BMB Reports

생화학분자생물학회 (Korean Society for Biochemistry and Molecular Biology)
권호 표지
DOI QR코드

DOI QR Code

Distinctive contribution of two additional residues in protein aggregation of Aβ42 and Aβ40 isoforms

  • Dongjoon Im (Department of Life Sciences, Korea University) ;
  • Tae Su Choi (Department of Life Sciences, Korea University)
  • 투고 : 2024.03.20
  • 심사 : 2024.04.26
  • 발행 : 2024.06.30
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Amyloid-β (Aβ) is one of the amyloidogenic intrinsically disordered proteins (IDPs) that self-assemble to protein aggregates, incurring cell malfunction and cytotoxicity. While Aβ has been known to regulate multiple physiological functions, such as enhancing synaptic functions, aiding in the recovery of the blood-brain barrier/brain injury, and exhibiting tumor suppression/antimicrobial activities, the hydrophobicity of the primary structure promotes pathological aggregations that are closely associated with the onset of Alzheimer's disease (AD). Aβ proteins consist of multiple isoforms with 37-43 amino acid residues that are produced by the cleavage of amyloid-β precursor protein (APP). The hydrolytic products of APP are secreted to the extracellular regions of neuronal cells. Aβ 1-42 (Aβ42) and Aβ 1-40 (Aβ40) are dominant isoforms whose significance in AD pathogenesis has been highlighted in numerous studies to understand the molecular mechanism and develop AD diagnosis and therapeutic strategies. In this review, we focus on the differences between Aβ42 and Aβ40 in the molecular mechanism of amyloid aggregations mediated by the two additional residues (Ile41 and Ala42) of Aβ42. The current comprehension of Aβ42 and Aβ40 in AD progression is outlined, together with the structural features of Aβ42/Aβ40 amyloid fibrils, and the aggregation mechanisms of Aβ42/Aβ40. Furthermore, the impact of the heterogeneous distribution of Aβ isoforms during amyloid aggregations is discussed in the system mimicking the coexistence of Aβ42 and Aβ40 in human cerebrospinal fluid (CSF) and plasma.

키워드

과제정보

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. RS-2023-00213155 and RS-2023-00221182 to T.S.C. & RS-2023-00274504 to D.I.), and the Korea Basic Science Institute (KBSI) National Research Facilities & Equipment Center (NFEC) funded by the Korea government (Ministry of Education) (2019R1A6C1010028 to T.S.C.). Figures were created with Biorender.com and all graphics related to fibril structures were produced using PyMOL (98).

참고문헌

  1. No authors listed (2023) 2023 Alzheimer's disease facts and figures. Alzheimers Dement 19, 1598-1695 https://doi.org/10.1002/alz.13016
  2. Gustavsson A, Norton N, Fast T et al (2023) Global estimates on the number of persons across the Alzheimer's disease continuum. Alzheimers Dement 19, 658-670 https://doi.org/10.1002/alz.12694
  3. Kepp KP, Robakis NK, Hoilund-Carlsen PF, Sensi SL and Vissel B (2023) The amyloid cascade hypothesis: an updated critical review. Brain 146, 3969-3990 https://doi.org/10.1093/brain/awad159
  4. Karran E, Mercken M and Strooper BD (2011) The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 10, 698-712 https://doi.org/10.1038/nrd3505
  5. Portugal Barron D and Guo Z (2024) The supersaturation perspective on the amyloid hypothesis. Chem Sci 15, 46-54 https://doi.org/10.1039/D3SC03981A
  6. An J, Kim K, Lim HJ et al (2024) Early onset diagnosis in Alzheimer's disease patients via amyloid-β oligomers-sensing probe in cerebrospinal fluid. Nat Commun 15, 1004
  7. Ashe KH (2020) The biogenesis and biology of amyloid beta oligomers in the brain. Alzheimers Dement 16, 1561-1567 https://doi.org/10.1002/alz.12084
  8. Yang Y, Arseni D, Zhang W et al (2022) Cryo-EM structures of amyloid-β 42 filaments from human brains. Science 375, 167-172 https://doi.org/10.1126/science.abm7285
  9. Kollmer M, Close W, Funk L et al (2019) Cryo-EM structure and polymorphism of Aβ amyloid fibrils purified from Alzheimer's brain tissue. Nat Commun 10, 4760
  10. Querol-Vilaseca M, Colom-Cadena M, Pegueroles J et al (2019) Nanoscale structure of amyloid-β plaques in Alzheimer's disease. Sci Rep 9, 5181
  11. Viles JH (2023) Imaging amyloid-β membrane interactions: ion-channel pores and lipid-bilayer permeability in Alzheimer's disease. Angew Chem Int Ed 62, e202215785
  12. Palop JJ and Mucke L (2010) Amyloid-β-induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networks. Nat Neurosci 13, 812-818 https://doi.org/10.1038/nn.2583
  13. Naia L, Shimozawa M, Bereczki E et al (2023) Mitochondrial hypermetabolism precedes impaired autophagy and synaptic disorganization in App knock-in Alzheimer mouse models. Mol Psychiatry 28, 3966-3981 https://doi.org/10.1038/s41380-023-02289-4
  14. Calvo-Rodriguez M, Hou SS, Snyder AC et al (2020) Increased mitochondrial calcium levels associated with neuronal death in a mouse model of Alzheimer's disease. Nat Commun 11, 2146
  15. Wang L, Benzinger TL, Su Y et al (2016) Evaluation of tau imaging in staging alzheimer disease and revealing interactions between β-amyloid and tauopathy. JAMA Neurol 73, 1070-1077 https://doi.org/10.1001/jamaneurol.2016.2078
  16. Le LTHL, Lee J, Im D et al (2023) Self-aggregating tau fragments recapitulate pathologic phenotypes and neurotoxicity of Alzheimer's disease in mice. Adv Sci 10, 2302035
  17. He Z, Guo JL, McBride JD et al (2018) Amyloid-β plaques enhance Alzheimer's brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat Med 24, 29-38 https://doi.org/10.1038/nm.4443
  18. Lewis J, Dickson DW, Lin WL et al (2001) Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293, 1487-1491 https://doi.org/10.1126/science.1058189
  19. Gotz J, Chen F, van Dorpe J and Nitsch RM (2001) Formation of neurofibrillary tangles in P301L tau transgenic mice induced by Aβ42 fibrils. Science 293, 1491-1495 https://doi.org/10.1126/science.1062097
  20. Busche MA and Hyman BT (2020) Synergy between amyloid-β and tau in Alzheimer's disease. Nat Neurosci 23, 1183-1193 https://doi.org/10.1038/s41593-020-0687-6
  21. Hansson O, Lehmann S, Otto M, Zetterberg H and Lewczuk P (2019) Advantages and disadvantages of the use of the CSF Amyloid β (Aβ) 42/40 ratio in the diagnosis of Alzheimer's disease. Alzheimer's Res Ther 11, 34
  22. Delaby C, Estelles T, Zhu N et al (2022) The Aβ1-42/Aβ1-40 ratio in CSF is more strongly associated to tau markers and clinical progression than Aβ1-42 alone. Alzheimer's Res Ther 14, 20
  23. Leuzy A, Mattsson-Carlgren N, Palmqvist S, Janelidze S, Dage JL and Hansson O (2022) Blood-based biomarkers for Alzheimer's disease. EMBO Mol Med 14, e14408
  24. Brand AL, Lawler PE, Bollinger JG et al (2022) The performance of plasma amyloid beta measurements in identifying amyloid plaques in Alzheimer's disease: a literature review. Alzheimers Res Ther 14, 195
  25. Chapleau M, Iaccarino L, Soleimani-Meigooni D and Rabinovici GD (2022) The role of amyloid PET in imaging neurodegenerative disorders: a review. J Nucl Med 63, S13-S19 https://doi.org/10.2967/jnumed.121.263195
  26. Sperling RA, Aisen PS, Beckett LA et al (2011) Toward defining the preclinical stages of Alzheimer's disease: recommendations from the national institute on aging-Alzheimer's association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 7, 280-292 https://doi.org/10.1016/j.jalz.2011.03.003
  27. Hansson O (2021) Biomarkers for neurodegenerative diseases. Nat Med 27, 954-963 https://doi.org/10.1038/s41591-021-01382-x
  28. Ovod V, Ramsey KN, Mawuenyega KG et al (2017) Amyloid β concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis. Alzheimers Dement 13, 841-849 https://doi.org/10.1016/j.jalz.2017.06.2266
  29. Lewczuk P, Lelental N, Spitzer P, Maler JM and Kornhuber J (2015) Amyloid-β 42/40 cerebrospinal fluid concentration ratio in the diagnostics of Alzheimer's disease: validation of two novel assays. J Alzheimer's Dis 43, 183-191 https://doi.org/10.3233/JAD-140771
  30. Sevigny J, Chiao P, Bussiere T et al (2016) The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Nature 537, 50-56 https://doi.org/10.1038/nature19323
  31. Cummings J, Aisen P, Apostolova LG, Atri A, Salloway S and Weiner M (2021) Aducanumab: appropriate use recommendations. J Prev Alzheimers Dis 8, 398-410 https://doi.org/10.14283/jpad.2021.41
  32. van Dyck CH, Swanson CJ, Aisen P et al (2022) Lecanemab in early Alzheimer's disease. N Engl J Med 388, 9-21 https://doi.org/10.1056/NEJMoa2212948
  33. Sims JR, Zimmer JA, Evans CD et al (2023) Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZERALZ 2 randomized clinical trial. JAMA 330, 512-527 https://doi.org/10.1001/jama.2023.13239
  34. Muller UC, Deller T and Korte M (2017) Not just amyloid: physiological functions of the amyloid precursor protein family. Nat Rev Neurosci 18, 281-298 https://doi.org/10.1038/nrn.2017.29
  35. O'Brien RJ and Wong PC (2011) Amyloid precursor protein processing and Alzheimer's disease. Annu Rev Neurosci 34, 185-204 https://doi.org/10.1146/annurev-neuro-061010-113613
  36. Brothers HM, Gosztyla ML and Robinson SR (2018) The physiological roles of amyloid-β peptide hint at new ways to treat Alzheimer's disease. Front Aging Neurosci 10, 118
  37. Kummer MP and Heneka MT (2014) Truncated and modified amyloid-beta species. Alzheimer's Res Ther 6, 28
  38. Esch FS, Keim PS, Beattie EC et al (1990) Cleavage of amyloid β peptide during constitutive processing of its precursor. Science 248, 1122-1124 https://doi.org/10.1126/science.2111583
  39. Vassar R, Bennett BD, Babu-Khan S et al (1999) β-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735-741 https://doi.org/10.1126/science.286.5440.735
  40. De Strooper B, Annaert W, Cupers P et al (1999) A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain. Nature 398, 518-522 https://doi.org/10.1038/19083
  41. Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL and Beyreuther K (1985) Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A 82, 4245-4249 https://doi.org/10.1073/pnas.82.12.4245
  42. Wiltfang J, Esselmann H, Cupers P et al (2001) Elevation of β-amyloid peptide in sporadic and familial Alzheimer's disease and its generation in PS1 knockout cells. J Biol Chem 276, 42645-42657 https://doi.org/10.1074/jbc.M102790200
  43. Takami M, Nagashima Y, Sano Y et al (2009) γ-secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of β-carboxyl terminal fragment. J Neurosci 29, 13042-13052 https://doi.org/10.1523/JNEUROSCI.2362-09.2009
  44. Qi-Takahara Y, Morishima-Kawashima M, Tanimura Y et al (2005) Longer forms of amyloid β protein: implications for the mechanism of intramembrane cleavage by γ-secretase. J Neurosci 25, 436-445 https://doi.org/10.1523/JNEUROSCI.1575-04.2005
  45. Wolfe MS (2019) Structure and function of the γ-secretase complex. Biochemistry 58, 2953-2966 https://doi.org/10.1021/acs.biochem.9b00401
  46. Lee JY, Feng Z, Xie XQ and Bahar I (2017) Allosteric modulation of intact gamma-secretase structural dynamics. Biophys J 113, 2634-2649 https://doi.org/10.1016/j.bpj.2017.10.012
  47. Bhattarai A, Devkota S, Do HN et al (2022) Mechanism of tripeptide trimming of amyloid β-peptide 49 by γ-secretase. J Am Chem Soc 144, 6215-6226 https://doi.org/10.1021/jacs.1c10533
  48. Petit D, Hitzenberger M, Lismont S et al (2019) Extracellular interface between APP and Nicastrin regulates Abeta length and response to gamma-secretase modulators. EMBO J 38, e101494
  49. Hellstrom-Lindahl E, Viitanen M and Marutle A (2009) Comparison of Abeta levels in the brain of familial and sporadic Alzheimer's disease. Neurochem Int 55, 243-252 https://doi.org/10.1016/j.neuint.2009.03.007
  50. Liu L, Lauro BM, He A et al (2023) Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement 19, 79-96 https://doi.org/10.1002/alz.12646
  51. Heo CE, Choi TS and Kim HI (2018) Competitive homoand hetero- self-assembly of amyloid-β 1-42 and 1-40 in the early stage of fibrillation. Int J Mass Spectrom 428, 15-21 https://doi.org/10.1016/j.ijms.2018.02.002
  52. Kuperstein I, Broersen K, Benilova I et al (2010) Neurotoxicity of Alzheimer's disease Abeta peptides is induced by small changes in the Abeta42 to Abeta40 ratio. EMBO J 29, 3408-3420 https://doi.org/10.1038/emboj.2010.211
  53. Gravina SA, Ho L, Eckman CB et al (1995) Amyloid-β Protein (Aβ) in Alzheimeri's disease brain: biochemical and immunocytochemical analysis with antibodies specific for forms ending at Aβ40 OR Aβ42(43). J Biol Chem 270, 7013-7016 https://doi.org/10.1074/jbc.270.13.7013
  54. Braun GA, Dear AJ, Sanagavarapu K, Zetterberg H and Linse S (2022) Amyloid-β peptide 37, 38 and 40 individually and cooperatively inhibit amyloid-β 42 aggregation. Chem Sci 13, 2423-2439 https://doi.org/10.1039/D1SC02990H
  55. Jakel L, Biemans EALM, Klijn CJM, Kuiperij HB and Verbeek MM (2020) Reduced influence of apoE on Aβ43 aggregation and reduced vascular Aβ43 toxicity as compared with Aβ40 and Aβ42. Mol Neurobiol 57, 2131-2141 https://doi.org/10.1007/s12035-020-01873-x
  56. Hampel H, Hardy J, Blennow K et al (2021) The amyloid-β pathway in Alzheimer's disease. Mol Psychiatry 26, 5481-5503 https://doi.org/10.1038/s41380-021-01249-0
  57. Rahman MM and Lendel C (2021) Extracellular protein components of amyloid plaques and their roles in Alzheimer's disease pathology. Mol Neurodegener 16, 59
  58. Xiao Y, Ma B, McElheny D et al (2015) Aβ(1-42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer's disease. Nat Struct Mol Biol 22, 499-505 https://doi.org/10.1038/nsmb.2991
  59. Sawaya MR, Hughes MP, Rodriguez JA, Riek R and Eisenberg DS (2021) The expanding amyloid family: structure, stability, function, and pathogenesis. Cell 184, 4857-4873 https://doi.org/10.1016/j.cell.2021.08.013
  60. Gremer L, Scholzel D, Schenk C et al (2017) Fibril structure of amyloid-β(1-42) by cryo-electron microscopy. Science 358, 116-119 https://doi.org/10.1126/science.aao2825
  61. Walti MA, Ravotti F, Arai H et al (2016) Atomic-resolution structure of a disease-relevant Aβ(1-42) amyloid fibril. Proc Natl Acad Sci U S A 113, E4976-E4984 https://doi.org/10.1073/pnas.1600749113
  62. Colvin MT, Silvers R, Ni QZ et al (2016) Atomic resolution structure of monomorphic Aβ42 amyloid fibrils. J Am Chem Soc 138, 9663-9674 https://doi.org/10.1021/jacs.6b05129
  63. Cerofolini L, Ravera E, Bologna S et al (2020) Mixing Aβ (1-40) and Aβ(1-42) peptides generates unique amyloid fibrils. Chem Commun 56, 8830-8833 https://doi.org/10.1039/D0CC02463E
  64. Paravastu AK, Leapman RD, Yau WM and Tycko R (2008) Molecular structural basis for polymorphism in Alzheimer's β-amyloid fibrils. Proc Natl Acad Sci U S A 105, 18349-18354 https://doi.org/10.1073/pnas.0806270105
  65. Zielinski M, Peralta Reyes FS, Gremer L et al (2023) Cryo-EM of Aβ fibrils from mouse models find tg-APP-ArcSwe fibrils resemble those found in patients with sporadic Alzheimer's disease. Nat Neurosci 26, 2073-2080 https://doi.org/10.1038/s41593-023-01484-4
  66. Schutz AK, Vagt T, Huber M et al (2015) Atomic-resolution three-dimensional structure of amyloid β fibrils bearing the Osaka mutation. Angew Chem Int Ed 54, 331-335 https://doi.org/10.1002/anie.201408598
  67. Ghosh U, Thurber KR, Yau WM and Tycko R (2021) Molecular structure of a prevalent amyloid-β fibril polymorph from Alzheimer's disease brain tissue. Proc Natl Acad Sci U S A 118, e2023089118
  68. Frieg B, Han M, Giller K et al (2024) Cryo-EM structures of lipidic fibrils of amyloid-β (1-40). Nat Commun 15, 1297
  69. Pfeiffer PB, Ugrina M, Schwierz N, Sigurdson CJ, Schmidt M and Fandrich M (2024) Cryo-EM analysis of the effect of seeding with brain-derived Aβ amyloid fibrils. J Mol Biol 436, 168422
  70. Yang Y, Murzin AG, Peak-Chew S et al (2023) Cryo-EM structures of Aβ40 filaments from the leptomeninges of individuals with Alzheimer's disease and cerebral amyloid angiopathy. Acta Neuropathol Commun 11, 191
  71. Meisl G, Kirkegaard JB, Arosio P et al (2016) Molecular mechanisms of protein aggregation from global fitting of kinetic models. Nat Protoc 11, 252-272 https://doi.org/10.1038/nprot.2016.010
  72. Wolfe LS, Calabrese MF, Nath A, Blaho DV, Miranker AD and Xiong Y (2010) Protein-induced photophysical changes to the amyloid indicator dye thioflavin T. Proc Natl Acad Sci U S A 107, 16863-16868 https://doi.org/10.1073/pnas.1002867107
  73. Meisl G, Yang X, Hellstrand E et al (2014) Differences in nucleation behavior underlie the contrasting aggregation kinetics of the Aβ40 and Aβ42 peptides. Proc Natl Acad Sci U S A 111, 9384-9389 https://doi.org/10.1073/pnas.1401564111
  74. Zhuang W, Sgourakis NG, Li Z, Garcia AE and Mukamel S (2010) Discriminating early stage Aβ42 monomer structures using chirality-induced 2DIR spectroscopy in a simulation study. Proc Natl Acad Sci U S A 107, 15687-15692 https://doi.org/10.1073/pnas.1002131107
  75. Yan Y and Wang C (2006) Aβ42 is more rigid than Aβ40 at the C terminus: implications for Aβ aggregation and toxicity. J Mol Biol 364, 853-862 https://doi.org/10.1016/j.jmb.2006.09.046
  76. Im D, Heo CE, Son MK, Park CR, Kim HI and Choi JM (2022) Kinetic Modulation of Amyloid-β (1-42) aggregation and toxicity by structure-based rational design. J Am Chem Soc 144, 1603-1611 https://doi.org/10.1021/jacs.1c10173
  77. Im D, Kim S, Yoon G et al (2023) Decoding the roles of amyloid-β (1-42)'s key oligomerization domains toward designing epitope-specific aggregation inhibitors. JACS Au 3, 1065-1075 https://doi.org/10.1021/jacsau.2c00668
  78. Tian Y and Viles JH (2022) pH dependence of amyloid-β fibril assembly kinetics: unravelling the microscopic molecular processes. Angew Chem Int Ed 61, e202210675
  79. Suh JM, Kim M, Yoo J, Han J, Paulina C and Lim MH (2023) Intercommunication between metal ions and amyloidogenic peptides or proteins in protein misfolding disorders. Coord Chem Rev 478, 214978
  80. Yi Y and Lim MH (2023) Current understanding of metal-dependent amyloid-β aggregation and toxicity. RSC Chem Biol 4, 121-131 https://doi.org/10.1039/D2CB00208F
  81. Heo CE, Park CR and Kim HI (2021) Effect of packing density of lipid vesicles on the Aβ42 fibril polymorphism. Chem Phys Lipids 236, 105073
  82. Kim S, Hyun DG, Nam Y et al (2023) Genipin and pyrogallol: two natural small molecules targeting the modulation of disordered proteins in Alzheimer's disease. Biomed Pharmacother 168, 115770
  83. Hyung SJ, DeToma AS, Brender JR et al (2013) Insights into antiamyloidogenic properties of the green tea extract (-)-epigallocatechin-3-gallate toward metal-associated amyloid-β species. Proc Natl Acad Sci U S A 110, 3743-3748 https://doi.org/10.1073/pnas.1220326110
  84. Yi Y, Lee J and Lim MH (2024) Amyloid-β-interacting proteins in peripheral fluids of Alzheimer's disease. Trends Chem 6, 128-143 https://doi.org/10.1016/j.trechm.2024.01.003
  85. Choi TS, Lee HJ, Han JY, Lim MH and Kim HI (2017) Molecular insights into human serum albumin as a receptor of amyloid-β in the extracellular region. J Am Chem Soc 139, 15437-15445 https://doi.org/10.1021/jacs.7b08584
  86. Yang X, Meisl G, Frohm B, Thulin E, Knowles TPJ and Linse S (2018) On the role of sidechain size and charge in the aggregation of Aβ42 with familial mutations. Proc Natl Acad Sci U S A 115, E5849-E5858
  87. Quartey MO, Nyarko JNK, Maley JM et al (2021) The Aβ(1-38) peptide is a negative regulator of the Aβ(1-42) peptide implicated in Alzheimer disease progression. Sci Rep 11, 431
  88. Moore BD, Martin J, de Mena L et al (2017) Short Aβ peptides attenuate Aβ42 toxicity in vivo. J Exp Med 215, 283-301
  89. Lasagna-Reeves CA and Kayed R (2011) Astrocytes contain amyloid-β annular protofibrils in Alzheimer's disease brains. FEBS Lett 585, 3052-3057 https://doi.org/10.1016/j.febslet.2011.08.027
  90. Baik SH, Kang S, Son SM and Mook-Jung I (2016) Microglia contributes to plaque growth by cell death due to uptake of amyloid β in the brain of Alzheimer's disease mouse model. Glia 64, 2274-2290 https://doi.org/10.1002/glia.23074
  91. Bolmont T, Haiss F, Eicke D et al (2008) Dynamics of the microglial/amyloid interaction indicate a role in plaque maintenance. J Neurosci 28, 4283-4292 https://doi.org/10.1523/JNEUROSCI.4814-07.2008
  92. Huang Y, Happonen KE, Burrola PG et al (2021) Microglia use TAM receptors to detect and engulf amyloid β plaques. Nat Immunol 22, 586-594 https://doi.org/10.1038/s41590-021-00913-5
  93. Suzuki N, Cheung TT, Cai XD et al (1994) An increased percentage of long amyloid β protein secreted by familial amyloid β protein precursor (βApp717) mutants. Science 264, 1336-1340 https://doi.org/10.1126/science.8191290
  94. De Jonghe C, Esselens C, Kumar-Singh S et al (2001) Pathogenic APP mutations near the γ-secretase cleavage site differentially affect Aβ secretion and APP C-terminal fragment stability. Hum Mol Genet 10, 1665-1671 https://doi.org/10.1093/hmg/10.16.1665
  95. Lichtenthaler SF, Ida N, Multhaup G, Masters CL and Beyreuther K (1997) Mutations in the transmembrane domain of APP altering γ-secretase specificity. Biochemistry 36, 15396-15403 https://doi.org/10.1021/bi971071m
  96. Coric V, Salloway S, van Dyck CH et al (2015) Targeting prodromal Alzheimer disease with avagacestat: a randomized clinical trial. JAMA Neurol 72, 1324-1333 https://doi.org/10.1001/jamaneurol.2015.0607
  97. Doody RS, Raman R, Farlow M et al (2013) A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med 369, 341-350 https://doi.org/10.1056/NEJMoa1210951
  98. Schrodinger (2021) The PyMOL Molecular Graphics System v. 2.5.