Abstract
Familial Alzheimer’s disease (FAD) is a genetically heterogeneous disorder that is caused by defects in at least three early onset genes (age of onset:<60 yr.): presenilin 2 (PS2) on chromosome 1 (1), presenilin 1 (PS1) on chromosome 14 (2), and amyloid protein precursor (APP) on chromosome 21 (3,4). Mutations within the APP gene are responsible for only a small portion (<2%) of reported cases of FAD (5), whereas up to half of all early onset FAD cases are caused by mutations in the PSEN1 and PSEN2 genes (6,7).
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Levy-Lahad, E., Wasco, W., Poorkaj, P., Romano, D. M., Oshima, J. M., Pettingell, W. H., et al. (1995) Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 269, 973–977.
Sherrington, R., Rogaev, E. I., Liang, Y., Rogaeva, E. A., Levesque, G., Ikeda, M., et al. (1995) Cloning of a novel gene bearing missense mutations in early onset familial Alzheimer disease. Nature 375, 754–760.
Tanzi, R. E., Gusella, J. F., Watkins, P. C., Bruns, G. A. P., St. George-Hyslop, P., van Keuren, M. L., et al. (1987) Amyloid β protein gene: cDNA, mRNA distribution and genetic linkage near the Alzheimer locus. Science 235, 880–884.
Goate, A., Chartier-Harlin, M., Mullan, M., Brown, J., Crawford, F., Fidani, L., et al. (1991) Segregation of a missense mutation in the amylois precursor protein gene with familial Alzheimer’s disease. Nature 349, 704–706.
Tanzi, R. E., Vaula, G., Romano, D. M., Mortilla, M., Huang, T. L., Tupler, R. G., et al. (1992) Assessment of amyloid β protein precursor gene mutations in a large set of familial and sporadic Alzheimer disease cases. Am. J. Hum. Genet. 51, 273–282.
Tanzi, R. E., Kovacs, D. M., Kim, T.-W., Moir, R. D., Guenette, S. Y., and Wasco, W. (1996) The gene defects responsible for familial Alzheimer’s disease. Neurobiol. Dis. 3, 159–168.
Tanzi, R. E., Kovacs, D. M., Kim, T.-W., Moir, R. D., Guenette, S. Y., and Wasco, W. (1996) The presenilin genes and their role in early-onset familial Alzheimer’s disease. Alzheimer’s Dis. Rev. 1, 91–98.
Doan, A., Thinakaran, G., Borchelt, D. R., Slunt, H. H., Ratovitsky, T., Podlisny, M., et al. (1996) Protein topology of presenilin 1. Neuron 17, 1023–1030.
Lehmann, S., Chiesa, R., and Harris, D. A. (1997) Evidence for a six-transmembrane domain structure of presenilin 1. J. Biol. Chem. 272, 12,047–12,051.
Thinakaran, G., Borchelt, D., Lee, M., Slunt, H., Spitzer, L., Kim, G., et al. (1996) Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 17, 181–190.
Kim, T.-W., Pettingell, W. H., Hallmark, O. G., Moir, R. D., Wasco, W., and Tanzi, R. E. (1997a) Endoproteolytic processing and proteasomal degradation of presenilin 2 in transfected cells. J. Biol. Chem. 272, 11,006–11,010.
Mercken, M., Takahashi, H., Honda, T., Sato, K., Murayama, M., Nakazato, Y., et al. (1996) Characterization of human presenilin 1 using N-terminal specific monoclonal antibodies: evidence that Alzheimer mutations affect proteolytic processing. FEBS. Lett. 389, 297–303.
Podlisny, M. B., Citron, M., Amarante, P., Sherrington, R., Xia, W., Zhang, J., et al. (1997) Presenilin proteins undergo heterogeneous endoproteolysis between Thr291 and Ala299 and occur as stable N-and C-terminal fragments in normal and Alzheimer brain tissue. Neurobiol. Dis. 3, 325–337.
Tomita, T., Maruyama, K., Saido, T. C., Kume, H., Shinozaki, K., Tokuhiro, S., et al. (1997) The presenilin 2 mutation (N141I) linked to familial Alzheimer Disease (Volga German families) increases the secretion of amyloid β protein ending at the 42nd (or 43rd) residue. Proc. Natl. Acad. Set USA 94, 2025–2030.
Jacobson, M. D., Weil, M., and Raff, M. C. (1997) Programmed cell death in animal development. Cell 88, 347–354.
Thompson, C. B. (1995) Apoptosis in the pathogenesis and treatment of disease. Science 267, 1456–1462.
Cohen, G. M. (1997) Caspases: the executioners of apoptosis. Biochem. J. 326, 1–16.
Villa, P., Kaufmann, S. H., Earnshaw, W. C. (1997) Caspases and caspase inhibitors. TIBS 22, 388–393.
Nicholson, D. W., and Thornberry, N. A. (1997) Caspases: killer proteases. TIBS 22, 299–36.
Tan, X. and Wang, J. Y. J. (1998) The caspase-RB connection in cell death. Trends Cell Biol. 8, 116–120.
Kim, T.-W., Pettingell, W. H., Jung, Y.-K., Kovacs, D. M., and Tanzi, R. E. (1997b) Alternative cleavage of Alzheimer-associated presenilins during apoptosis by caspase-3 family protease. Science 277, 373–376.
Grünberg, J., Walter, J., Loetscher, H., Deuschle, U., Jacobsen, H., and Haass, C. (1998) Alzheimer’s disease associated presenilin-1 holoprotein and its 18-20 kDa C-terminal fragment are death substrates for proteases of the caspase family. Biochemistry 37, 2263–2270.
Gossen, M. and Bujard, H. (1992) Tight control. of gene expression in mammalian cells by tetracycline-responsive promoters. Proc. Natl. Acad. Sci. USA 89, 5547–5551.
Baker, S. J., Markowitz, S., Fearon, E. R., Wilson, J. K. V., and Vogelstein, B. (1990) Suppression of human colorectal carcinoma cell growth by wild type p53. Science 249, 912–915.
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
Kim, TW. (2000). Apoptotic Proteolytic Cleavage of the Presenilins by Caspases. In: Hooper, N.M. (eds) Alzheimer's Disease. Methods in Molecular Medicine™, vol 32. Humana Press. https://doi.org/10.1385/1-59259-195-7:309
Download citation
DOI: https://doi.org/10.1385/1-59259-195-7:309
Publisher Name: Humana Press
Print ISBN: 978-0-89603-737-3
Online ISBN: 978-1-59259-195-4
eBook Packages: Springer Protocols