Work

The Role of Presenilins in γ-Secretase Activity

Year: 2001

Type: review

Abstract: Alzheimer's disease amyloid-β peptide amyloid-β precursor protein familial AD presenilin transmembrane domain tumor necrosis factor-α converting enzyme Notch intracellular domain endoplasmic reticulum It is an aphorism that basic biological research lays the groundwork for solving important biomedical problems. However, the reverse is true as well: focusing on problems of human disease can lead to important new insights into the intricacies of nature. Research on Alzheimer's disease (AD)1provides a case study for the latter, where the race to identify molecular players involved in pathogenesis has unveiled some unexpected and fascinating aspects of protease biochemistry and proteolysis-dependent signal transduction. The 40–42-residue amyloid-β peptide (Aβ) is implicated in the early pathogenic events that lead to AD, and this peptide is carved out of the amyloid-β precursor protein (APP) by β- and γ-secretases (Fig. 1 A) (1Selkoe D.J. Nature. 1999; 399: A23-31Crossref PubMed Scopus (1520) Google Scholar). These two proteases are considered such important drug targets that the search for inhibitors of Aβ production within pharmaceutical companies has gone on for years even though both β- and γ-secretases remained unknown until very recently. Last year, β-secretase was identified as a new membrane-tethered member of the aspartyl protease family (2Vassar R. Bennett B.D. Babu-Khan S. Kahn S. Mendiaz E.A. Denis P. Teplow D.B. Ross S. Amarante P. Loeloff R. et al.Science. 1999; 286: 735-741Crossref PubMed Scopus (3271) Google Scholar, 3Sinha S. Anderson J.P. Barbour R. Basi G.S. Caccavello R. Davis D. Doan M. Dovey H.F. Frigon N. Hong J. et al.Nature. 1999; 402: 537-540Crossref PubMed Scopus (1474) Google Scholar, 4Yan R. Bienkowski M.J. Shuck M.E. Miao H. Tory M.C. Pauley A.M. Brashier J.R. Stratman N.C. Mathews W.R. Buhl A.E. et al.Nature. 1999; 402: 533-537Crossref PubMed Scopus (1329) Google Scholar, 5Hussain I. Powell D. Howlett D.R. Tew D.G. Meek T.D. Chapman C. Gloger I.S. Murphy K.E. Southa C.D. Ryan D.M. et al.Mol. Cell. Neurosci. 1999; 14: 419-427Crossref PubMed Scopus (997) Google Scholar, 6Lin X. Koelsch G. Wu S. Downs D. Dashti A. Tang J. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 1456-1460Crossref PubMed Scopus (738) Google Scholar), a finding that should greatly facilitate drug discovery. α-Secretases, which prevent Aβ formation by cleaving in the middle of the amyloid domain (7Esch F.S. Keim P.S. Beattie E.C. Blacher R.W. Culwell A.R. Oltersdorf T. McClure D. Ward P.J. Science. 1990; 248: 1122-1124Crossref PubMed Scopus (1202) Google Scholar), have now been shown to be members of the ADAM family (adisintegrin andmetalloprotease) (8Lammich S. Kojro E. Postina R. Gilbert S. Pfeiffer R. Jasionowski M. Haass C. Fahrenholz F. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 3922-3927Crossref PubMed Scopus (977) Google Scholar, 9Buxbaum J.D. Liu K.N. Luo Y. Slack J.L. Stocking K.L. Peschon J.J. Johnson R.S. Castner B.J. Cerretti D.P. Black R.A. J. Biol. Chem. 1998; 273: 27765-27767Abstract Full Text Full Text PDF PubMed Scopus (834) Google Scholar). At the same time, the mysterious γ-secretase is giving up its secrets as well. Genetic studies of families susceptible to autosomal dominant, early onset (<60 years) AD underscore the importance of Aβ formation to the disease process (10Hardy J. Trends Neurosci. 1997; 20: 154-159Abstract Full Text Full Text PDF PubMed Scopus (1267) Google Scholar, 11Selkoe D.J. Science. 1997; 275: 630-631Crossref PubMed Scopus (844) Google Scholar). Several different missense mutations in the APP gene on chromosome 21 cause familial AD (FAD), and these mutations are found immediately near the α-, β-, or γ-secretase processing sites. A Lys → Asn/Met → Leu double mutation near the β-secretase cleavage site found in a Swedish pedigree leads to increased Aβ production (both Aβ40 and Aβ42) (12Citron M. Oltersdorf T. Haass C. McConlogue L. Hung A.Y. Seubert P. Vigo-Pelfrey C. Lieberburg I. Selkoe D.J. Nature. 1992; 360: 672-674Crossref PubMed Scopus (1527) Google Scholar), and indeed purified β-secretase cuts peptide substrates with the “Swedish mutation” better than peptides based on the wild-type sequence (2Vassar R. Bennett B.D. Babu-Khan S. Kahn S. Mendiaz E.A. Denis P. Teplow D.B. Ross S. Amarante P. Loeloff R. et al.Science. 1999; 286: 735-741Crossref PubMed Scopus (3271) Google Scholar, 4Yan R. Bienkowski M.J. Shuck M.E. Miao H. Tory M.C. Pauley A.M. Brashier J.R. Stratman N.C. Mathews W.R. Buhl A.E. et al.Nature. 1999; 402: 533-537Crossref PubMed Scopus (1329) Google Scholar, 6Lin X. Koelsch G. Wu S. Downs D. Dashti A. Tang J. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 1456-1460Crossref PubMed Scopus (738) Google Scholar). The several FAD-causing mutations in APP near the γ-secretase processing site also affect Aβ production, but in these cases the mutations alter the specificity of the protease, leading to increases in the 42-residue Aβ variant (13Suzuki N. Cheung T.T. Cai X.D. Odaka A. Otvos Jr., L. Eckman C. Golde T.E. Younkin S.G. Science. 1994; 264: 1336-1340Crossref PubMed Scopus (1343) Google Scholar, 14Tamaoka A. Odaka A. Ishibashi Y. Usami M. Sahara N. Suzuki N. Nukina N. Mizusawa H. Shoji S. Kanazawa I. Mori H. J. Biol. Chem. 1994; 269: 32721-32724Abstract Full Text PDF PubMed Google Scholar). These findings bolstered the “amyloid hypothesis” of AD pathogenesis, because Aβ42 is particularly prone to fibril formation (15Jarrett J.T. Berger E.P. Lansbury Jr., P.T. Biochemistry. 1993; 32: 4693-4697Crossref PubMed Scopus (1747) Google Scholar) and is the protein initially deposited in the neuritic plaques that characterize the disease (16Iwatsubo T. Odaka A. Suzuki N. Mizusawa H. Nukina N. Ihara Y. Neuron. 1994; 13: 45-53Abstract Full Text PDF PubMed Scopus (1540) Google Scholar). Genes encoding the polytopic presenilin-1 and presenilin-2 (PS1 and PS2), found on chromosomes 14 and 1, respectively, were later identified as major loci for FAD (17Sherrington R. Rogaev E.I. Liang Y. Rogaeva E.A. Levesque G. Ikeda M. Chi H. Lin C. Li G. Holman K. et al.Nature. 1995; 375: 754-760Crossref PubMed Scopus (3565) Google Scholar, 18Levy-Lahad E. Wasco W. Poorkaj P. Romano D.M. Oshima J. Pettingell W.H., Yu, C.E. Jondro P.D. Schmidt S.D. Wang K. et al.Science. 1995; 269: 973-977Crossref PubMed Scopus (2220) Google Scholar), and mutations in the presenilins were likewise found to increase Aβ42 production in transfected cell lines (19Borchelt D.R. Thinakaran G. Eckman C.B. Lee M.K. Davenport F. Ratovitsky T. Prada C.M. Kim G. Seekins S. Yager D. et al.Neuron. 1996; 17: 1005-1013Abstract Full Text Full Text PDF PubMed Scopus (1329) Google Scholar, 20Citron M. Westaway D. Xia W. Carlson G. Diehl T. Levesque G. Johnson-Wood K. Lee M. Seubert P. Davis A. et al.Nat. Med. 1997; 3: 67-72Crossref PubMed Scopus (1157) Google Scholar, 21Tomita T. Maruyama K. Saido T.C. Kume H. Shinozaki K. Tokuhiro S. Capell A. Walter J. Grunberg J. Haass C. Iwatsubo T. Obata K. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 2025-2030Crossref PubMed Scopus (349) Google Scholar), transgenic animals (19Borchelt D.R. Thinakaran G. Eckman C.B. Lee M.K. Davenport F. Ratovitsky T. Prada C.M. Kim G. Seekins S. Yager D. et al.Neuron. 1996; 17: 1005-1013Abstract Full Text Full Text PDF PubMed Scopus (1329) Google Scholar, 20Citron M. Westaway D. Xia W. Carlson G. Diehl T. Levesque G. Johnson-Wood K. Lee M. Seubert P. Davis A. et al.Nat. Med. 1997; 3: 67-72Crossref PubMed Scopus (1157) Google Scholar, 22Duff K. Eckman C. Zehr C., Yu, X. Prada C.M. Perez-tur J. Hutton M. Buee L. Harigaya Y. Yager D. Morgan D. Gordon M.N. Holcomb L. Refolo L. Zenk B. Hardy J. Younkin S. Nature. 1996; 383: 710-713Crossref PubMed Scopus (1310) Google Scholar), and human plasma (23Scheuner D. Eckman C. Jensen M. Song X. Citron M. Suzuki N. Bird T.D. Hardy J. Hutton M. Kukull W. et al.Nat. Med. 1996; 2: 864-870Crossref PubMed Scopus (2253) Google Scholar). Thus, presenilins somehow modulate γ-secretase activity. In fact, deletion of PS1 in mice dramatically reduced γ-secretase activity (24De B. P. K. H. G. W. K. F. Nature. 1998; PubMed Scopus Google Scholar), and of both PS1 and in of this APP processing A. L. W. D. L. B. Biol. 2000; 2: PubMed Scopus Google Scholar, P. Song W. D. M. A. Biol. 2000; 2: PubMed Scopus Google Scholar), that presenilins are for by out an within the middle of the transmembrane domain of its by and processing by (Fig. 1 a of the γ-secretase cleavage site in APP can FAD-causing mutations increase these mutations are immediately to the to Aβ42 Xia W. B. Selkoe D.J. Biochemistry. 1999; PubMed Scopus Google Scholar). A study near the γ-secretase cleavage site and the on Aβ40 and Aβ42 production important for the that the is in a with the protease Wang R. H. K. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: PubMed Scopus Google Scholar). studies likewise that γ-secretase has sequence specificity E. B. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, K. T. Shinozaki K. Kume H. H. Saido T.C. S. Iwatsubo T. Obata K. 1996; PubMed Scopus Google Scholar, N. G. K. Biochemistry. 1997; PubMed Scopus Google Scholar). the sequence γ-secretase to process its APP sites. can be by within the as a of the site of a that with the that γ-secretase an The of inhibitors to of by an aspartyl protease Xia W. B. Selkoe D.J. Biochemistry. 1999; PubMed Scopus Google Scholar). γ-secretase to have sequence specificity for its inhibitors as for its substrates Xia W. B. Selkoe D.J. Biochemistry. 1999; PubMed Scopus Google Scholar). are for the of a to Aβ40 leading to the that these two Aβ are by different γ-secretases M. Diehl Gordon G. Seubert P. Selkoe D.J. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar, H. D. R. M. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). The findings that mutations affect and that prevent Aβ production the presenilins are with the to sequence with and to a protein involved in in initially a in γ-secretase processing of APP (17Sherrington R. Rogaev E.I. Liang Y. Rogaeva E.A. Levesque G. Ikeda M. Chi H. Lin C. Li G. Holman K. et al.Nature. 1995; 375: 754-760Crossref PubMed Scopus (3565) Google Scholar). of presenilins lead to increased γ-secretase activity M. Westaway D. Xia W. Carlson G. Diehl T. Levesque G. Johnson-Wood K. Lee M. Seubert P. Davis A. et al.Nat. Med. 1997; 3: 67-72Crossref PubMed Scopus (1157) Google Scholar). However, presenilins processing within the of the transmembrane domain and (Fig. 1 to G. D.R. Lee M.K. L. Kim G. Ratovitsky T. Davenport F. C. M. et al.Neuron. 1996; 17: Full Text Full Text PDF PubMed Scopus Google Scholar, A. Grunberg J. B. A. Citron M. R. K. Selkoe D.J. Haass C. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). studies an for the presenilins A. Thinakaran G. D.R. Ratovitsky T. M. Selkoe D.J. M. Neuron. 1996; 17: Full Text Full Text PDF PubMed Scopus Google Scholar, X. I. Neuron. 1996; 17: Full Text Full Text PDF PubMed Scopus Google Scholar, X. I. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar), and have also been S. R. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, Proc. Natl. Acad. Sci. U. S. A. 1997; 94: PubMed Scopus Google These are to even of the G. D.R. Lee M.K. L. Kim G. Ratovitsky T. Davenport F. C. M. et al.Neuron. 1996; 17: Full Text Full Text PDF PubMed Scopus Google Scholar, T. Thinakaran G. D.R. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, Citron M. Amarante P. R. Xia W. J. Diehl T. Levesque G. P. Haass C. et 1997; 3: PubMed Scopus Google Scholar, H. Capell A. B. Citron M. Selkoe D.J. H. K. Haass C. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar) and be found the cell M. J. P. M. Selkoe D.J. R. A.M. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). of presenilins leads to of presenilin with the for for and G. T. Davenport F. D.R. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). FAD-causing presenilin are likewise to with a missense mutation in PS1 that leads to the out of a that the cleavage site G. D.R. Lee M.K. L. Kim G. Ratovitsky T. Davenport F. C. M. et al.Neuron. 1996; 17: Full Text Full Text PDF PubMed Scopus Google Scholar, T. Thinakaran G. D.R. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). PS1 variant is an FAD-causing presenilin increased Aβ42 production (19Borchelt D.R. Thinakaran G. Eckman C.B. Lee M.K. Davenport F. Ratovitsky T. Prada C.M. Kim G. Seekins S. Yager D. et al.Neuron. 1996; 17: 1005-1013Abstract Full Text Full Text PDF PubMed Scopus (1329) Google Scholar, H. H. U. B. Citron M. R. Haass C. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). PS1 is to wild-type a of this PS1 variant is in T. Thinakaran G. D.R. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Xia W. M. Mori H. Selkoe D.J. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar) and a molecular the and A. Grunberg J. B. A. Citron M. R. K. Selkoe D.J. Haass C. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar, G. F. M. H. A. T. S. A. Song Rogaeva E. et Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Google Scholar), that can with the same as wild-type These are with the that the of presenilin is the and that the is an However, several have been which are of to H. H. B. U. M. Citron M. H. H. Haass C. Biochemistry. 1999; PubMed Scopus Google Scholar, H. M. H. G. B. Hardy Capell A. L. R. K. Haass C. Biol. 2000; 2: PubMed Scopus Google Scholar). is to the of for biological and the of γ-secretase as an aspartyl protease that an the of presenilins were and found to two to within and the Xia W. Diehl Selkoe D.J. Nature. 1999; PubMed Scopus Google Scholar). These to with within the and with the γ-secretase cleavage in APP (Fig. 1 of to PS1 and these → PS1 in a with to γ-secretase processing of on APP processing were even mutations to Xia W. Diehl Selkoe D.J. Nature. 1999; PubMed Scopus Google Scholar) or H. H. B. U. M. Citron M. H. H. Haass C. Biochemistry. 1999; PubMed Scopus Google Scholar, U. K. H. Walter J. Grunberg J. M. Haass C. Biochemistry. 1999; PubMed Scopus Google Scholar) were the of these two as and that the are because of These have been by several and have been for both PS1 and G. F. M. H. A. T. S. A. Song Rogaeva E. et Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Google Scholar, H. H. B. U. M. Citron M. H. H. Haass C. Biochemistry. 1999; PubMed Scopus Google Xia W. Diehl Selkoe D.J. Nature. 1999; PubMed Scopus Google Scholar, U. K. H. Walter J. Grunberg J. M. Haass C. Biochemistry. 1999; PubMed Scopus Google Scholar, Xia W. T. Selkoe D.J. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, H. K. Capell A. H. S. Hardy Yu, X. M. K. et Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar), a study that the be of with the A. H. H. S. M. R. Haass C. Biol. 2000; 2: PubMed Scopus Google Scholar). The are for γ-secretase of in presenilin mutation in the PS1 variant γ-secretase even though is of this presenilin variant Xia W. Diehl Selkoe D.J. Nature. 1999; PubMed Scopus Google Scholar). these that presenilins be the of with as presenilin the two and the two presenilin to the site of The of because of a in human leads to a variant that is M. S. A. R. H. Walter J. Capell A. H. Haass C. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar), that a be to The presenilins are also for processing of the Notch a for S. Science. 1999; PubMed Scopus Google Scholar). in the Notch is by a protease, in a that is to the cell (Fig. 1 with a the of Notch is by a to tumor necrosis factor-α converting enzyme C. F. N. C. J.R. A. P. Black R.A. A. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, A. X. D.J. R. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). such as and are the identified that the APP (8Lammich S. Kojro E. Postina R. Gilbert S. Pfeiffer R. Jasionowski M. Haass C. Fahrenholz F. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 3922-3927Crossref PubMed Scopus (977) Google Scholar, 9Buxbaum J.D. Liu K.N. Luo Y. Slack J.L. Stocking K.L. Peschon J.J. Johnson R.S. Castner B.J. Cerretti D.P. Black R.A. J. Biol. Chem. 1998; 273: 27765-27767Abstract Full Text Full Text PDF PubMed Scopus (834) Google Scholar). The is within the transmembrane domain to the Notch intracellular domain which to the where with and the family of R. Nature. 1998; PubMed Scopus Google Scholar). formation is for the Notch of a mutation near the transmembrane cleavage site in in an in mice to that of the protein A. R. Nature. 2000; PubMed Scopus Google Scholar). The APP and Notch processing are are both by but also the transmembrane of both are by a protease that of PS1 in mice is with a to that of H. H. D.J. M.E. Nature. 1997; PubMed Scopus Google Scholar, J. Xia W. Selkoe D.J. S. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar), and the double is even A. D. W. P. K. L. L. F. H. et Natl. Acad. Sci. U. S. A. 1999; 96: PubMed Scopus Google D.B. Ikeda M. H. P.S. A. Genes 1999; 13: PubMed Scopus Google Scholar). in PS1 dramatically formation B. W. P. P. K. A. R. Nature. 1999; PubMed Scopus Google Scholar), and the of presenilins in of production A. L. W. D. L. B. Biol. 2000; 2: PubMed Scopus Google Scholar, P. Song W. D. M. A. Biol. 2000; 2: PubMed Scopus Google Scholar). of with γ-secretase inhibitors the transmembrane cleavage site within APP likewise production B. W. P. P. K. A. R. Nature. 1999; PubMed Scopus Google Scholar) and C. P. C. Xia W. G. Selkoe D.J. J. 2000; PubMed Scopus Google Scholar) and Notch a gene C. P. C. Xia W. G. Selkoe D.J. J. 2000; PubMed Scopus Google Scholar). the two in presenilins are for cleavage of the Notch as with γ-secretase of PS1 or in of and M. J. P. M. Selkoe D.J. R. A.M. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, H. K. Capell A. H. S. Hardy Yu, X. M. K. et Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, A. H. H. S. M. R. Haass C. Biol. 2000; 2: PubMed Scopus Google Scholar, C. P. C. Xia W. G. Selkoe D.J. J. 2000; PubMed Scopus Google Scholar). Thus, presenilins are the of the γ-secretases that process are also the of the proteases that the transmembrane of a for the that presenilins be presenilins are found in the and early Levesque L. K. I. G. Westaway D. P.S. B. P. B. J. Biol. 1999; PubMed Scopus Google Scholar), γ-secretase activity on the cell and in the and C. A. Hung A.Y. Selkoe D.J. Nature. 1992; PubMed Scopus Google Scholar, J. D. B. Neuron. 1995; 14: Full Text PDF PubMed Scopus Google Scholar, T. B. P.J. N. D. K. K. Med. 1997; 3: PubMed Scopus Google Scholar, D.G. S. Iwatsubo T. Lee R.W. Med. 1997; 3: PubMed Scopus Google Scholar, S. J.D. B. Xia W. Selkoe D.J. X. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, C. T. Capell A. U. H. Ihara Y. Haass C. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). of presenilin have been found the cell in with the of Notch M. J. P. M. Selkoe D.J. R. A.M. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar), and of this should be for this is that the of APP and Notch with presenilins in the W. J. R. Selkoe D.J. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: PubMed Scopus Google Scholar, A. K. U. C. G. K. Med. 1997; 3: PubMed Scopus Google Scholar, M. P. J. W. Wu R. A.M. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: PubMed Scopus Google Scholar). APP and Notch are substrates for with presenilin presenilin is the However, as the of Notch likewise M. J. P. M. Selkoe D.J. R. A.M. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar), and and can also with presenilins in the of a γ-secretase or presenilin is W. T. J. A.M. Selkoe D.J. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: PubMed Scopus Google Scholar). presenilins with APP or are the site and specificity of Notch cleavage that of Notch to be within its transmembrane the site of cleavage is to the the APP γ-secretase site is in the middle of the cleavage of the has been the this for sequence a to Leu of the Notch transmembrane R. Nature. 1998; PubMed Scopus Google Scholar), a of mutations in the APP transmembrane is by of these events in purified enzyme insights to this that APP but also Notch of sequence G. A. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). the of γ-secretase and the of presenilins in this activity been by the of an enzyme Li et M. J. M.K. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: PubMed Scopus Google Scholar) a γ-secretase that the of the protease activity in were with and γ-secretase activity was by Aβ production a of Aβ40 and Aβ42 were in the same as in and that Aβ40 and Aβ42 formation in likewise production of these Aβ in the protease of the by γ-secretase activity with the two of PS1 also Aβ the that presenilins are of a γ-secretase that presenilins are the of γ-secretases has studies inhibitors to the site of the et M. J. M.K. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: PubMed Scopus Google Scholar, D. T. P. A. G. J.L. Biochemistry. 2000; PubMed Scopus Google Scholar) identified a that γ-secretase activity with an of in the protease and a a found in aspartyl protease the the to aspartyl of this to presenilin M. J.L. J. T. C. A. M.K. Nature. 2000; PubMed Scopus Google Scholar). of the on of the to of the presenilin on the in the of the these wild-type PS1 PS1 which is to but is et Diehl T. Xia W. Selkoe D.J. Biol. 2000; 2: PubMed Scopus Google Scholar) identified inhibitors a of and these were a the γ-secretase cleavage site in of such to a an that likewise and to PS1 in cell and PS1 be with to the that the to and D. J.D. C.M. F. Jr., Wang et Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar) likewise identified presenilin as the molecular of γ-secretase These is be to to the site of the these that presenilins the of inhibitors in two of the studies are to the The site is the both are by γ-secretase and The studies also identify the protease for the transmembrane cleavage of because γ-secretase inhibitors by et Diehl T. Xia W. Selkoe D.J. Biol. 2000; 2: PubMed Scopus Google Scholar) also this Notch These findings the amyloid of AD FAD-causing mutations identified to for of FAD are in the precursor protein leading to Aβ (APP) or to be in the proteases that the in Aβ At the same time, an important for drug has been is of cleavage of γ-secretase substrates presenilins are for the of these in is The that presenilins are γ-secretases a of fascinating with to protease biochemistry as as protease out in a the transmembrane a or with to of and with the such a site and the of the the with a site on the of the protease, with of the to the site within the protease that the of the with the protease is an the enzyme have some for or the near the site of cleavage that the and protease can the for the of presenilins and proteases J. Xia W. Selkoe D.J. Biochemistry. 1999; PubMed Scopus Google Scholar), that polytopic a for than that proteases somehow transmembrane polytopic proteases or sequence with in the family of proteases that process in and an that is a sequence for a of D. J. J. J.L. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). to presenilins two for but aspartyl are a very of to the of as to polytopic proteases are to of and membrane-tethered the presenilins a near of the that is also found in the protease family H. M. H. G. B. Hardy Capell A. L. R. K. Haass C. Biol. 2000; 2: PubMed Scopus Google Scholar, H. Haass C. et al.Nat. Google Scholar), polytopic aspartyl proteases that also have transmembrane and two J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). finding the that presenilins indeed be polytopic aspartyl to the is to identify the of the γ-secretase of activity and of a purified enzyme of the into γ-secretase should studies than the of in or the than different FAD mutations in presenilins cause increases in Aβ42 production some on this can be in of Aβ should to AD but should also of the of an of polytopic

Source: Journal of Biological Chemistry

DOI: 10.1074/jbc.r000026200

Authors: Michael S. Wolfe, Christian Haass

Institutions: Brigham and Women's Hospital, Harvard University, Adolf-Butenandt-Institut für Physiologische Chemie, Physikalische Biochemie und Zellbiologie, Ludwig-Maximilians-Universität München

Language: English

Topic: Alzheimer's disease research and treatments

Subfield: Physiology (medical)

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,430