Summary
Amyloid β-peptide (Aβ), the major component of senile plaques, is generated by proteolytic processing from the β-amyloid precursor protein (βAPP). Mutations within the βAPP gene cause early onset familial AD (FAD) by affecting Aβ generation. Interestingly, the much more abundant mutations within the presenilin (PS) genes also result in the abnormal generation of a 42 residue Aβ (Aβ42), thus clearly supporting a pivotal role of Aβ for the pathology of AD. PS proteins are proteolytically processed into stable 30kDa N-terminal fragments (NTF) and 20kDa C-terminal fragments (CTF). Beside the conventional proteolytic pathway, PS proteins can also be cleaved further C-terminal by proteases of the caspase superfamily. PS proteins were localized within the endoplasmic reticulum (ER) and early Golgi, compartments which we have demonstrated to be involved in Aβ42 generation and intracellular accumulation. Using Caenorhabditis elegans as a simple animal model, we demonstrate that PS proteins are involved in NOTCH signaling. FAD causing mutations interfere with the biological function of PS proteins in NOTCH signaling.
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References
Baumeister R, Leimer U, Zweckbronner I, Jakubek C, Grünberg J, Haass C (1997) Human presenilin-1, but not familial Alzheimer’s disease (FAD) mutants, facilitate caenorhabditis elegans notch signaling independently of proteolytic processing. Genes function 1: 149–159
Borchelt D, Thinakaran G, Eckman C, Lee M, Davenport F, Ratovitsky T, Prada C-M, Kim G, Seekins S, Yager D, Slunt H, Wang R, Seeger M, Levey A, Gandy S, Copeland N, Jenkins N, Price D, Younkin S, Sisodia SS (1996) Familial Alzheimer’s disease-linked presenilin-1 variants elevate Aβ1–42/1–40 ratio in vitro and in vivo. Neuron 17: 1005–10013
Capell A, Saffrich R, Olivo J-C, Meyn L, Walter J, Grünberg J, Dotti C, Haass C (1997) Expression and proteolytic processing of presenilin proteins is developmentally regulated during neuronal differentiation. J Neurochem 69: 2432–2440
Citron M, Westaway D, Xia W, Carlson G, Diehl TS, Levesque G, Johnson-Wood K, Lee, M, Seubert P, Davis A, Kholodenko D, Motter R, Sherrington R, Perry B, Yao H, Strome R, Lieberburg I, Rommens J, Kim S, Schenk D, Fraser P, St. George-Hyslop P, Selkoe DJ (1997) Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice. Nature Med 3: 67–72
Cook DG, Sung JC, Golde TE, Felsenstein KM, Wojczyk BS, Tanzi RE, Trojanowski JQ, Lee V M-Y, Doms RW (1996) Expression and analysis of presenilin 1 in a human neuronal system: Localization in cell bodies and dendrites. Proc Natl Acad Sci USA 93: 9223–9228
Cook DG, Forman MS, Sung JC, Leight S, Kolson DL, Iwatsubo T, Lee V M-Y, Doms RW (1997) Alzheimer’s Aβ (1-42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells. Nature Med 3: 1021–1023
De Strooper B, Beullens M, Contreras B, Levesque L, Craessaerts K, Cordell B, Moechars D, Bollen M, Fraser P, St. George-Hyslop P, Van Leuven F (1997) Phosphorylation, subcellular localization and membrane orientation of the Alzheimer’s disease-associated presenilins. J Biol Chem 272: 3590–3598
Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-Tur J, Hutton M, Buee L, Harigaya Y, Yager D, Morgan D, Gordon MN, Holcomb L, Refolo L, Zenk B, Hardy J, Younkin SG (1996) Increased amyloid-β42 (43) in brains of mice expressing mutant presenilin 1. Nature 383: 710–713
Grünberg J, Walter J, Hendriks L, van Broeckhoven C, Loetscher H, Deuschle U, Jacobsen H, Haass C (1998) Alternative processing of the Alzheimer’s disease associated presenilin-1 involving proteases of the caspase family. Biochemistry (in press)
Haass C (1997) Presenilins: genes for life and death. Neuron 18: 687–690
Haass C, Selkoe DJ (1993) Cellular processing of β-amyloid precursor protein and the genesis of amyloid β-peptide. Cell 75: 1039–1042
Hartmann T, Bieger SC, Brühl B, Tienari PJ, Ida N, Allsop D, Roberts GW, Masters CL, Dotti CG, Unsicker K, Beyreuther K (1997) Distinct sites of intracellular production for Alzheimer’s disease Aβ40/42 amyloid peptides. Nature Med 3: 1016–1020
Hartmann H, Busciglio J, Baumann K-H, Staufenbiel M, Yankner B (1997) Developmental regulation of presenilin-1 processing in the brain suggests a role in neuronal differentiation. J Biol Chem 272: 14505–14508
Kim T-W, Pettingell H, Jung Y-K, Kovacs D, Tanzi R (1997) Alternative cleavage of Alzheimer-associated presenilins during apoptosis by a caspase-3 family protease. Science 277: 373–376
Kovacs DM, Fausett HJ, Page K J, Kim TW, Moir RD, Merriam DE, Hollister RD, Hallmark OG, Mancini R, Felsenstein KM, Hyman BT, Tanzi RE, Wasco W (1996) Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells. Nature Med 2: 224–229
Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu C, Jondro PD, Schmidt SD, Wang K, Crowley AC, Fu Y-H, Guenette SY, Galas D, Nemens E, Wijsman EM, Bird TD, Schellenberg GD, Tanzi RE (1995) Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 269: 973–977
Levitan D, Greenwald I (1995) Facilitation of lin-12-mediated signaling by sel-12, a Caenorhabditis elegans S182 Alzheimer’s disease gene. Nature 377: 351–354
Levitan D, Doyle T, Brousseau D, Lee M, Thinakaran G, Slunt H, Sisodia S, Greenwald I (1996) Assessment of normal and mutant human presenilin function in Caenorhabditis elegans. Proc Natl Acad Sci USA 93: 14940–14944
Loetscher H, Deuschle U, Brockhaus M, Reinhardt D, Nelboeck P, Mous J, Grünberg J, Haass C, Jacobsen H (1997) Presenilins are processed by caspase-type proteases. J Biol Chem 272: 20655–20659
Perez-Tur J, Froehlich S, Prihar G, Crook R, Baker M, Duff K, Wragg M, Busfield F, Lendon C, Clark RF, Roques P, Fuldner RA, Johnston J, Cowburn R, Forseil C, Axelman K, Lilius L, Houlden H, Karran E, Roberts GW, Rossor M, Adams MD, Hardy J, Goate A, Lannfelt L, Hutton M (1995) A mutation in Alzheimer’s disease destroying a splice acceptor site in the presenilin-1 gene. NeuroReport 7: 297–301
Podlisny M, Citron M, Amarante P, Sherrington R, Xia W, Zhang J, Diehl T, Levesque G, Fraser P, Haass C, Koo E, Seubert P, St. George-Hyslop P, Teplow D, Selkoe D (1997) Presenilins 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
Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holamn K, Tsuda T, Mar L, Sorbi S, Nacmias B, Piacentini S, Amaducci L, Chumakkov I, Cohen D, Lannfelt L, Fraser PE, Rommens JM, St. George-Hyslop PH (1995) Familial Alzheimer’s disease kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature 376: 775–778
Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird TD, Hardy J, Hutton M, Kukull W, Larson E, Levy-Lahad E, Viitanen M, Peskind E, Poorkaj P, Schellenberg G, Tanzi R, Wasco W, Lannfelt L, Selkoe DJ, Younkin S (1996) Secreted amyloid β-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 Med 2: 864–870
Selkoe DJ (1996) Amyloid β-protein and the genetics of Alzheimer’s disease. J Biol Chem 271: 18295–18298
Shen J, Bronson RT, Chen DF, Xia W, Selkoe DJ, Tonegawa S (1997) Skeletal and CNS defects in presenilin-1-deficient mice. Cell 89: 629–639
Sherrington R, Rogaev El, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin J-F, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I, Pollen D, Brookes A, Sanseau P, Polinsky RJ, Wasco W, da Silva HAR, Haines JL, Pericak-Vance MA, Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George-Hyslop PH (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375: 754–760
Suzuki N, Cheung TT, Cai XD, Odaka A, Otvos L jr, Eckman C, Golde TE, Younkin SG (1994) An increased percentage of long amyloid β protein secreted by familial amyloid β protein precursor (βAPP 717) mutants. Science 264: 1336–1340
Tanzi RE, Kovacs DM, Kim T-W, Moir R, Guenette SY, Wasco W (1996) The gene defects responsible for Alzheimer’s disease. Neurobiol Dis 3: 159–168
Thinakaran G, Borchelt DR, Lee MK, Slunt HH, Spitzer L, Kim G, Ratovitsky T, Davenport F, Nordstedt C, Seeger M, Hardy J, Levey AI, Gandy SE, Jenkins NA, Copeland, NG, Pric, DL Sisodia SS (1996) Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 17: 181–190
Tomita T, Maruyama K, Saido TC, Kume H, Shinozaki K, Tokuhiro S, Capell A, Walter J, Grünberg J, Haass C, Iwatsubo T, Obata K (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 Sci USA 94: 2025–2030
Vito P, Lacana L, D’Adamio L (1996a) Interfering with apoptosis: Ca2 +-binding protein ALG-2 and Alzheimer’s disease gene ALG-3. Science 271: 521–525
Vito P, Wolozin B, Ganjei JK, Iwasaki K, Lacana E, D’Adamio L (1996b) Requirement of the familial Alzheimer’s disease gene PS2 for apoptosis. J Biol Chem 271: 31025–31028
Walter J, Capell A, Grünberg J, Pesold B, Schindzielorz A, Prior R, Podlisny MB, Fraser P, St.George-Hyslop P, Selkoe DJ, Haass C (1996) The Alzheimer’s disease — associated presenilins are differentially phosphorylated proteins located predominantly within the endoplasmic reticulum. Mol Med 2: 673–691
Weidemann A, Paliga K, Dürrwang U, Czech C, Evin G, Masters C, Beyreuther K (1997) Formation of stable complexes between two Alzheimer’s disease gene products: presenilin-2 and β-amyloid precursor protein. Nature Med 3: 328–332
Wild-Bode C, Yamazaki T, Capell A, Leimer U, Steiner H, Ihara Y, Haass C (1997) Intracellular generation and accumulation of Amyloid β-peptide terminating at amino acid 42. J Biol Chem 272: 16085–16088
Wolozin B, Iwasaki K, Vito P, Ganjei JK, Lacana E, Sunderland T, Zhao B, Kusiak JW, Wasco W, D’Adamio L (1996) Participation of presenilin 2 in apoptosis: Enhanced basal activity conferred by an Alzheimer mutation. Science 274: 1710–1713
Wong PC, Zheng H, Chen H, Becher MW, Sirinathsinghji DJS, Trumbauer ME, Chen HY, Price DL, Van der Ploeg LHT, Sisodia SS (1997) Presenilin 1 is required for Notchl and D//1 expression in the paraxial mesoderm. Nature 387: 288–292
Xia W, Zhang J, Kholodenko D, Citron M, Teplow DB, Haass C, Seubert P, Koo EH, Selkoe DJ (1997) Enhanced production and oligomeraization of the 42-residue amyloid β-protein by CHO cells stably expressing mutant presenilins. J Biol Chem 272: 7977–7982
Xia W, Zhang J, Perez R, Koo EH, Selkoe DJ (1997) Interaction between amyloid precursor protein and presenilins in mammalian cells: implications for the pathogenesis of Alzheimer’s disease, Proc Natl Acad Sci USA 94: 8208–8213
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Haass, C. et al. (1998). Proteolytic processing of Alzheimer’s disease associated proteins. In: Jellinger, K., Fazekas, F., Windisch, M. (eds) Ageing and Dementia. Journal of Neural Transmission. Supplementa, vol 53. Springer, Vienna. https://doi.org/10.1007/978-3-7091-6467-9_14
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DOI: https://doi.org/10.1007/978-3-7091-6467-9_14
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