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Cited by 118Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Dissociation between the Processivity and Total Activity of γ-Secretase: Implications for the Mechanism of Alzheimer's Disease-Causing Presenilin Mutations

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Quintero-Monzon, Omar, Martin, Morgan M., Fernandez, Marty A., Cappello, Christina A., Krzysiak, Amanda J., Osenkowski, Pamela, Wolfe, Michael S.·2011·Biochemistry
DOI 10.1021/bi2007146PMC PMC3205908
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Abstract

The amyloid β-peptide (Aβ), strongly implicated in the pathogenesis of Alzheimer's disease (AD), is produced from the amyloid β-protein precursor (APP) through consecutive proteolysis by β- and γ-secretases. The latter protease contains presenilin as the catalytic component of a membrane-embedded aspartyl protease complex. Missense mutations in presenilin are associated with early-onset familial AD, and these mutations generally both decrease Aβ production and increase the ratio of the aggregation-prone 42-residue form (Aβ42) to the 40-residue form (Aβ40). The connection between these two effects is not understood. Besides Aβ40 and Aβ42, γ-secretase produces a range of Aβ peptides, the result of initial cutting at the ε site to form Aβ48 or Aβ49 and subsequent trimming every three or four residues. Thus, γ-secretase displays both overall proteolytic activity (ε cutting) and processivity (trimming) toward its substrate APP. Here we tested whether a decrease in total activity correlates with decreased processivity using wild-type and AD-mutant presenilin-containing protease complexes. Changes in pH, temperature, and salt concentration that reduced the overall activity of the wild-type enzyme did not consistently result in increased proportions of longer Aβ peptides. Low salt concentrations and acidic pH were notable exceptions that subtly alter the proportion of individual Aβ peptides, suggesting that the charged state of certain residues may influence processivity. Five different AD mutant complexes, representing a broad range of effects on overall activity, Aβ42:Aβ40 ratios, and ages of disease onset, were also tested, revealing again that changes in total activity and processivity can be dissociated. Factors that control initial proteolysis of APP at the ε site apparently differ significantly from factors affecting subsequent trimming and the distribution of Aβ peptides.

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  • PSEN1 mutations increase the faster release of long Aβ peptide species due to altered carboxypeptidase-like γ-secretase activity that increases the proportion of Aβ42, Aβ43, and even longer Aβ peptide species.

    “PSEN1 mutations increase the faster release of long A 𝛃 peptide species due to altered carboxypeptidase-like 𝛄 -secretase activity that increases the proportion of A 𝛃 42, A 𝛃 43, and even longer A 𝛃 peptide species (A 𝛃 45, A 𝛃 46) (104, 172, 489, 572).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [489]

    The Results (page unavailable) report that all five tested PS1-mutant complexes increased the proportion of longer Aβ peptides, including Aβ43 and, for some mutants, peptides of at least 46 residues. The Discussion (page unavailable) attributes this pattern to reduced γ-secretase processivity. The paper does not establish faster release of those peptides; it says longer forms are poorly secreted and the longest forms are not secreted at all. It also reports decreased Aβ45 for one mutant, so the increase does not apply to every listed species. (LLM, conf=0.87)

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Research works printed but not linked: 69

  1. [1]Glenner GG Wong CW 1984 Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein Biochem Biophys Res Comm 120 885 890 6375662
  2. [2]Masters CL Simms G Weinman NA Multhaup G McDonald BL Beyreuther K 1985 Amyloid plaque core protein in Alzheimer disease and Down syndrome Proc Natl Acad Sci U S A 82 4245 4249 3159021 PMC397973
  3. [3]Cole SL Vassar R 2008 The role of APP processing by BACE1, the beta-secretase, in Alzheimer’s disease pathophysiology J Biol Chem 283 29621 29625 18650431 PMC2662048
  4. [4]Wolfe MS 2006 The gamma-secretase complex: membrane-embedded proteolytic ensemble Biochemistry 45 7931 7939 16800619
  5. [5]Jarrett JT Berger EP Lansbury PT Jr 1993 The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer’s disease Biochemistry 32 4693 4697 8490014
  6. [8]Shankar GM Li S Mehta TH Garcia-Munoz A Shepardson NE Smith I Brett FM Farrell MA Rowan MJ Lemere CA Regan CM Walsh DM Sabatini BL Selkoe DJ 2008 Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory Nat Med 14 837 842 18568035 PMC2772133
  7. [9]Tanzi RE Bertram L 2005 Twenty years of the Alzheimer’s disease amyloid hypothesis: a genetic perspective Cell 120 545 555 15734686
  8. [10]Francis R McGrath G Zhang J Ruddy DA Sym M Apfeld J Nicoll M Maxwell M Hai B Ellis MC Parks AL Xu W Li J Gurney M Myers RL Himes CS Hiebsch R Ruble C Nye JS Curtis D 2002 aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of betaAPP, and presenilin protein accumulation Dev Cell 3 85 97 12110170
  9. [11]Takasugi N Tomita T Hayashi I Tsuruoka M Niimura M Takahashi Y Thinakaran G Iwatsubo T 2003 The role of presenilin cofactors in the gamma-secretase complex Nature 422 438 441 12660785
  10. [12]Kimberly WT LaVoie MJ Ostaszewski BL Ye W Wolfe MS Selkoe DJ 2003 γ-Secretase is a membrane protein complex comprised of presenilin, nicastrin, aph-1, and pen-2 Proc Natl Acad Sci U S A 100 6382 6387 12740439 PMC164455
  11. [13]Edbauer D Winkler E Regula JT Pesold B Steiner H Haass C 2003 Reconstitution of gamma-secretase activity Nat Cell Biol 5 486 488 12679784
  12. [14]Wolfe MS Xia W Ostaszewski BL Diehl TS Kimberly WT Selkoe DJ 1999 Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity Nature 398 513 517 10206644
  13. [15]Li YM Xu M Lai MT Huang Q Castro JL DiMuzio-Mower J Harrison T Lellis C Nadin A Neduvelil JG Register RB Sardana MK Shearman MS Smith AL Shi XP Yin KC Shafer JA Gardell SJ 2000 Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1 Nature 405 689 694 10864326
  14. [16]Esler WP Kimberly WT Ostaszewski BL Diehl TS Moore CL Tsai JY Rahmati T Xia W Selkoe DJ Wolfe MS 2000 Transition-state analogue inhibitors of γ-secretase bind directly to presenilin-1 Nature Cell Biology 2 428 434 10878808
  15. [17]Kaether C Capell A Edbauer D Winkler E Novak B Steiner H Haass C 2004 The presenilin C-terminus is required for ER-retention, nicastrin-binding and gamma-secretase activity Embo J 23 4738 4748 15549135 PMC535090
  16. [18]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 Price DL Sisodia SS 1996 Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo Neuron 17 181 190 8755489
  17. [19]Ratovitski T Slunt HH Thinakaran G Price DL Sisodia SS Borchelt DR 1997 Endoproteolytic processing and stabilization of wild-type and mutant presenilin J Biol Chem 272 24536 24541 9305918
  18. [20]Thinakaran G Harris CL Ratovitski T Davenport F Slunt HH Price DL Borchelt DR Sisodia SS 1997 Evidence that levels of presenilins (PS1 and PS2) are coordinately regulated by competition for limiting cellular factors J Biol Chem 272 28415 28422 9353300
  19. [21]Edbauer D Winkler E Haass C Steiner H 2002 Presenilin and nicastrin regulate each other and determine amyloid beta-peptide production via complex formation Proc Natl Acad Sci U S A 99 8666 8671 12048259 PMC124353
  20. [22]Arawaka S Hasegawa H Tandon A Janus C Chen F Yu G Kikuchi K Koyama S Kato T Fraser PE St George-Hyslop P 2002 The levels of mature glycosylated nicastrin are regulated and correlate with gamma-secretase processing of amyloid beta-precursor protein J Neurochem 83 1065 1071 12437577
  21. [23]Kimberly WT LaVoie MJ Ostaszewski BL Ye W Wolfe MS Selkoe DJ 2002 Complex N-linked glycosylated nicastrin associates with active gamma-secretase and undergoes tight cellular regulation J Biol Chem 277 35113 35117 12130643
  22. [24]Leem JY Vijayan S Han P Cai D Machura M Lopes KO Veselits ML Xu H Thinakaran G 2002 Presenilin 1 is required for maturation and cell surface accumulation of nicastrin J Biol Chem 277 19236 19240 11943765
  23. [25]Tomita T Katayama R Takikawa R Iwatsubo T 2002 Complex N-glycosylated form of nicastrin is stabilized and selectively bound to presenilin fragments FEBS Lett 520 117 121 12044882
  24. [26]Kornilova AY Bihel F Das C Wolfe MS 2005 The initial substrate-binding site of gamma-secretase is located on presenilin near the active site Proc Natl Acad Sci U S A 102 3230 3235 15722417 PMC552920
  25. [27]Weidemann A Eggert S Reinhard FB Vogel M Paliga K Baier G Masters CL Beyreuther K Evin G 2002 A Novel var epsilon-Cleavage within the Transmembrane Domain of the Alzheimer Amyloid Precursor Protein Demonstrates Homology with Notch Processing Biochemistry 41 2825 2835 11851430
  26. [28]Kakuda N Funamoto S Yagishita S Takami M Osawa S Dohmae N Ihara Y 2006 Equimolar production of amyloid beta-protein and amyloid precursor protein intracellular domain from beta-carboxyl-terminal fragment by gamma-secretase J Biol Chem 281 14776 14786 16595682
  27. [29]Sato T Dohmae N Qi Y Kakuda N Misonou H Mitsumori R Maruyama H Koo EH Haass C Takio K Morishima-Kawashima M Ishiura S Ihara Y 2003 Potential link between amyloid beta-protein 42 and C-terminal fragment gamma 49–99 of beta-amyloid precursor protein J Biol Chem 278 24294 24301 12707272
  28. [30]Qi-Takahara Y Morishima-Kawashima M Tanimura Y Dolios G Hirotani N Horikoshi Y Kametani F Maeda M Saido TC Wang R Ihara Y 2005 Longer forms of amyloid beta protein: implications for the mechanism of intramembrane cleavage by gamma-secretase J Neurosci 25 436 445 15647487 PMC6725472
  29. [31]Funamoto S Morishima-Kawashima M Tanimura Y Hirotani N Saido TC Ihara Y 2004 Truncated carboxyl-terminal fragments of beta-amyloid precursor protein are processed to amyloid beta-proteins 40 and 42 Biochemistry 43 13532 13540 15491160
  30. [32]Takami M Nagashima Y Sano Y Ishihara S Morishima-Kawashima M Funamoto S Ihara Y 2009 gamma-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment J Neurosci 29 13042 13052 19828817 PMC6665297
  31. [33]Sato T Diehl TS Narayanan S Funamoto S Ihara Y De Strooper B Steiner H Haass C Wolfe MS 2007 Active gamma-secretase complexes contain only one of each component J Biol Chem 282 33985 33993 17911105
  32. [34]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 S 1996 Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1 Nature 383 710 713 8878479
  33. [35]Citron M Westaway D Xia W Carlson G Diehl T 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 beta-protein in both transfected cells and transgenic mice Nat Med 3 67 72 8986743
  34. [37]Lemere CA Lopera F Kosik KS Lendon CL Ossa J Saido TC Yamaguchi H Ruiz A Martinez A Madrigal L Hincapie L Arango JC Anthony DC Koo EH Goate AM Selkoe DJ Arango JC 1996 The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 deposition and severe cerebellar pathology Nat Med 2 1146 1150 8837617
  35. [38]Song W Nadeau P Yuan M Yang X Shen J Yankner BA 1999 Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations Proc Natl Acad Sci U S A 96 6959 6963 10359821 PMC22024
  36. [40]Wolfe MS 2007 When loss is gain: reduced presenilin proteolytic function leads to increased Abeta42/Abeta40. Talking Point on the role of presenilin mutations in Alzheimer disease EMBO Rep 8 136 140 17268504 PMC1796780
  37. [41]De Strooper B 2007 Loss-of-function presenilin mutations in Alzheimer disease. Talking Point on the role of presenilin mutations in Alzheimer disease EMBO Rep 8 141 146 17268505 PMC1796779
  38. [42]Li YM Lai MT Xu M Huang Q DiMuzio-Mower J Sardana MK Shi XP Yin KC Shafer JA Gardell SJ 2000 Presenilin 1 is linked with gamma-secretase activity in the detergent solubilized state Proc Natl Acad Sci U S A 97 6138 6143 10801983 PMC18571
  39. [43]Cacquevel M Aeschbach L Osenkowski P Li D Ye W Wolfe MS Li H Selkoe DJ Fraering PC 2008 Rapid purification of active gamma-secretase, an intramembrane protease implicated in Alzheimer’s disease J Neurochem 104 210 220 17986218
  40. [44]Klafki H Abramowski D Swoboda R Paganetti PA Staufenbiel M 1996 The carboxyl termini of beta-amyloid peptides 1–40 and 1–42 are generated by distinct gamma-secretase activities J Biol Chem 271 28655 28659 8910499
  41. [45]Tarlton JF Knight PJ 1996 Comparison of reflectance and transmission densitometry, using document and laser scanners, for quantitation of stained Western blots Anal Biochem 237 123 128 8660546
  42. [46]Osenkowski P Li H Ye W Li D Aeschbach L Fraering PC Wolfe MS Selkoe DJ Li H 2009 Cryoelectron microscopy structure of purified gamma-secretase at 12 A resolution J Mol Biol 385 642 652 19013469 PMC2830092
  43. [47]Osenkowski P Ye W Wang R Wolfe MS Selkoe DJ 2008 Direct and potent regulation of gamma-secretase by its lipid microenvironment J Biol Chem 283 22529 22540 18539594 PMC2504869
  44. [48]Fraering PC Ye W Strub JM Dolios G LaVoie MJ Ostaszewski BL Van Dorsselaer A Wang R Selkoe DJ Wolfe MS 2004 Purification and Characterization of the Human gamma-Secretase Complex Biochemistry 43 9774 9789 15274632
  45. [49]Moehlmann T Winkler E Xia X Edbauer D Murrell J Capell A Kaether C Zheng H Ghetti B Haass C Steiner H 2002 Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Abeta 42 production Proc Natl Acad Sci U S A 99 8025 8030 12048239 PMC123014
  46. [50]Bentahir M Nyabi O Verhamme J Tolia A Horre K Wiltfang J Esselmann H De Strooper B 2006 Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms J Neurochem 96 732 742 16405513
  47. [51]Steiner H Kostka M Romig H Basset G Pesold B Hardy JA Capell A Meyn L Grim MG Baumeister R Fechteler K Haass C 2000 Glycine 384 is required for presenilin-1 function and is conserved in bacterial polytopic aspartyl proteases Nature Cell Biol 2 848 851 11056541
  48. [52]De Jonghe C Cras P Vanderstichele H Cruts M Vanderhoeven I Smouts I Vanmechelen E Martin JJ Hendriks L Van Broeckhoven C 1999 Evidence that Abeta42 plasma levels in presenilin-1 mutation carriers do not allow for prediction of their clinical phenotype Neurobiol Dis 6 280 287 10448055
  49. [53]Cruts M Backhovens H Wang SY Van Gassen G Theuns J De Jonghe CD Wehnert A De Voecht J De Winter G Cras P 1995 Molecular genetic analysis of familial early-onset Alzheimer’s disease linked to chromosome 14q24.3 Hum Mol Genet 4 2363 2371 8634711
  50. [54]Sherrington R Rogaev EI Liang Y Rogaeva EA Levesque G Ikeda M Chi H Lin C Li G Holman K 1995 Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease Nature 375 754 760 7596406
  51. [55]Capell A Grunberg J Pesold B Diehlmann A Citron M Nixon R Beyreuther K Selkoe DJ Haass C 1998 The proteolytic fragments of the Alzheimer’s disease-associated presenilin-1 form heterodimers and occur as a 100–150-kDa molecular mass complex J Biol Chem 273 3205 3211 9452432
  52. [56]Zhang J Kang DE Xia W Okochi M Mori H Selkoe DJ Koo EH 1998 Subcellular distribution and turnover of presenilins in transfected cells J Biol Chem 273 12436 12442 9575200
  53. [57]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 signalling independently of proteolytic processing Genes and Function 1 149 159 9680315
  54. [59]Maruyama K Tomita T Shinozaki K Kume H Asada H Saido TC Ishiura S Iwatsubo T Obata K 1996 Familial Alzheimer’s disease-linked mutations at Val717 of amyloid precursor protein are specific for the increased secretion of A beta 42(43) Biochem Biophys Res Commun 227 730 735 8886002
  55. [60]Kounnas MZ Danks AM Cheng S Tyree C Ackerman E Zhang X Ahn K Nguyen P Comer D Mao L Yu C Pleynet D Digregorio PJ Velicelebi G Stauderman KA Comer WT Mobley WC Li YM Sisodia SS Tanzi RE Wagner SL 2010 Modulation of gamma-secretase reduces beta-amyloid deposition in a transgenic mouse model of Alzheimer’s disease Neuron 67 769 780 20826309 PMC2947312
  56. [61]Tokuda T Fukushima T Ikeda S Sekijima Y Shoji S Yanagisawa N Tamaoka A 1997 Plasma levels of amyloid beta proteins Abeta1–40 and Abeta1–42(43) are elevated in Down’s syndrome Ann Neurol 41 271 273 9029078
  57. [62]Czirr E Cottrell BA Leuchtenberger S Kukar T Ladd TB Esselmann H Paul S Schubenel R Torpey JW Pietrzik CU Golde TE Wiltfang J Baumann K Koo EH Weggen S 2008 Independent generation of Abeta42 and Abeta38 peptide species by gamma-secretase J Biol Chem 283 17049 17054 18426795
  58. [63]Saito T Suemoto T Brouwers N Sleegers K Funamoto S Mihira N Matsuba Y Yamada K Nilsson P Takano J Nishimura M Iwata N Van Broeckhoven C Ihara Y Saido TC 2011 Potent amyloidogenicity and pathogenicity of Abeta43 Nat Neurosci in press 21725313
  59. [64]Walker ES Martinez M Brunkan AL Goate A 2005 Presenilin 2 familial Alzheimer’s disease mutations result in partial loss of function and dramatic changes in Abeta 42/40 ratios J Neurochem 92 294 301 15663477
  60. [65]Kumar-Singh S Theuns J Van Broeck B Pirici D Vennekens K Corsmit E Cruts M Dermaut B Wang R Van Broeckhoven C 2006 Mean age-of-onset of familial alzheimer disease caused by presenilin mutations correlates with both increased Abeta42 and decreased Abeta40 Hum Mutat 27 686 695 16752394
  61. [66]Shimojo M Sahara N Murayama M Ichinose H Takashima A 2007 Decreased Abeta secretion by cells expressing familial Alzheimer’s disease-linked mutant presenilin 1 Neurosci Res 57 446 453 17210196
  62. [67]Fluhrer R Fukumori A Martin L Grammer G Haug-Kroper M Klier B Winkler E Kremmer E Condron MM Teplow DB Steiner H Haass C 2008 Intramembrane proteolysis of GXGD-type aspartyl proteases is slowed by a familial Alzheimer disease-like mutation J Biol Chem 283 30121 30128 18768471 PMC2573083
  63. [68]Page RM Baumann K Tomioka M Perez-Revuelta BI Fukumori A Jacobsen H Flohr A Luebbers T Ozmen L Steiner H Haass C 2008 Generation of Abeta38 and Abeta42 is independently and differentially affected by familial Alzheimer disease-associated presenilin mutations and gamma-secretase modulation J Biol Chem 283 677 683 17962197
  64. [69]Kretner B Fukumori A Gutsmiedl A Page RM Luebbers T Galley G Baumann K Haass C Steiner H 2011 Attenuated A{beta}42 Responses to Low Potency {gamma}-Secretase Modulators Can Be Overcome for Many Pathogenic Presenilin Mutants by Second-generation Compounds J Biol Chem 286 15240 15251 21357415 PMC3083200
  65. [70]Qi Y Morishima-Kawashima M Sato T Mitsumori R Ihara Y 2003 Distinct mechanisms by mutant presenilin 1 and 2 leading to increased intracellular levels of amyloid beta-protein 42 in Chinese hamster ovary cells Biochemistry 42 1042 1052 12549925
  66. [71]Jankowsky JL Fadale DJ Anderson J Xu GM Gonzales V Jenkins NA Copeland NG Lee MK Younkin LH Wagner SL Younkin SG Borchelt DR 2004 Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase Hum Mol Genet 13 159 170 14645205
  67. [72]Winkler E Hobson S Fukumori A Dumpelfeld B Luebbers T Baumann K Haass C Hopf C Steiner H 2009 Purification, pharmacological modulation, and biochemical characterization of interactors of endogenous human gamma-secretase Biochemistry 48 1183 1197 19159235
  68. [73]Fukumori A Fluhrer R Steiner H Haass C 2010 Three-amino acid spacing of presenilin endoproteolysis suggests a general stepwise cleavage of gamma-secretase-mediated intramembrane proteolysis J Neurosci 30 7853 7862 20534834 PMC6632680
  69. [75]Okochi M Fukumori A Jiang J Itoh N Kimura R Steiner H Haass C Tagami S Takeda M 2006 Secretion of the Notch-1 Abeta-like peptide during Notch signaling J Biol Chem 281 7890 7898 16434391

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Authors
Quintero-Monzon, O., Martin, M. M., Fernandez, M. A., Cappello, C. A., Krzysiak, A. J., Osenkowski, P., & Wolfe, M. S.
Affiliations
  • Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States
  • Brigham and Women's Hospital (US)
Corresponding author
Wolfe, Michael S.
ORCID
Venue
Biochemistry
Publisher
American Chemical Society (ACS)
Published
2011-09-30
Volume
50
Issue
42
Pages
9023-9035
ISSN
  • 0006-2960 (ISSN-L)
  • 1520-4995
DOI
10.1021/bi2007146
PMC
PMC3205908
OpenAlex
W2162588539
Cited by
118
References
5
Citations by year
2026: 5 · 2025: 4 · 2024: 6 · 2023: 2 · 2022: 10 · 2021: 10 · 2020: 12 · 2019: 13 · 2018: 7 · 2017: 3 · 2016: 13 · 2015: 7 · 2014: 7 · 2013: 8 · 2012: 11
FWCI
5.67
Type
journal article
Language
en
Open access
Locations
  • Biochemistry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Howard Hughes Medical Institute
  • F. Hoffmann-La Roche
  • National Institute on Aging (R01 AG17575, R01AG017574)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
gamma-secretase, presenilin mutations, Alzheimer's disease, amyloid-beta, processivity, proteolytic activity, APP proteolysis, pH and salt effects, aspartic protease
MeSH terms
Alzheimer Disease, Animals, Cell Line, Enzyme Activation, Cricetinae, Humans, Peptide Fragments, Protein Processing, Post-Translational, Substrate Specificity, Amyloid beta-Peptides, Mutagenesis, Site-Directed, CHO Cells, Amyloid beta-Protein Precursor, Catalytic Domain, Presenilin-1, Presenilin-2, Amyloid Precursor Protein Secretases, Proteolysis

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