Summary
In contrast to rare mutations in the amyloid presursor protein (APP) gene, missense mutations in the presenilin 1 (PS1) and presenilin 2 (PS2) genes, on chromosomes 14 and 1 respectively, are the most common causes of early-onset familial Alzheimer’s disease (AD)(Sherrington et al. 1995)(Rogaev et al. 1995)(Levy-Lahad et al. 1995). Presenilin genes encode proteins with at least seven putative transmembrane domains and an extruded cytoplasmic “loop”, the latter with a preponderance of acidic amino acid residues: these proteins are expressed in a variety of cell types. While the physiologic function of these genes is unknown, their protein products have been demonstrated to accumulate in intracellular sites including the endoplasmic reticulum, and the Golgi apparatus. Similarly, the mechanism by which the 30 different point mutations have been identified in PS1 and PS2 to date cause the clinical and neuropathological hallmarks of Alzheimer disease is unknown. However, fibroblasts from heterozygous carriers of PS1 and PS2 mutations secrete increased levels of the amyloidogenic long-tailed amyloid β-peptides ending at residues 42 or 43 (Aβ42)(Martin 1995)(Scheuner et al. 1996). Increased levels of Aβ42 and other Aβ-peptides can also be measured in postmortem brain tissue from human patients dying with early-onset FAD associated with PS1 mutations(Lemere et al. 1996). To determine whether overproduction of Aβ peptides occurs in brain as an early biochemical event prior to the onset of neurodegeneration, we constructed transgenic mice with either mutant or wild-type human PS1 and mated them with another line of transgenic mice overexpressing wild-type human βAPP695 under the control of the same transcriptional regulatory element. These studies reveal that mutant PS1 transgenes but not wild-type PS1 transgenes act in a dominant fashion to programme over-production of long-tailed Aβ42 peptides in brain, and that this biochemical difference is present by at least 2–4 months of age and in the absence of any detectable neuropathologic lesions. These advances in our understanding of presenilin function are discussed in relation to the two schools of thought on AD pathogenesis, “tau-ist”and “ßaptist”, and also with regards the hypothesis that similarities between AD and prion diseases reflect the existence of shared pathogenic pathways.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
Alzheimer, D. C. G. (1995). The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nature Genetics 11: 219–222.
Arriagada, P. V., J. H. Growdon, E. T. Hedley-Whyte and B. T. Hyman (1992). Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s Disease. Neurology 42: 631–639.
Askanas, V., R. B. Alvarez, M. Mirabella and W. K. Engel (1996). Use of Anti-Neurofilament antibody to identify paired-helical filaments in Inclusion-Body Myositis. Ann. Neurol 39: 389–391.
Askanas, V., M. Bilak, W. K. Engel, R. B. Alvarez, F. Tomé and A. Leclerc (1993). Prion protein is abnormally accumulated in inclusion-body myositis. NeuroReport 5: 25–28.
Askanas, V. and W. K. Engel (1995). New advances in the understanding of sporadic inclusion-body myositis and hereditary inclusion-body myopathies. Curr. Opinion Rheumatol. 7: 486–496.
Askanas, V., W. King Engel and R. B. Alvarez (1992). Light and electron microscopic localization of β-amyloid protein in muscle biopsies of patients with inclusion-body myositis. Am. J. Pathol 141: 31–36.
Askanas, V., J. McFerrin, S. Basque, R. B. Alvarez, E. Sarkozi and W. K. Engel (1996). Transfer of beta-amyloid precursor protein gene using adenovirus vector causes mitochondrial abnormalities in cultured normal human cells. PNAS 93: 1314–1319.
Borchelt, D. R., G. Thinakaran, C. B. Eckman, M. K. Lee, F. Davenport, T. Ratovitsky, C.-M. Prada, G. Kim, S. Seekins, D. Yager, H. H. Slunt, R. Wang, M. Seeger, A. I. Levey, S. E. Gandy, N. G. Copeland, N. A. Jenkins, D. L. Price, S. G. Younkin and S. S. Sisodia (1996). Familial Alzheimer’s Disease-Linked presnilin 1 Variants elevate Aβ 1-42/1-40 ratio In Vitro and In Vivo. Neuron 17: 1005–1013.
Brown, P., C. J. Gibbs, Jr., P. Rodgers-Johnson, D. M. Asher, M. P. Sulima, A. Bacote, L. G. Goldfarb and D. C. Gajdusek (1994). Human spongiform encephalopathy: the National Institutes of Health series of 300 cases of experimentally transmitted disease. Ann. Neurol. 35: 513–529.
Brown, P., F. Jannotta, C. J. Gibbs, Jr., H. Baron, D. C. Guiroy and D. C. Gajdusek (1990). Coexistence of Creutzfeldt-Jakob disease and Alzheimer’s disease in the same patient. Neurology 40: 226–228.
Bugiani, O., G. Giaccone, L. Verga, B. Polio, B. Frangione, M. R. Farlow, F. Tagliavini and B. Ghetti (1993). βPP participates in PrP-amyloid plaques of Gerstmann-Straussler-Scheinker disease, Indiana kindred. J. Neuropathol. Exp. Neurol 52: 64–70.
Bugiani, o., F. Tagliavini and G. Giaccone (1991). Amyloid deposits and senile plaques in Alzheimer’s disease, Down Syndrome, and Aging. Ann NY Acad Sci 640: 122–127.
Carpenter, S. (1996). Inclusion Body Myositis, a review. J. Neuropathology and Experimental Neurology 55: 1105–1114.
Citron, M., D. Westaway, W. Xia, G. A. Carlson, T. Diehl, G. Levesque, K. Johnson-Wood, M. Lee, P. Seubert, A. Davis, D. Kholodenko, R. Motter, R. Sherrington, B. Perry, H. Yao, R. Strome, I. Lieberburg, J. Rommens, S. Kim, D. Schenk, P. Fraser, St. George-Hyslop and D. Selkoe (1997). Mutant presenilins of Alzheimer’s Disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice. Nature Medicine 3: 67–72.
DeArmond, S. J. (1993). Alzheimer’s disease and Creutzfeldt-Jakob disease: overlap of pathogenic mechanisms. Current Opinion in Neurobiology 6: 872–881.
Duff, K., C. Eckman, C. Zehr, X. Yu, C.-M. Prada, J. Perez-tur, M. Hutton, L. Buee, Y. Harigaya, D. Yager, D. Morgan, M. Gordon, L. Holcomb, L. Refolo, B. Zenk, J. Hardy and S. Younkin (1996). Increased amyloid-β42 (43) in brains of mice expressing presenilin 1. Nature 383: 710–713.
El Hachimi, K. H., L. Cervenakova, P. Brown, L. Goldfarb, R. Rubenstein, D. C. Gajdusek and J.-F. Foncin (1996). Mixed features of Alzheimer disease and Creutzfeldt-Jakob disease in a family with a presenilin 1 mutation in chromosome 14. Amyloid: Int. J. Exp. Clin. Invest. 3: 223–233.
Foncin, J.-F., D. Salmon, V. Supino-Viterbo, R. G. Feldman, G. Macchi, P. Mariotti, C. Scopetta, G. Caruso and A. C. Bruni (1985). Alzheimer’s Presenile dementia transmitted in an extended kindred. Rev. Neurol. (Paris) 141: 194–202.
Forloni, G., N. Angeretti, R. Chiesa, E. Monzani, M. Salmona, O. Bugiani and F. Tagliavini (1993). Neurotoxicity of a prion protein fragment. Nature 362: 543–546.
Fraser, P., J. Nguyen, H. Inouye, W. K. Surewicz and D. J. Selkoe (1992). Fibril formation by primate rodent and Dutch-hemorrhagic analogues of Alzheimer amyloid B-protein. Biochemistry 31: 10716–10723.
Frommelt, P., R. Schnabel, W. Kuhne, L. E. Nee and R. J. Polinsky (1991). Familial Alzheimer Disease: a large multigenerational German kindred. Alzheimer Dis. Assoc. Disorders 5: 36–43.
Gaches, J. and V. Supino-Viterbo (1977). Association de maladies d’Alzheimer et de Creutzfeldt-Jakob. Acta Neurol. Belg. 77: 202–212.
Gajdusek, D. C. (1977). Unconventional viruses and the origin and disappearance of kuru. Science 197: 943–960.
Games, D., et al. (1995). Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 373: 523–527.
Ghetti, B., P. Piccardo, M. G. Spillantini, Y. Ichimiya, M. Porro, F. Perini, T. Kitamoto, J. Tateishi, C. Seiler, B. Frangione, O. Bugiani, G. Giaccone, F. Prelli, M. Goedert, S. R. Dlouhy and F. Tagliavini (1996). Vascular variant of prion protein cerebral amyloidosis with x-positive neurofibrillary tangles: The phenotype of a stop codonl 45 mutation in PRNP. Proc. Natl. Acad. Sci. U.S.A. 93: 744–748.
Ghetti, B., F. Tagliavini, C. L. Masters, K. Beyreuther, G. Giaccone, L. Verga, M. R. Farlo, P. M. Conneally, S. R. Dlouhy, B. Azzarelli and O. Bugiani (1989). Gerstmann-Sträussler-Scheinker disease. II. Neurofibrillary tangles and plaques with PrP-amyloid coexist in an affected family. Neurology 39: 1453–1461.
Goate, A. M., M.-C. Chartier-Harlin, M. Mullan, J. Brown, F. Crawford, L. Fidani, L. Guiffra, A. Haynes and J. A. Hardy (1991). Segregation of a missense mutation in the amyloid precursor protein gene with Familial Alzheimer Disease. Nature 349: 704–706.
Goldfarb, L. G., E. Mitrova, P. Brown, B. H. Toh and D. C. Gajdusek (1990) Mutation in codon 200 of scrapie amyloid protein gene in two clusters of Creutzfeldt-Jakob disease in Slovakia. Lancet 336: 514–515.
Grosveld, F., G. B. van Assendelft, D. R. Greaves and G. Kollias (1987). Positionindependent, high-level expression of the human ß-globin gene in transgenic mice. Cell 51: 975–985.
Haltia, M., M. Viitanen, R. Sulkava, V. Ala-Hurula, M. Poyhonen, L. G. Goldfarb, P. Brown, E. Levy, H. Houlden, R. Crook, A. Goate, R. Clark, K. Korenblat, s. Pandir, D. Keller, L. Lilius, L. Lui, K. Axelman, L. Forsell, B. Winblad, L. Lannfelt and J. Hardy (1994). Chromosome 14-encoded Alzheimer’s disease; Genetic and clincopathological description. Ann. neurol 36: 362–367.
Hardy, J. A. and G. A. Higgins (1992). The amyloid cascade hypothesis. Science 256: 184–85.
Hsiao, K., H. F. Baker and T. J. Crow (1989). Linkage of a prion protein missense variant to Gerstmann-Straussler Syndrome. Nature 338: 342–345.
Hsiao, K., H. F. Baker, T. J. Crow, M. Poulter, F. Owen, J. D. Terwilliger, D. Westaway, J. Ott and S. B. Prusiner (1989). Linkage of a prion protein missense variant to Gerstmann-Sträussler syndrome. Nature 338: 342–345.
Hsiao, K., S. Dlouhy, M. R. Farlow, C. Cass, M. Da Costa, M. Conneally, M. E. Hodes, B. Ghetti and S. B. Prusiner (1992). Mutant prion proteins in Gerstmann-Sträussler-Scheinker disease with neurofibrillary tangles. Nat. Genet. 1: 68–71.
Hsiao, K., Z. Meiner, E. Kahana, C. Cass, I. Kahana, D. Avrahami, G. Scarlato, O. Abramsky, S. B. Prusiner and R. Gabizon (1991). Mutation of the prion protein in Libyan Jews with Creutzfeldt-Jakob disease. N. Engl. J. Med. 324: 1091–1097.
Hsiao, K. H., P. Chapman, S. Nilsen, C. Eckman, Y. Harigawa, S. Younkin, F. S. Yang and G. Cole (1996). Correlative memory deficits, a-beta elevation, and amyloid plaques in transgenic mice. Science 274: 99–102.
Hsiao, K. K., D. R. Borchelt, K. Olson, R. Johannsdottir, C. Kitt, W. Yunis, S. Xu, C. Eckman, S. Younkin, D. Price, C. Iadecola, H. B. Clark and G. A. Carlson (1995). Age-related CNS disorder and early death in transgenic FVB/N mice overexpressing Alzheimer amyloid precursor proteins. Neuron 15: 1203–1218.
Ikeda, S.-i., N. Yanagisawa, D. Allsop and G. G. Glenner (1994). Gerstmann-Sträussler-Scheinker diease showing β-protein type cerebellar and cerebral amyloid angiopathy. Acta Neuropathol. 88: 262–266.
L’Hernault, S. W. L. and P. M. Arduengo (1992). Mutation of a putative sperm membrane protein in Caenohabitis elegans prevents sperm differentiation but not its associated meiotic divisions. J.Cell Biol. 119: 55–69.
Lemere, C. A., F. Lopera, K. Kosik, C. L. Lendon, J. Ossa, T. C. Saido, H. Yamaguchi, A. Ruiz, A. Martinez, L. Madrigal, L. Hincapie, J. C. Arango I, D. C. Anthony, E. H. Koo, A. M. Goate, D. J. Selkoe and J. C. Arango V (1996). The E280A presenilin 1 Alzheimer mutation produces increased Abeta42 deposition and severe cerebellar pathology. Nature medicine 2: 1146–1150.
Levy-Lahad, E., W. Wasco, P. Poorjaj, D. M. Romano, J. Oshima, W. H. Pettingell, C.-e. Yu, P. D. Jondro, S. D. Shmidt, K. Wang, A. C. Crowley, Y.-H. Fu, S. Y. Guenette, D. Galas, e. Nemens, E. M. Wijsman, T. D. Bird, G. D. Schellenberg and R. E. Tanzi (1995). Candidate gene for the chromosome 1 familial Alzheimer’s Disease locus. Science 269: 973–977.
Liberski, P. P., W. Papeerz and J. Alwasiak (1987). Creutzfeldt-Jakob disease with plaques and parted helical filaments. Acta Neurol Scand. 76: 428–432.
Manuelidis, E. E., J. M. de Figueiredo, J. H. Kim, W. W. Fritch and L. Manuelidis (1988). Transmission studies from blood of Alzheimer disease patients and healthy relatives. Proc. Natl Acad. Sci. USA 85: 4898–4901.
Martin, R. N. e. a. (1995). High levels of amyloid beta-protein from S182 (Glu246) familial Alzheimer’s cells. Neuroreport 7: 217–220.
Masliah, E., L. Hansen, T. Albright, M. Mallory and R. D. terry (1991). Immunoelectron microscopic study of synaptic pathology in Alzheimer’s disease. Acta Neuropathol (Berl) 81 (428–433).
Masliah, E., R. D. Terry, M. Alford, R. M. DeTeresa and L. A. Hansen (1991). Cortical and subcortical patterns of synaptohysin-like immunoreactivity in Alzherimer’s disease. Am. J. Pathol. 138: 235–246.
Mendell, J. R., Z. Sahenk, T. Gales and L. Paul (1991). Amyloid filaments in inclusion body myositis. Arch. Neurol. 48: 1229–1234.
Moser, M., Colello, R.J., Pott, U., and Oesch, B. (1995). Developmental Expression of the Prion Protein in Glial Cells. Neuron 14: 509–517.
Mullan, M., H. Houlden, M. Windelspecht, L. Fidani, C. Lombardi, P. Diaz, M. Rossor, R. Crook, J. Hardy, K. Duff and F. Crawford (1992). A locus for familial early-onset Alzheimer’s disease on the long arm of chromosome 14, proximal to the α-1-antichymotrypsin gene. Nat. Genet. 2: 340–342.
Muramoto, T., T. Kitamoto, H. Koga and J. Tateishi (1992). The coexistence of Alzheimer’s disease and Creutzfeldt-Jakob disease in a patient with dementia of long duration. Acta Neuropathol. 84: 686–689.
Nalbantoglu, J., G. Karpati and S. Carpenter (1994). Conspicuous accumulation of a singel-stranded DNA binding protein in skeletal muscel fibers in Inclusio Body Myositis. Am. J. Pathol 144: 874–882.
Parchi, P. and P. Gambetti (1995). Human prion diseases. Current Opinion in Neurobiology 8: 286–293.
Powers, J. M., Y. Liu, S. Hair, R. J. Kascsak, L. D. Lewis and L. A. Levy (1991). Concomitant Creutzfeldt-Jakob and Alzheimer diseases. Acta Neuropathol. 83: 95–98.
Prusiner, S. B., M. Scott, D. Foster, K.-M. Pan, D. Groth, C. Mirenda, M. Torchia, S.-L. Yang, D. Serban, G. A. Carlson, P. C. Hoppe, D. Westaway and S. J. DeArmond (1990). Transgenetic studies implicate interactions between homologous PrP isoforms in scrapie prion replication. Cell 63: 673–686.
Rogaev, E. I., R. Sherrington, E. A. Rogaeva, G. Levesque, M. Ikeda, Y. Liang, H. Chi, C. Lin, K. Holman, T. Tsuda, L. Mar, S. Sorbi, B. Nacmias, S. Piacentini, L. Amaducci, I. Chumakov, D. Cohen, L. Lannfelt, P. E. Fraser, J. M. Rommens and P. St George-Hyslop (1995). Familial Alzheimer’s disease in kindreds with missense mutations in a novel gene on chromosome 1 related to the Alzheimer’s Disease type 3 gene. Nature 376: 775–778.
Rogaev, E. I., R. Sherrington, C. Wu, G. Levesque, Y. Liang, E. A. Rogaeva, M. Ikeda, K. Holman, C. Lin, W. J. Lukiw, P. J. de Jong, P. E. Fraser, J. M. Rommens and P. St George-Hyslop (1997). Analysis of the 5’ sequence, genomic structure, and alternative splicing of the presenilin-1 gene (PSEN1) associated with Early Onset Alzheimer Disease. Genomics 40: 415–424.
Sarkozi, E., V. Askanas and W. K. Engel (1994). Abnormal accumulation of prion protein mRNA in muscle fibers of patients with sporadic Inclusion-Body Myositis and hereditary Inclusion-Body Myopathy. Am, J. Pathol. 145: 1280–1284.
Scheuner, D., J. Eckman, M., X. Song, M. Citron, N. Suzuki, T. D. Bird, J. Hardy, M. Hutton, W. Kukull, E. Larson, E. Levy-Lahad, M. Viitanen, E. Peskind, P. Poorkaj, G. Schellenberg, R. Tanzi, W. wasco, L. Lannfelt, D. Selkoe and S. Younkin (1996). Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nature medicine 2: 864–870.
Scott, M., D. Groth, D. Foster, M. Torchia, S.-L. Yang, S. J. DeArmond and S. B. Prusiner (1993). Propagation of prions with artificial properties in transgenic mice expressing chimeric PrP genes. Cell 73: 979–988.
Scott, M. R., R. Köhler, D. Foster and S. B. Prusiner (1992). Chimeric prion protein expression in cultured cells and transgenic mice. Protein Sci. 1: 986–997.
Sherriff, F., C. L. Joachim, M. V. Squier and M. M. Esiri (1995). Ubiquitinated inclusions in inclusion-body myositis patients are immunoreactive for cathepsin D but not β-amyloid. Neuroscience Letters 194: 37–40.
Sherrington, R., E. Rogaev, Y. Liang, E. Rogaeva, G. Levesque, M. Ikeda, H. Chi, C. Lin, K. Holman, T. Tsuda, L. Mar, P. Fraser, J. M. Rommens and P. St George-Hyslop (1995). Cloning of a gene bearing missense mutations in early onset familial Alzheimer’s disease. Nature 375: 754–760.
St George-Hyslop, P., et al. (1992). Genetic Evidence for a novel Familial Alzheimer Disease gene on chromosome 14. Nature Genetics 2: 330–334.
Strittmatter, W. J., A. M. Saunders, D. Schmechel, D. Goldgaber, A. D. Roses and e. al. (1993). Apolipoprotein E: high affinity binding to B/A4 amyloid and increased frequency of type 4 allele in Familial Alzheimers Disease. Proc.Natl. Acad. Sci.USA 90: 1977–1981.
Telling, G. C, M. Scott, J. Mastrianni, R. Gabizon, M. Torchia, F. E. Cohen, S. J. DeArmond and S. B. Prusiner (1995). Prion Propagation in Mice Expressing Human and Chimeric PrP transgenes implicates the Interaction of Cellular PrP with Another Protein. Cell 83: 79–90.
Thinakaran, G., D. R. Borchelt, M. K. Lee, H. H. Slunt, L. Spotzer, G. Kim, T. Ratovitsky, F. Davenport, C. Nordstedt, M. Seeger, J. Hardy, A. I. Levey, S. E. Gandy, N. A. Jenkins, N. G. Copeland, D. L. Price and S. S. Sisodia (1996). Endoproteolysis of Presenilin 1 and accumulation of processed derivatives in vivo. Neuron 17: 181–190.
Van Broeckhoven, C, H. Backhovens, M. Cruts, G. De Winter, M. Bruyland, P. Cras and J.-J. Martin (1992). Mapping of a gene predisposing to early-onset Alzheimer’s disease to chromosome 14q24.3. Nat. Genet. 2: 335–339.
Weidemann, A., K. Paliga, U. Durrwang, C. Czech, G. Evin, C. L. Masters and K. Beyreuther (1997). Formation of stable complexes between two Alzheimer’s disease gene products: Presenilin-2 and β-amyloid precursor protein. Nature medicine 3.
Westaway, D., S. J. DeArmond, J. Cayetano-Canlas, D. Groth, D. Foster, S.-L. Yang, M. Torchia, G. A. Carlson and S. B. Prusiner (1994). Degeneration of skeletal muscle, peripheral nerves, and the central nervous system in transgenic mice overexpressing wild-type prion proteins. Cell 76: 117–129.
Yehiely, F., P. Bamborough, M. Da Costa, B. J. Perry, G. Thinakaran, F. E. Cohen, G. A. Carlson and S. B. Prusiner (1997). Identification of candidate proteins binding to prion protein. Neurobiology of Disease 3: 339–355.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1998 Springer Science+Business Media New York
About this chapter
Cite this chapter
Westaway, D. et al. (1998). Presenilin Proteins and the Pathogenesis of Early-Onset Familial Alzheimer’s Disease: β-Amyloid Production and Parallels to Prion Diseases. In: Morrison, D.R.O. (eds) Prions and Brain Diseases in Animals and Humans. NATO ASI Series, vol 295. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-1896-3_17
Download citation
DOI: https://doi.org/10.1007/978-1-4899-1896-3_17
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4899-1898-7
Online ISBN: 978-1-4899-1896-3
eBook Packages: Springer Book Archive