The Binding of Different Substrate Molecules at the Docking Site and the Active Site of γ-Secretase Can Trigger Toxic Events in Sporadic and Familial Alzheimer’s Disease
Abstract
:1. Introduction
2. Results
2.1. Multiscale Molecular Dynamics (MD) Studies of Dimerization of C99-βCTF-APP Molecules in Cholesterol–Lipid Bilayers (Figure 1 and Figure 2)
2.2. Multiscale MD Studies of Saturation of γ-Secretase with its C99-βCTF-APP Substrate (Figure 3)
2.3. Multiscale MD Studies of Nicastrin’s Function in the γ-Secretase Complex with the Exposed N-Terminal end of the Bound Aβ Substrate (Figure 4)
2.4. Multiscale Molecular Dynamics Studies of γ-Secretase with Two Substrates of Different Lengths (Figure 5)
2.5. Multiscale Molecular Dynamics Studies of the Docking of Free C99-βCTF-APP Substrate to γ-Secretase Complexes with No Bound Substrate (Figure 6)
2.6. AA-MD Studies of Docking of the C-Terminal Domain of C99-βCTF-APP to the Cytosolic Section of the Presenilin Subunit (Figure 7)
2.7. Substrate Channeling between BACE1 and γ-Secretase (Figure 8)
3. Discussion
3.1. The Two-Substrate Mechanism and Pathogenic Changes in the Types of Aβ Products
3.2. The C99-βCTF-APP Substrate and Its Different Aβ Products Can Together Contribute to the Pathogenic Events
3.3. The C99-βCTF-APP Path Is More Likely to Support the Toxic Two-Substrate Mechanism Than the C83-αCTF-APP Path
3.4. The Two-Substrate Mechanism Can Explain Toxic Changes in Aβ Production in All Sporadic and FAD Cases of the Disease
3.5. The Two-Substrate Mechanism and Development of Novel Drug Design Strategies
3.6. Concluding Remarks
4. Materials and Methods
4.1. Preparation of Molecular Structures for Multiscale Molecular Dynamics (MD) Calculations
4.2. Coarse-Grained Molecular Dynamics Calculations
4.3. All-Atom Molecular Dynamics Calculations
4.4. Statistical Analysis of Molecular Dynamics Results
4.5. Multiscale Molecular Dynamics Studies of Protein–Protein Interaction
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
aa-MD | All-atom molecular dynamics |
BACE1 | Beta-site APP-cleaving enzyme 1 |
C83-α-CTF-APP | C-terminal 83 amino acids-α-C-terminal fragment of amyloid precursor protein |
C99-β-CTF-APP | C-terminal 99 amino acids-β-C-terminal fragment of amyloid precursor protein |
cg-MD | Coarse-grained molecular dynamics |
CHOL | Cholesterol |
FAD | Familial Alzheimer’s disease |
MD | Molecular dynamics |
OPM | Orientations of Proteins in Membranes (OPM) database |
POPA | Phosphatidic acid |
POPC | Phosphatidylcholine |
POPE | Phosphatidylethanolamine |
POPI | Phosphatidylinositol |
POPS | Phosphatidylserine |
PSM | Sphingomyelin (PSM) |
RMSD | Root-mean-square deviation |
RMSF | Root-mean-square fluctuation |
TM | Transmembrane |
References
- Scheltens, P.; Blennow, K.; Breteler, M.M.; de Strooper, B.; Frisoni, G.B.; Salloway, S.; Van der Flier, W.M. Alzheimer’s disease. Lancet 2016, 388, 505–517. [Google Scholar] [CrossRef]
- Imbimbo, B.P.; Panza, F.; Frisardi, V.; Solfrizzi, V.; D’Onofrio, G.; Logroscino, G.; Seripa, D.; Pilotto, A. Therapeutic intervention for Alzheimer’s disease with gamma-secretase inhibitors: Still a viable option? Expert Opin. Investig. Drugs 2010, 20, 325–341. [Google Scholar] [CrossRef]
- Castro, M.A.; Hadziselimovic, A.; Sanders, C.R. The vexing complexity of the amyloidogenic pathway. Protein Sci. A Publ. Protein Soc. 2019, 28, 1177–1193. [Google Scholar] [CrossRef]
- Toyn, J.H.; Ahlijanian, M.K. Interpreting Alzheimer’s disease clinical trials in light of the effects on amyloid-β. Alzheimers Res. 2014, 6, 14. [Google Scholar] [CrossRef]
- Sambamurti, K.; Greig, N.H.; Utsuki, T.; Barnwell, E.L.; Sharma, E.; Mazell, C.; Bhat, N.R.; Kindy, M.S.; Lahiri, D.K.; Pappolla, M.A. Targets for AD treatment: Conflicting messages from gamma-secretase inhibitors. J. Neurochem. 2011, 117, 359–374. [Google Scholar] [CrossRef] [Green Version]
- Burton, C.R.; Meredith, J.E.; Barten, D.M.; Goldstein, M.E.; Krause, C.M.; Kieras, C.J.; Sisk, L.; Iben, L.G.; Polson, C.; Thompson, M.W.; et al. The amyloid-beta rise and gamma-secretase inhibitor potency depend on the level of substrate expression. J. Biol. Chem. 2008, 283, 22992–23003. [Google Scholar] [CrossRef] [Green Version]
- Svedružić, Ž.M.; Popović, K.; Šendula-Jengić, V. Decrease in catalytic capacity of γ-secretase can facilitate pathogenesis in sporadic and Familial Alzheimer’s disease. Mol. Cell. Neurosci. 2015, 67, 55–65. [Google Scholar] [CrossRef]
- Svedružić, Ž.M.; Vrbnjak, K.; Martinović, M.; Miletić, V. Structural Analysis of the Simultaneous Activation and Inhibition of γ-Secretase Activity in the Development of Drugs for Alzheimer’s Disease. Pharmaceutics 2021, 13, 514. [Google Scholar] [CrossRef]
- Svedružić, Z.M.; Popovic, K.; Sendula-Jengic, V. Modulators of gamma-secretase activity can facilitate the toxic side-effects and pathogenesis of Alzheimer’s disease. PLoS ONE 2013, 8, e50759. [Google Scholar] [CrossRef] [Green Version]
- Svedružić, Z.M.; Popovic, K.; Smoljan, I.; Sendula-Jengic, V. Modulation of gamma-Secretase Activity by Multiple Enzyme-Substrate Interactions: Implications in Pathogenesis of Alzheimer’s Disease. PLoS ONE 2012, 7, e32293. [Google Scholar] [CrossRef]
- Yagishita, S.; Morishima-Kawashima, M.; Tanimura, Y.; Ishiura, S.; Ihara, Y. DAPT-induced intracellular accumulations of longer amyloid beta-proteins: Further implications for the mechanism of intramembrane cleavage by gamma-secretase. Biochemistry 2006, 45, 3952–3960. [Google Scholar] [CrossRef]
- Walsh, R. Are improper kinetic models hampering drug development? PeerJ 2014, 2, e649. [Google Scholar] [CrossRef] [Green Version]
- Kakuda, N.; Funamoto, S.; Yagishita, S.; Takami, M.; Osawa, S.; Dohmae, N.; Ihara, Y. Equimolar production of amyloid beta-protein and amyloid precursor protein intracellular domain from beta-carboxyl-terminal fragment by gamma-secretase. J. Biol. Chem. 2006, 281, 14776–14786. [Google Scholar] [CrossRef] [Green Version]
- Yin, Y.I.; Bassit, B.; Zhu, L.; Yang, X.; Wang, C.; Li, Y.M. {gamma}-Secretase Substrate Concentration Modulates the Abeta42/Abeta40 Ratio: Implications for Alzheimer’s disease. J. Biol. Chem. 2007, 282, 23639–23644. [Google Scholar] [CrossRef] [Green Version]
- Jonsson, T.; Atwal, J.K.; Steinberg, S.; Snaedal, J.; Jonsson, P.V.; Bjornsson, S.; Stefansson, H.; Sulem, P.; Gudbjartsson, D.; Maloney, J.; et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature 2012, 488, 96–99. [Google Scholar] [CrossRef]
- Hur, J.Y.; Frost, G.R.; Wu, X.; Crump, C.; Pan, S.J.; Wong, E.; Barros, M.; Li, T.; Nie, P.; Zhai, Y.; et al. The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer’s disease. Nature 2020, 586, 735–740. [Google Scholar] [CrossRef]
- Wolfe, M.S. Probing Mechanisms and Therapeutic Potential of γ-Secretase in Alzheimer’s Disease. Molecules 2021, 26. [Google Scholar] [CrossRef]
- Motulsky, H.; Christopoulos, A. Fitting Models to Biological Data Using Linear and Nonlinear Regression: A Practical Guide to Curve Fitting, 1st ed.; Oxford University Press: Oxford, UK, 2004; p. 352. [Google Scholar]
- Fersht, A. Structure and Mechanism in Protein Science: A Guide to Enzyme Catalysis and Protein Folding, 4th ed.; World Scientific Publishing Co., Ltd.: Singapore, 2018; p. 656. [Google Scholar]
- Johnson, K.A. Fitting enzyme kinetic data with KinTek global kinetic explorer. Methods Enzymol. 2009, 467, 601–626. [Google Scholar]
- Tipton, K.F. (Ed.) Enzyme Assays, 2nd ed.; Oxford University Press: Oxford, UK, 2002; p. 282. [Google Scholar]
- Klotz, I.M. Ligand-Receptor Energetics: A Guide for the Perplexed, 1st ed.; Wiley: Hoboken, NJ, USA, 1997; p. 192. [Google Scholar]
- Yang, G.; Zhou, R.; Guo, X.; Yan, C.; Lei, J.; Shi, Y. Structural basis of γ-secretase inhibition and modulation by small molecule drugs. Cell 2021, 184, 521–533.e514. [Google Scholar] [CrossRef]
- Aguayo-Ortiz, R.; Chávez-García, C.; Straub, J.E.; Dominguez, L. Characterizing the structural ensemble of γ-secretase using a multiscale molecular dynamics approach. Chem. Sci. 2017, 8, 5576–5584. [Google Scholar] [CrossRef] [Green Version]
- Bolduc, D.M.; Montagna, D.R.; Gu, Y.; Selkoe, D.J.; Wolfe, M.S. Nicastrin functions to sterically hinder γ-secretase-substrate interactions driven by substrate transmembrane domain. Proc. Natl. Acad. Sci. USA 2016, 113, E509–E518. [Google Scholar] [CrossRef]
- Lee, J.Y.; Feng, Z.; Xie, X.Q.; Bahar, I. Allosteric Modulation of Intact γ-Secretase Structural Dynamics. Biophys. J. 2017, 113, 2634–2649. [Google Scholar] [CrossRef]
- Pantelopulos, G.A.; Straub, J.E.; Thirumalai, D.; Sugita, Y. Structure of APP-C99(1-99) and implications for role of extra-membrane domains in function and oligomerization. Biochim. Biophys. Acta. Biomembr. 2018, 1860, 1698–1708. [Google Scholar] [CrossRef]
- Bhattarai, A.; Devkota, S.; Do, H.N.; Wang, J.; Bhattarai, S.; Wolfe, M.S.; Miao, Y. Mechanism of Tripeptide Trimming of Amyloid β-Peptide 49 by γ-Secretase. J. Am. Chem. Soc. 2022, 144, 6215–6226. [Google Scholar] [CrossRef]
- Bai, X.C.; Rajendra, E.; Yang, G.; Shi, Y.; Scheres, S.H. Sampling the conformational space of the catalytic subunit of human γ-secretase. Elife 2015, 4, e11182. [Google Scholar] [CrossRef]
- Kornilova, A.Y.; Bihel, F.; Das, C.; Wolfe, M.S. The initial substrate-binding site of gamma-secretase is located on presenilin near the active site. Proc. Natl. Acad. Sci. USA 2005, 102, 3230–3235. [Google Scholar] [CrossRef] [Green Version]
- Yagishita, S.; Morishima-Kawashima, M.; Ishiura, S.; Ihara, Y. Abeta46 is processed to Abeta40 and Abeta43, but not to Abeta42, in the low density membrane domains. J. Biol. Chem. 2008, 283, 733–738. [Google Scholar] [CrossRef] [Green Version]
- Checler, F.; Afram, E.; Pardossi-Piquard, R.; Lauritzen, I. Is γ-secretase a beneficial inactivating enzyme of the toxic APP C-terminal fragment C99? J. Biol. Chem. 2021, 296, 100489. [Google Scholar] [CrossRef]
- Barrett, P.J.; Song, Y.; Van Horn, W.D.; Hustedt, E.J.; Schafer, J.M.; Hadziselimovic, A.; Beel, A.J.; Sanders, C.R. The amyloid precursor protein has a flexible transmembrane domain and binds cholesterol. Science 2012, 336, 1168–1171. [Google Scholar] [CrossRef] [Green Version]
- Richter, L.; Munter, L.M.; Ness, J.; Hildebrand, P.W.; Dasari, M.; Unterreitmeier, S.; Bulic, B.; Beyermann, M.; Gust, R.; Reif, B.; et al. Amyloid beta 42 peptide (Abeta42)-lowering compounds directly bind to Abeta and interfere with amyloid precursor protein (APP) transmembrane dimerization. Proc. Natl. Acad. Sci. USA 2010, 107, 14597–14602. [Google Scholar] [CrossRef] [Green Version]
- Eggert, S.; Midthune, B.; Cottrell, B.; Koo, E.H. Induced dimerization of the amyloid precursor protein leads to decreased amyloid-beta protein production. J. Biol. Chem. 2009, 284, 28943–28952. [Google Scholar] [CrossRef]
- Gorman, P.M.; Kim, S.; Guo, M.; Melnyk, R.A.; McLaurin, J.; Fraser, P.E.; Bowie, J.U.; Chakrabartty, A. Dimerization of the transmembrane domain of amyloid precursor proteins and familial Alzheimer’s disease mutants. BMC Neurosci. 2008, 9, 17. [Google Scholar] [CrossRef] [Green Version]
- Song, Y.; Hustedt, E.J.; Brandon, S.; Sanders, C.R. Competition between homodimerization and cholesterol binding to the C99 domain of the amyloid precursor protein. Biochemistry 2013, 52, 5051–5064. [Google Scholar] [CrossRef] [Green Version]
- Roel-Touris, J.; Bonvin, A. Coarse-grained (hybrid) integrative modeling of biomolecular interactions. Comput. Struct. Biotechnol. J. 2020, 18, 1182–1190. [Google Scholar] [CrossRef]
- Chen, G.F.; Xu, T.H.; Yan, Y.; Zhou, Y.R.; Jiang, Y.; Melcher, K.; Xu, H.E. Amyloid beta: Structure, biology and structure-based therapeutic development. Acta Pharmacol. Sin. 2017, 38, 1205–1235. [Google Scholar] [CrossRef] [Green Version]
- Grant, B.J.; Skjærven, L.; Yao, X.Q. Comparative Protein Structure Analysis with Bio3D-Web. Methods Mol. Biol. 2020, 2112, 15–28. [Google Scholar] [CrossRef]
- Beel, A.J.; Mobley, C.K.; Kim, H.J.; Tian, F.; Hadziselimovic, A.; Jap, B.; Prestegard, J.H.; Sanders, C.R. Structural studies of the transmembrane C-terminal domain of the amyloid precursor protein (APP): Does APP function as a cholesterol sensor? Biochemistry 2008, 47, 9428–9446. [Google Scholar] [CrossRef] [Green Version]
- Beel, A.J.; Sakakura, M.; Barrett, P.J.; Sanders, C.R. Direct binding of cholesterol to the amyloid precursor protein: An important interaction in lipid-Alzheimer’s disease relationships? Biochim. Biophys. Acta 2010, 1801, 975–982. [Google Scholar] [CrossRef] [Green Version]
- Humphrey, W.; Dalke, A.; Schulten, K. VMD: Visual molecular dynamics. J. Mol. Graph. 1996, 14, 33–38. [Google Scholar] [CrossRef]
- Pettersen, E.F.; Goddard, T.D.; Huang, C.C.; Couch, G.S.; Greenblatt, D.M.; Meng, E.C.; Ferrin, T.E. UCSF Chimera--a visualization system for exploratory research and analysis version. J. Comput. Chem. 2004, 25, 1605–1612. [Google Scholar] [CrossRef] [Green Version]
- Skjærven, L.; Yao, X.Q.; Scarabelli, G.; Grant, B.J. Integrating protein structural dynamics and evolutionary analysis with Bio3D. BMC Bioinform. 2014, 15, 399. [Google Scholar] [CrossRef] [PubMed]
- Zhou, R.; Yang, G.; Guo, X.; Zhou, Q.; Lei, J.; Shi, Y. Recognition of the amyloid precursor protein by human γ-secretase. Science 2019, 363, eaaw0930. [Google Scholar] [CrossRef] [PubMed]
- Van Der Spoel, D.; Lindahl, E.; Hess, B.; Groenhof, G.; Mark, A.E.; Berendsen, H.J. GROMACS: Fast, flexible, and free. J. Comput. Chem. 2005, 26, 1701–1718. [Google Scholar] [CrossRef] [PubMed]
- Kakuda, N.; Takami, M.; Okochi, M.; Kasuga, K.; Ihara, Y.; Ikeuchi, T. Switched Aβ43 generation in familial Alzheimer’s disease with presenilin 1 mutation. Transl. Psychiatry 2021, 11, 558. [Google Scholar] [CrossRef] [PubMed]
- Steiner, H.; Fukumori, A.; Tagami, S.; Okochi, M. Making the final cut: Pathogenic amyloid-β peptide generation by γ-secretase. Cell Stress 2018, 2, 292–310. [Google Scholar] [CrossRef] [Green Version]
- Qi, Y.; Ingolfsson, H.I.; Cheng, X.; Lee, J.; Marrink, S.J.; Im, W. CHARMM-GUI Martini Maker for Coarse-Grained Simulations with the Martini Force Field. J. Chem. Theory Comput. 2015, 11, 4486–4494. [Google Scholar] [CrossRef] [PubMed]
- Liu, L.; Ding, L.; Rovere, M.; Wolfe, M.S.; Selkoe, D.J. A cellular complex of BACE1 and γ-secretase sequentially generates Aβ from its full-length precursor. J. Cell Biol. 2019, 218, 644–663. [Google Scholar] [CrossRef] [Green Version]
- Svedružić, Ž.M.; Odorčić, I.; Chang, C.H.; Svedružić, D. Substrate Channeling via a Transient Protein-Protein Complex: The case of D-Glyceraldehyde-3-Phosphate Dehydrogenase and L-Lactate Dehydrogenase. Sci. Rep. 2020, 10, 10404. [Google Scholar] [CrossRef]
- McDade, E.; Voytyuk, I.; Aisen, P.; Bateman, R.J.; Carrillo, M.C.; De Strooper, B.; Haass, C.; Reiman, E.M.; Sperling, R.; Tariot, P.N.; et al. The case for low-level BACE1 inhibition for the prevention of Alzheimer disease. Nat. Rev. Neurol. 2021, 17, 703–714. [Google Scholar] [CrossRef]
- Liu, Y.; Zhang, W.; Li, L.; Salvador, L.A.; Chen, T.; Chen, W.; Felsenstein, K.M.; Ladd, T.B.; Price, A.R.; Golde, T.E.; et al. Cyanobacterial peptides as a prototype for the design of potent β-secretase inhibitors and the development of selective chemical probes for other aspartic proteases. J. Med. Chem. 2012, 55, 10749–10765. [Google Scholar] [CrossRef]
- Bhattarai, S.; Devkota, S.; Meneely, K.M.; Xing, M.; Douglas, J.T.; Wolfe, M.S. Design of Substrate Transmembrane Mimetics as Structural Probes for γ-Secretase. J. Am. Chem. Soc. 2020, 142, 3351–3355. [Google Scholar] [CrossRef] [PubMed]
- Dehury, B.; Tang, N.; Kepp, K.P. Molecular dynamics of C99-bound γ-secretase reveal two binding modes with distinct compactness, stability, and active-site retention: Implications for Aβ production. Biochem. J. 2019, 476, 1173–1189. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jämsä, A.; Belda, O.; Edlund, M.; Lindström, E. BACE-1 inhibition prevents the γ-secretase inhibitor evoked Aβ rise in human neuroblastoma SH-SY5Y cells. J. Biomed. Sci. 2011, 18, 76. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- De la Fuente, I.M.; Martínez, L.; Carrasco-Pujante, J.; Fedetz, M.; López, J.I.; Malaina, I. Self-Organization and Information Processing: From Basic Enzymatic Activities to Complex Adaptive Cellular Behavior. Front. Genet. 2021, 12, 644615. [Google Scholar] [CrossRef]
- Van Noorden, C.J.; Jonges, G.N. Analysis of enzyme reactions in situ. Histochem. J. 1995, 27, 101–118. [Google Scholar] [CrossRef]
- Saura, C.A.; Choi, S.Y.; Beglopoulos, V.; Malkani, S.; Zhang, D.; Shankaranarayana Rao, B.S.; Chattarji, S.; Kelleher, R.J., 3rd; Kandel, E.R.; Duff, K.; et al. Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Neuron 2004, 42, 23–36. [Google Scholar] [CrossRef] [Green Version]
- Guix, F.X.; Wahle, T.; Vennekens, K.; Snellinx, A.; Chavez-Gutierrez, L.; Ill-Raga, G.; Ramos-Fernandez, E.; Guardia-Laguarta, C.; Lleo, A.; Arimon, M.; et al. Modification of gamma-secretase by nitrosative stress links neuronal ageing to sporadic Alzheimer’s disease. EMBO Mol. Med. 2012, 4, 660–673. [Google Scholar] [CrossRef]
- Refolo, L.M.; Eckman, C.; Prada, C.M.; Yager, D.; Sambamurti, K.; Mehta, N.; Hardy, J.; Younkin, S.G. Antisense-induced reduction of presenilin 1 expression selectively increases the production of amyloid beta42 in transfected cells. J. Neurochem. 1999, 73, 2383–2388. [Google Scholar] [CrossRef] [Green Version]
- Andreoli, V.; Trecroci, F.; La Russa, A.; Cittadella, R.; Liguori, M.; Spadafora, P.; Caracciolo, M.; Di Palma, G.; Colica, C.; Gambardella, A.; et al. Presenilin enhancer-2 gene: Identification of a novel promoter mutation in a patient with early-onset familial Alzheimer’s disease. Alzheimer’s Dement. J. Alzheimer’s Assoc. 2011, 7, 574–578. [Google Scholar] [CrossRef]
- Theuns, J.; Remacle, J.; Killick, R.; Corsmit, E.; Vennekens, K.; Huylebroeck, D.; Cruts, M.; Van Broeckhoven, C. Alzheimer-associated C allele of the promoter polymorphism -22C>T causes a critical neuron-specific decrease of presenilin 1 expression. Hum. Mol. Genet. 2003, 12, 869–877. [Google Scholar] [CrossRef] [Green Version]
- Wang, S.C.; Oelze, B.; Schumacher, A. Age-specific epigenetic drift in late-onset Alzheimer’s disease. PLoS ONE 2008, 3, e2698. [Google Scholar] [CrossRef] [PubMed]
- Nishimura, M.; Nakamura, S.I.; Kimura, N.; Liu, L.; Suzuki, T.; Tooyama, I. Age-related modulation of gamma-secretase activity in non-human primate brains. J. Neurochem. 2012, 123, 21–28. [Google Scholar] [CrossRef] [PubMed]
- Tamayev, R.; D’Adamio, L. Inhibition of gamma-secretase worsens memory deficits in a genetically congruous mouse model of Danish dementia. Mol Neurodegener 2012, 7, 19. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fukumoto, H.; Rosene, D.L.; Moss, M.B.; Raju, S.; Hyman, B.T.; Irizarry, M.C. Beta-secretase activity increases with aging in human, monkey, and mouse brain. Am. J. Pathol. 2004, 164, 719–725. [Google Scholar] [CrossRef]
- Li, R.; Lindholm, K.; Yang, L.B.; Yue, X.; Citron, M.; Yan, R.; Beach, T.; Sue, L.; Sabbagh, M.; Cai, H.; et al. Amyloid beta peptide load is correlated with increased beta-secretase activity in sporadic Alzheimer’s disease patients. Proc. Natl. Acad. Sci. USA 2004, 101, 3632–3637. [Google Scholar] [CrossRef] [Green Version]
- Rovelet-Lecrux, A.; Hannequin, D.; Raux, G.; Le Meur, N.; Laquerriere, A.; Vital, A.; Dumanchin, C.; Feuillette, S.; Brice, A.; Vercelletto, M.; et al. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat. Genet. 2006, 38, 24–26. [Google Scholar] [CrossRef]
- Sleegers, K.; Brouwers, N.; Gijselinck, I.; Theuns, J.; Goossens, D.; Wauters, J.; Del-Favero, J.; Cruts, M.; van Duijn, C.M.; Van Broeckhoven, C. APP duplication is sufficient to cause early onset Alzheimer’s dementia with cerebral amyloid angiopathy. Brain A J. Neurol. 2006, 129, 2977–2983. [Google Scholar] [CrossRef] [Green Version]
- Bourgeois, A.; Lauritzen, I.; Lorivel, T.; Bauer, C.; Checler, F.; Pardossi-Piquard, R. Intraneuronal accumulation of C99 contributes to synaptic alterations, apathy-like behavior, and spatial learning deficits in 3×TgAD and 2×TgAD mice. Neurobiol. Aging 2018, 71, 21–31. [Google Scholar] [CrossRef]
- Shen, J.; Kelleher, R.J., 3rd. The presenilin hypothesis of Alzheimer’s disease: Evidence for a loss-of-function pathogenic mechanism. Proc. Natl. Acad. Sci. USA 2007, 104, 403–409. [Google Scholar] [CrossRef] [Green Version]
- Kern, A.; Behl, C. The unsolved relationship of brain aging and late-onset Alzheimer disease. Biochim. Biophys. Acta 2009, 1790, 1124–1132. [Google Scholar] [CrossRef]
- Miners, J.S.; Jones, R.; Love, S. Differential changes in Aβ42 and Aβ40 with age. J. Alzheimer’s Dis. JAD 2014, 40, 727–735. [Google Scholar] [CrossRef] [PubMed]
- Szaruga, M.; Munteanu, B.; Lismont, S.; Veugelen, S.; Horré, K.; Mercken, M.; Saido, T.C.; Ryan, N.S.; De Vos, T.; Savvides, S.N.; et al. Alzheimer’s-Causing Mutations Shift Aβ Length by Destabilizing γ-Secretase-Aβn Interactions. Cell 2017, 170, 443–456.e14. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lauritzen, I.; Pardossi-Piquard, R.; Bauer, C.; Brigham, E.; Abraham, J.D.; Ranaldi, S.; Fraser, P.; St-George-Hyslop, P.; Le Thuc, O.; Espin, V.; et al. The β-secretase-derived C-terminal fragment of βAPP, C99, but not Aβ, is a key contributor to early intraneuronal lesions in triple-transgenic mouse hippocampus. J. Neurosci. Off. J. Soc. Neurosci. 2012, 32, 16243–16255. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mondragón-Rodríguez, S.; Gu, N.; Manseau, F.; Williams, S. Alzheimer’s Transgenic Model Is Characterized by Very Early Brain Network Alterations and β-CTF Fragment Accumulation: Reversal by β-Secretase Inhibition. Front. Cell. Neurosci. 2018, 12, 121. [Google Scholar] [CrossRef] [PubMed]
- Ganguly, G.; Chakrabarti, S.; Chatterjee, U.; Saso, L. Proteinopathy, oxidative stress and mitochondrial dysfunction: Cross talk in Alzheimer’s disease and Parkinson’s disease. Drug Des. Dev. Ther. 2017, 11, 797–810. [Google Scholar] [CrossRef] [Green Version]
- Thathiah, A.; De Strooper, B. The role of G protein-coupled receptors in the pathology of Alzheimer’s disease. Nat. Rev. Neurosci. 2011, 12, 73–87. [Google Scholar] [CrossRef]
- Jurisch-Yaksi, N.; Sannerud, R.; Annaert, W. A fast growing spectrum of biological functions of γ-secretase in development and disease. Biochim. Biophys. Acta 2013, 1828, 2815–2827. [Google Scholar] [CrossRef] [Green Version]
- Hunter, S.; Brayne, C. Integrating the molecular and the population approaches to dementia research to help guide the future development of appropriate therapeutics. Biochem. Pharm. 2014, 88, 652–660. [Google Scholar] [CrossRef]
- Gomes, G.N.; Levine, Z.A. Defining the Neuropathological Aggresome across in Silico, in Vitro, and ex Vivo Experiments. J. Phys. Chem. B 2021, 125, 1974–1996. [Google Scholar] [CrossRef]
- Fan, J.; Donkin, J.; Wellington, C. Greasing the wheels of Abeta clearance in Alzheimer’s disease: The role of lipids and apolipoprotein E. Biofactors 2009, 35, 239–248. [Google Scholar] [CrossRef]
- Lauritzen, I.; Pardossi-Piquard, R.; Bourgeois, A.; Pagnotta, S.; Biferi, M.G.; Barkats, M.; Lacor, P.; Klein, W.; Bauer, C.; Checler, F. Intraneuronal aggregation of the β-CTF fragment of APP (C99) induces Aβ-independent lysosomal-autophagic pathology. Acta Neuropathol. 2016, 132, 257–276. [Google Scholar] [CrossRef] [PubMed]
- Axelsen, P.H.; Komatsu, H.; Murray, I.V. Oxidative stress and cell membranes in the pathogenesis of Alzheimer’s disease. Physiology 2011, 26, 54–69. [Google Scholar] [CrossRef] [PubMed]
- Gralle, M.; Botelho, M.G.; Wouters, F.S. Neuroprotective secreted amyloid precursor protein acts by disrupting amyloid precursor protein dimers. J. Biol. Chem. 2009, 284, 15016–15025. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Berchtold, N.C.; Cribbs, D.H.; Coleman, P.D.; Rogers, J.; Head, E.; Kim, R.; Beach, T.; Miller, C.; Troncoso, J.; Trojanowski, J.Q.; et al. Gene expression changes in the course of normal brain aging are sexually dimorphic. Proc. Natl. Acad. Sci. USA 2008, 105, 15605–15610. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Funamoto, S.; Morishima-Kawashima, M.; Tanimura, Y.; Hirotani, N.; Saido, T.C.; Ihara, Y. Truncated carboxyl-terminal fragments of beta-amyloid precursor protein are processed to amyloid beta-proteins 40 and 42. Biochemistry 2004, 43, 13532–13540. [Google Scholar] [CrossRef] [PubMed]
- Kisby, B.; Jarrell, J.T.; Agar, M.E.; Cohen, D.S.; Rosin, E.R.; Cahill, C.M.; Rogers, J.T.; Huang, X. Alzheimer’s Disease and Its Potential Alternative Therapeutics. J. Alzheimers Dis. Park. 2019, 9, 477. [Google Scholar] [CrossRef]
- Armbrust, F.; Bickenbach, K.; Marengo, L.; Pietrzik, C.; Becker-Pauly, C. The Swedish dilemma—The almost exclusive use of APPswe-based mouse models impedes adequate evaluation of alternative β-secretases. Biochim. Et Biophys. Acta. Mol. Cell Res. 2022, 1869, 119164. [Google Scholar] [CrossRef]
- Qi, Y.; Morishima-Kawashima, M.; Sato, T.; Mitsumori, R.; Ihara, Y. Distinct mechanisms by mutant presenilin 1 and 2 leading to increased intracellular levels of amyloid beta-protein 42 in Chinese hamster ovary cells. Biochemistry 2003, 42, 1042–1052. [Google Scholar] [CrossRef]
- Qi-Takahara, Y.; Morishima-Kawashima, M.; Tanimura, Y.; Dolios, G.; Hirotani, N.; Horikoshi, Y.; Kametani, F.; Maeda, M.; Saido, T.C.; Wang, R.; et al. Longer forms of amyloid beta protein: Implications for the mechanism of intramembrane cleavage by gamma-secretase. J. Neurosci. Off. J. Soc. Neurosci. 2005, 25, 436–445. [Google Scholar] [CrossRef] [Green Version]
- Webb, B.; Sali, A. Comparative Protein Structure Modeling Using MODELLER. Curr. Protoc. Bioinform. 2016, 54, 5.6.1–5.6.37. [Google Scholar] [CrossRef] [Green Version]
- Lee, J.; Patel, D.S.; Ståhle, J.; Park, S.J.; Kern, N.R.; Kim, S.; Lee, J.; Cheng, X.; Valvano, M.A.; Holst, O.; et al. CHARMM-GUI Membrane Builder for Complex Biological Membrane Simulations with Glycolipids and Lipoglycans. J. Chem. Theory Comput. 2019, 15, 775–786. [Google Scholar] [CrossRef] [PubMed]
- Lomize, M.A.; Pogozheva, I.D.; Joo, H.; Mosberg, H.I.; Lomize, A.L. OPM database and PPM web server: Resources for positioning of proteins in membranes. Nucleic Acids Res. 2012, 40, D370–D376. [Google Scholar] [CrossRef] [PubMed]
- Lee, J.; Cheng, X.; Swails, J.M.; Yeom, M.S.; Eastman, P.K.; Lemkul, J.A.; Wei, S.; Buckner, J.; Jeong, J.C.; Qi, Y.; et al. CHARMM-GUI Input Generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM Simulations Using the CHARMM36 Additive Force Field. J. Chem. Theory Comput. 2016, 12, 405–413. [Google Scholar] [CrossRef] [PubMed]
- Bai, X.C.; Yan, C.; Yang, G.; Lu, P.; Ma, D.; Sun, L.; Zhou, R.; Scheres, S.H.W.; Shi, Y. An atomic structure of human γ-secretase. Nature 2015, 525, 212–217. [Google Scholar] [CrossRef] [Green Version]
- Audagnotto, M.; Kengo Lorkowski, A.; Dal Peraro, M. Recruitment of the amyloid precursor protein by γ-secretase at the synaptic plasma membrane. Biochem. Biophys. Res. Commun. 2018, 498, 334–341. [Google Scholar] [CrossRef]
- Aguayo-Ortiz, R.; Straub, J.E.; Dominguez, L. Influence of membrane lipid composition on the structure and activity of γ-secretase. Phys. Chem. Chem. Phys. PCCP 2018, 20, 27294–27304. [Google Scholar] [CrossRef]
- Krzemińska, A.; Moliner, V.; Świderek, K. Dynamic and Electrostatic Effects on the Reaction Catalyzed by HIV-1 Protease. J. Am. Chem. Soc. 2016, 138, 16283–16298. [Google Scholar] [CrossRef] [Green Version]
- Li, H.; Robertson, A.D.; Jensen, J.H. Very fast empirical prediction and rationalization of protein pKa values. Proteins 2005, 61, 704–721. [Google Scholar] [CrossRef]
- Li, Y.M.; Lai, M.T.; Xu, M.; Huang, Q.; DiMuzio-Mower, J.; Sardana, M.K.; Shi, X.P.; Yin, K.C.; Shafer, J.A.; Gardell, S.J. Presenilin 1 is linked with gamma-secretase activity in the detergent solubilized state. Proc. Natl. Acad. Sci. USA 2000, 97, 6138–6143. [Google Scholar] [CrossRef] [Green Version]
- Pahari, S.; Sun, L.; Basu, S.; Alexov, E. DelPhiPKa: Including salt in the calculations and enabling polar residues to titrate. Proteins 2018, 86, 1277–1283. [Google Scholar] [CrossRef]
- Arnarez, C.; Uusitalo, J.J.; Masman, M.F.; Ingólfsson, H.I.; de Jong, D.H.; Melo, M.N.; Periole, X.; de Vries, A.H.; Marrink, S.J. Dry Martini, a coarse-grained force field for lipid membrane simulations with implicit solvent. J. Chem. Theory Comput. 2015, 11, 260–275. [Google Scholar] [CrossRef] [PubMed]
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Svedružić, Ž.M.; Šendula Jengić, V.; Ostojić, L. The Binding of Different Substrate Molecules at the Docking Site and the Active Site of γ-Secretase Can Trigger Toxic Events in Sporadic and Familial Alzheimer’s Disease. Int. J. Mol. Sci. 2023, 24, 1835. https://doi.org/10.3390/ijms24031835
Svedružić ŽM, Šendula Jengić V, Ostojić L. The Binding of Different Substrate Molecules at the Docking Site and the Active Site of γ-Secretase Can Trigger Toxic Events in Sporadic and Familial Alzheimer’s Disease. International Journal of Molecular Sciences. 2023; 24(3):1835. https://doi.org/10.3390/ijms24031835
Chicago/Turabian StyleSvedružić, Željko M., Vesna Šendula Jengić, and Lucija Ostojić. 2023. "The Binding of Different Substrate Molecules at the Docking Site and the Active Site of γ-Secretase Can Trigger Toxic Events in Sporadic and Familial Alzheimer’s Disease" International Journal of Molecular Sciences 24, no. 3: 1835. https://doi.org/10.3390/ijms24031835
APA StyleSvedružić, Ž. M., Šendula Jengić, V., & Ostojić, L. (2023). The Binding of Different Substrate Molecules at the Docking Site and the Active Site of γ-Secretase Can Trigger Toxic Events in Sporadic and Familial Alzheimer’s Disease. International Journal of Molecular Sciences, 24(3), 1835. https://doi.org/10.3390/ijms24031835