strooper, B. (1996) Amyloidogenic processing of human amyloid precursor protein in hippocampal neurons devoid of cathepsin D. J. Biol. Chem. 271, 27,241–27,244.
Higaki, H., Quon, D., Zhong, Z., and Cordell, B. (1995) Inhibition of β-amyloid formation identifies proteolytic precursors and subcellular site of catabolism. Neuron 14, 651–659.
Allsop, D., Christie, G., Gray, C., Holmes, S., Markwell, R., Owen, D., et al. (1997) Studies on inhibition of β-amyloid formation in APP751-transfected IMR-32 cells and SPA4CT-transfected SHSY5Y cells, in Alzheimer’s Disease: Biology, Diagnostics and Therapeutics (Iqbal, K., Winblad, B., Nishimura, T., Takeda, M. and Wisniewski, H. M., eds.), Wiley, New York, pp. 717–727.
Citron, M., Diehl, T. S., Gordon, G., Biere, A. L., Seubert, P., and Selkoe, D. J. (1996) Evidence that the 42-and 40-amino acid forms of amyloid β protein are generated from the β-amyloid precursor protein by different protease activities. Proc. Natl. Acad. Sci. USA 93, 13,170–13,175.
Klafki, H., Abramowski, D., Swoboda, R., Paganetti, P. A., and Staufenbiel, M. (1996) The carboxyl termini of β-amyloid peptides 1-40 and 1-42 are generated by distinct γ-secretase activities. J. Biol. Chem. 271, 28655-28659.
Christie, G., Markwell, R. E., Gray, C. W., Smith, L., Godfrey, F., Mansfield, F., et al. (1999) Alzheimers disease: correlation of the suppression of β-amyloid peptide secretion from cultured cells with inhibition of the chymotrypsin-like activity of the proteasome. J. Neurochem. in press.
Ishiura, S. (1991) Proteolytic cleavage of the Alzheimer’s disease amyloid A4 precursor protein. J. Neurochem. 56, 363–369
Evin, G., Cappai, R., Li, Q. X., Culvenor, J. G., Small, D. H., Beyreuther, K., and Masters, C. L. (1995) Candidate γ-secretases in the generation of the carboxyl terminus of the Alzheimer’s disease βA4 amyloid: possible involvement of cathepsin D. Biochemistry 34, 14185–14192
Weidemann, A., Konig, G., Bunke, D., Fischer, P., Salbaum, J. M., Masters, C. L. and Beyreuther, K. (1989) Identification, biogenesis, and localization of precursors of Alzheimer’s disease A4 amyloid protein. Cell 57, 115–126.
Hartmann, T., Bieger, S. C., Bruhl, B., Tienari, P. J., Ida, N., Allsop, D., et al. (1997) Distinct sites of intracellular production for Alzheimer’s disease Aβ 40/42 amyloid peptides. Nature (Med.) 3, 1016–1020
Whitson, J. S., Selkoe, D. J., and Cotman, C. W. (1989) Amyloid β-protein enhances the survival of hippocampal neurons in vitro. Science 243, 1488–1490.
Whitson, J. S., Glabe, C. G., Shintani, E., Abcar, A., and Cotman, C. W. (1990) β-amyloid protein promotes neuritic branching in hippocampal cultures. Neurosci. Lett. 110, 319–324.
Yankner, B. A., Duffey, L. K., and Kirschner, D. A. (1990) Neurotrophic and neurotoxic effects of amyloid β protein. Reversal by tachykinin neuropeptides. Science 250, 279–281.
Pike, C. J., Walencewicz, A. J., Glabe, C. G., and Cotman, C. W. (1991) In vitroaging of β-amyloid protein causes peptide aggregation and neurotoxicity. Brain Res. 563, 311–314.
Yan, S. D., Chen X. Fu J., Chen, M., Zhu, H., Roher, A., Slattery, T., et al. (1996) RAGE and amyloid-β peptide neurotoxicity in Alzheimer’s disease. Nature 382, 685–691.
Harper, J. D., Wong, S. S., Lieber, C. M., and Lansbury, P. T. (1997) Observation of metastable Aβ amyloid protofibrils by atomic force microscopy. Chem. Biol. 4, 119–125
Roher, A. E., Chaney, M. O., Kuo, Y. M., Webster, S. D., Stine, W. B., Haverkamp, L. J., et al. (1996) Morphology and toxicity of Aβ (1-42) dimer derived from neuritic and vascular amyloid deposits of Alzheimer’s disease. J. Biol. Chem. 271, 20631–20635.
Walsh, D. M., Lomakin, A., Benedek, G. B., Condron, M. M., and Teplow, D. B. (1997) Amyloid β-protein fibrillogenesis. Detection of a protofibrillar intermedi-ate. J. Biol. Chem. 272, 22364–22372.
Geula, C., Wu, C.-K., Saroff, D., Lorenzo, A., Yuan, M., and Yankner, B. A. (1998) Aging renders the brain vulnerable to amyloid β-protein neurotoxicity. Nature Med. 4, 827–831.
Eikelenboom, P., Zhan, S. S., van-Gool, W. A., and Allsop, D. (1994) Inflammatory mechanisms in Alzheimer’s disease. Trends Pharmacol. Sci. 15, 447–450.
Webster, S., Bonnell, B., and Rogers, J. (1997) Charge-based binding of complement component C 1 q to the Alzheimer amyloid β-peptide. Am. J. Pathol. 150, 1531–1536.
Webster, S., Bradt, B., Rogers, J., and Cooper, N. (1997) Aggregation state-dependent activation of the classical complement pathway by the amyloid β peptide. J. Neurochem. 69, 388–398.
El-Khoury, J., Hickman, S. E., Thomas, C. A., Cao, L., Silverstein, S. C., and Loike, J. D. (1996) Scavenger receptor-mediated adhesion of microglia to β-amyloid fibrils. Nature 382, 716–719.
Paresce, D. M., Ghosh R. N., and MaxfieldF. R. (1996) Microglial cells internalize aggregates of the Alzheimer’s disease amyloid β-protein via a scavenger receptor. Neuron 17, 553–565.
Mattson, M. (1997) Cellular actions of β-amyloid precursor protein and its soluble and fibrillogenic derivatives. Physiol. Rev. 77, 1081–1132.
Nishimoto, I., Okamoto, T., Matsuura, Y., Takahashi, S., Okamoto, T., Murayama, Y., and Ogata, E. (1993) Alzheimer amyloid protein precursor complexes with brain GTP-binding protein G(0). Nature 362, 75–79.
VanNostrand, W. E., Wagner, S. L., Suzuki, M., Choi, B. H., Farrow, J. S., Geddes, J. W., Cotman, C. W., and Cunningham, D. D. (1989) Protease nexin-II, a potent antichymotrypsin, shows identity to amyloid β-protein precursor. Nature 341, 546–549.
Smith, R. P., Higuchi, D. A., and Broze, G. J. J. (1990) Platelet coagulation factor Xia-inhibitor, a form of Alzheimer amyloid precursor protein. Science 248, 1126–1128.
Miyazaki, K., Hasegawa, M., Funahashi, K., and Umeda, M. (1993)Ametalloproteinase inhibitor domain in Alzheimer amyloid protein precursor. Nature 362, 839–841.
Allsop, D., Clements, A., Kennedy, H., Walsh, D., and Williams, C. (1994) Mechanism of cerebral amyloidosis in Alzheimer’s disease, in Amyloid Protein Precursor in Development, Aging and Alzheimer’s Disease (Masters, C. L., Beyreuther, K., Trillet M., and Christen, Y., eds.), Springer-Verlag, Berlin, pp. 47–59.
Multhaup G., Mechler, H., and Masters, C. L. (1995) Characterization of the high affinity heparin binding site of the Alzheimer’s disease βA4 amyloid precursor protein (APP) and its enhancement by zinc(II). J. Mol. Recognit. 8, 247–57.
Beher, D., Hesse, L., Masters, C. L., and Multhaup, G. (1996) Regulation of amyloid protein precursor (APP) binding to collagen and mapping of the binding sites on APP and collagen type I. J. Biol. Chem. 271, 1613–1620.
Ghiso, J. A., Rostagno, J. E., Gardella, L., Liem, P. D., Gorevic, P. D., and Frangione, B. (1992) A 109-amino-acid C-terminal fragment of Alzheimer’s-disease amyloid precursor protein contains a sequence,-RHDS-, that promotes cell adhesion. Biochem. J. 288, 1053–1059.
Breen, K. C., Bruce, M., and Anderton, B. H. (1991) Beta amyloid precursor protein mediates neuronal cell-cell and cell-surface adhesion. J. Neurosci. Res. 28, 90–100.
Ninomiya, H., Roch, J. M., Sundsmo, M. P., Otero, D. A., and Saitoh, T. (1993) Amino acid sequence RERMS represents the active domain of amyloid β/A4 protein precursor that promotes fibroblast growth. J. Cell Biol. 121, 879–886.
Jin, L. W., Ninomiya, H., Roch, J. M., Schubert, D., Masliah, E., Otero, D. A., and Saitoh, T. (1994) Peptides containing the RERMS sequence of amyloid β/A4 protein precursor bind cell surface and promote neurite extension. J. Neurosci. 14, 5461–5470.
Ninomiya, H., Roch, J. M., Jin, L. W. and Saitoh, T. (1994) Secreted form of amyloid β/A4 protein precursor (APP) binds to two distinct APP binding sites on rat B103 neuron-like cells through two different domains, but only one site is involved in neuritotropic activity. J. Neurochem. 63, 495–500.
Goodman, Y. and Mattson, M. P. (1994) Secreted forms of β-amyloid precursor protein protect hippocampal neurons against amyloid β-peptide-induced oxidative injury. Exp. Neurol. 128, 1–12.
Mattson, M. P., Cheng, B., Culwell, A. R., Esch, F. S., Lieberburg, I., and Rydel, R. E. (1993) Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the β-amyloid precursor protein. Neuron (1993) 10, 243–254.
Smith-Swintosky, V. L., Pettigrew, L. C., Craddock, S. D., Culwell, A. R., Rydel, R. E., and Mattson, M. P. (1994) Secreted forms of β-amyloid precursor protein protect against ischemic brain injury. J. Neurochem. 63, 781–784.
Masliah, E., Westland, C. E., Rockenstein, E. M., Abraham, C. R., Mallory, M., Veinberg, I., et al. (1997) Amyloid precursor proteins protect neurons of transgenic mice against acute and chronic excitotoxic injuries in vivo. Neuroscience 78, 135–146.
Ohsawa I., Takamura, C., and Kohsaka, S. (1997) The amino-terminal region of amyloid precursor protein is responsible for neurite outgrowth in rat neocortical explant culture. Biochem. Biophys. Res. Commun. 236, 59–65.
Furukawa, K., Sopher, B. L., Rydel, R. E., Begley, J. G., Pham, D. G., Martin, G. M., et al. (1996) Increased activity-regulating and neuroprotective efficacy of α-secretase-derived secreted amyloid precursor protein conferred by a C-terminal heparin-binding domain. J. Neurochem. 67, 1882–1894.
Hardy, J. and Allsop, D. (1991) Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol. Sci. 12, 383–388.
Levy E., Carman, M. D., Fernandez-Madrid I. J., Power, M. D., Lieberburg I., van-Duinen, S. G., et al. (1990) Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 248 (4959), 1124–1126.
Wisniewski T., Ghiso, J., and Frangione, B. (1991) Peptides homologous to the amyloid protein of Alzheimer’s disease containing a glutamine for glutamic acid substitution have accelerated amyloid fibril formation. Biochem. Biophys. Res. Commun. 179, 1247–1254.
Clements, A., Walsh, D. M., Williams, C. H., and Allsop, D. (1993) Effects of the mutations Glu22 to Gln and Ala21 to Gly on the aggregation of a synthetic fragment of the Alzheimer’s amyloid β/A4 peptide. Neurosci. Lett. 161, 17–20.
Goate, A., Chartier-Harlin, M. C., Mullan, M., Brown, J., Crawford, F., Fidani, L., et al. (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349, 704–706.
Chartier-Harlin M. C., Crawford, F., Houlden, H., Warren, A., Hughes, D., Fidani, L., et al. (1991) Early-onset Alzheimer’s disease caused by mutations at codon 717 of the β-amyloid precursor protein gene. Nature 353, 844–846.
Murrell, J., Farlow, M., Ghetti, B., and Benson, M. D. (1991) A mutation in the amyloid precursor protein associated with hereditary Alzheimer’s disease. Science 254, 97–99.
Younkin, S. G. (1995) Evidence that Aβ 42 is the real culprit in Alzheimer’s disease. Ann. Neurol. 37, 287–288.
Burdick, D., Soreghan, B., Kwon, M., Kosmoski, J., Knauer, M., Henschen, A., et al. (1992) Assembly and aggregation properties of synthetic Alzheimer’s A4/β amyloid peptide analogs. J. Biol. Chem. 267, 546–554.
Citron, M., Oltersdorf, T., Haass, C., McConlogue, L., Hung, A. Y., Seubert, P., et al. (1992) Mutation of the β-amyloid precursor protein in familial Alzheimer’s disease increases β-protein production. Nature 360, 672–674.
Cai, X. D., Golde, T. E., and Younkin, S. G. (1993) Release of excess amyloid P protein from a mutant amyloid β protein precursor. Science 259, 514–516.
Clements, A., Allsop, D., Walsh, D. M., and Williams, C. H. (1996) Aggregation and metal-binding properties of mutant forms of the amyloid Aβ peptide of Alzheimer’s disease. J. Neurochem. 66, 740–747.
Haass, C., Hung, A. Y., Selkoe, D. J., and Teplow, D. B. (1994) Mutations associated with a locus for familial Alzheimer’s disease result in alternative processing of amyloid β-protein precursor. J. Biol. Chem. 269, 17741–17748.
Sherrington, R., Rogaev, E. I., Liang, Y., Rogaeva, E.A., Levesque, G., Ikeda, M., et al. (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375, 754–760.
Levy-Lahad, W., Poorkaj, P., Romano, D. M., Oshima, J., Pettingell, W. H., et al. (1995) Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 269, 973–977.
Borchelt, D. R., Thinakaran, G., Eckman, C. B., Lee, M. K., Davenport, F., Ratovitsky, T., et al. (1996) Familial Alzheimer’s disease-linked presenilin 1 variants elevate Aβ 1-42/1-40 ratio in vitro and in vivo. Neuron 17, 1005–1013.
Mehta, N. D., Refolo, L. M., Eckman, C., Sanders, S., Yager, D., Perez-Tur, J., et al. (1998) Increased Aβ42(43) from cell lines expressing presenilin 1 mutations. Ann. Neurol. 43, 256–258.
Hutton, M., Lendon, C. L., Rizzu, P., Baker, M., Froelich, S., Houlden, H., et al. (1998) Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393, 702–705.
Poorkaj, P., Bird, T. D., Wijsman, E., Nemens, E., Garruto, R. M., Anderson, L., et al. (1998) Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann. Neurol. 43, 815–825.
Spillantini, M. G., Bird, T. D., and Ghetti, B. (1998) Frontotemporal dementia and Parkinsonism linked to chromosome 17: anew group of tauopathies. Brain Pathol. 8, 387–402.
Busciglio, J., Lorenzo, A., Yeh, J., and Yankner, B. A. (1995) β-amyloid fibrils induce tau phosphorylation and loss of microtubule binding. Neuron 14, 879–888.
Takashima, A., Noguchi, K., Michel, G., Mercken, M., Hoshi, M., Ishiguro, K., and Imahori, K. (1996) Exposure of rat hippocampal neurons to amyloid β peptide (25-35) induces the inactivation of phosphatidyl inositol-3 kinase and the activation of tau protein kinase I/glycogen synthase kinase-3 β. Neurosci. Lett. 203, 33–36.
Sturchler-Pierrat, C., Abramowski, D., Duke, M., Wiederhold, K.-H., Mistl, C., Rothacher, S., et al. (1997) Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc. Natl. Acad. Sci. USA 94, 13,287–13,292.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2000 Humana Press Inc., Totowa, NJ
About this protocol
Cite this protocol
Allsop, D. (2000). Introduction to Alzheimer's Disease. In: Hooper, N.M. (eds) Alzheimer's Disease. Methods in Molecular Medicine™, vol 32. Humana Press. https://doi.org/10.1385/1-59259-195-7:1
Download citation
DOI: https://doi.org/10.1385/1-59259-195-7:1
Publisher Name: Humana Press
Print ISBN: 978-0-89603-737-3
Online ISBN: 978-1-59259-195-4
eBook Packages: Springer Protocols