{"id":67,"date":"2021-04-14T19:42:27","date_gmt":"2021-04-14T19:42:27","guid":{"rendered":"http:\/\/dlab.clemson.edu\/?p=67"},"modified":"2026-05-18T15:01:50","modified_gmt":"2026-05-18T15:01:50","slug":"mitigation-of-amyloid-aggregation-and-toxicity","status":"publish","type":"post","link":"https:\/\/dlab.clemson.edu\/?p=67","title":{"rendered":"Mitigation of amyloid aggregation and toxicity"},"content":{"rendered":"

Amyloid aggregation is associated with an increasing list of degenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and type-2 diabetes. The hallmark common to all amyloid diseases is the deposition of beta-sheet rich fibrils formed of by misfolding and aggregation of otherwise soluble proteins and peptides. Mounting experiments suggest that soluble oligomers instead of mature fibrils are more toxic. As the intrinsically transient and heterogenous intermediates of amyloid aggregation, these oligomeric species are highly elusive. In addition, not all oligomers are toxic. The objective of our research is to uncover the structure and dynamics of amyloid aggregation and focus on the early aggregation process in order to pinpoint the toxic subspecies.  In our lab, we apply multiscale molecular dynamics simulations to model the aggregation of various amyloidogenic proteins and peptides, characterize the free energy landscape of the assembly process, and identify the structural and dynamics signatures of the toxic oligomers by working closely with experimental groups. The obtained molecular and structural insights to amyloid toxicity will help better understand the disease mechanisms and aid in the design of therapeutic strategies against amyloidosis.<\/p>\n

Our strategy of mitigating amyloid toxicity is to minimize the population of toxic oligomers and\/or reduce the direct exposure of cells to these toxic species. The overall population of toxic oligomers can be reduced by stabilizing monomers, non-toxic or “off-pathway” oligomers, or accelerating the formation of non- or less-toxic fibrils. The direct cell exposure to toxic oligomers can also be achieved by caging these culprits. In our lab, we have been exploring the applications of small molecules, endogenous proteins and peptides, and engineered nanomaterials with specific physicochemical properties as amyloid-mitigating agents. For instance, we have uncovered the amyloid-mitigation mechanisms of several naturally-occurring polyphenols (e.g., resveratrol, curcumin, and EGCG) reported in the literature to be able to inhibit the aggregation of different amyloid peptides. For the aggregation of human islet amyloid polypeptide (hIAPP, aka amylin) associated with beta-cell death in type-2 diabetes, we also studied the effects of various IAPP-colocalizing molecules including insulin, zinc ion, c-peptide and hydrogen ion at low pH in the beta-cell granule, where hIAPP is stored without apparent aggregation for hours between meals at mM concentrations. In the search for anti-amyloid nanomedicine, we have been studying the physicochemical determinants of nanoparticles in mitigating amyloid aggregation and toxicity. All these research projects are highly inter-disciplinary and collaborative, and results from the synergy between simulations and experiments. Molecular modeling and dynamics simulations have been employed not only to help explain experimental characterizations and elucidate molecular mechanisms but also to make predictions and guide experimental validations.<\/p>\n

Fig. 1 – A) The free energy landscape of amyloid aggregation as a function of the aggregation size and fraction of \u03b2\u2010sheet content (QFibril), obtained from computer simulations of model peptides. The landscape encompasses initial oligomerization of monomers to low \u03b2\u2010sheet oligomers, nucleation of \u03b2\u2010sheet structures in the oligomers (i.e., \u03b2\u2010sheet rich oligomers including \u03b2\u2010barrels), and their subsequent elongation into cross\u2010\u03b2 fibrils. B) Nanomaterials have been found to reduce the population of toxic \u03b2\u2010sheet\u2010rich oligomers by stabilizing monomers (e.g., dendrimers), low \u03b2\u2010sheet oligomers (e.g., graphene quantum dots), or protofibrils (e.g., gold nanoparticles coated with \u03b2\u2010lactoglobulin amyloid fragments and poly (2\u2010hydroxyl ethyl acrylate) star polymers). IAPP was used as the representative peptide. GQD: graphene quantum dot. bLg\u2010AuNP: \u03b2\u2010lactoglobulin amyloid fragment.<\/figcaption=\"\"><\/figure>\n

 <\/p>\n

29. Z. Zhang, G. Huang, S. Gupta, E. Sargent, H. Tang, F. Ding, \u201cDeterminants for Sub-stoichiometric Inhibition of IAPP and A-Beta Amyloid Aggregations by Bri2 BRICHOS\u201d, ACS Chemical Neuroscience, 16(6): 1150\u20131160 (2025) doi:10.1021\/acschemneuro.4c00839<\/p>\n

28. A. Chaari, N. Saikia, P. Paul, M. Yousef, F. Ding, M. Ladjimi, \u201cExperimental and computational investigation of the effect of Hsc70 structural variants on inhibiting amylin aggregation\u201d, Biophysical Chemistry, 309:107235 (2024) doi:10.1016\/j.bpc.2024.107235<\/p>\n

27. Y. Wang, J. Xu, J. Yan, X. Fan, G. Wei, C. Wang, F. Ding*, Y. Sun*, \u201cSEVI Inhibits A\u03b2 Amyloid Aggregation by Capping the \u03b2-Sheet Elongation Edges\u201d, Journal of Chemical Information and Modeling, 63(11):3567-3578 (2023) doi: 10.1021\/acs.jcim.3c00414<\/p>\n

26. Andrikopoulos N., Li Y., Nandakumar A., Quinn J., Davis T., Ding F.*, Saikia N.*, Ke P.C.*, \u201cZinc-Epigallocatechin-3-gallate Network-Coated Nanocomposites against the Pathogenesis of Amyloid-Beta\u201d, ACS Applied Materials & Interfaces, 15, 6, 7777\u20137792 (2023) doi:10.1021\/acsami.2c20334<\/p>\n

25. N. Benhamou Goldfajn, H. Tang, F. Ding, \u201cSub-Stoichiometric Inhibition of Insulin against IAPP Aggregation is Attenuated by the Incompletely Processed N-Terminus of proIAPP\u201d, ACS Chemical Neuroscience, 13(13): 2006\u20132016 (2022) doi:10.1021\/acschemneuro.2c00231<\/p>\n

24. H. Tang, Y. Li, A. Kakinen, N. Andrikopoulos, Y. Sun, E. Kwak, T. P. Davis, F. Ding* and P. C. Ke*, \u201cGraphene Quantum Dots Obstruct the Membrane Axis of Alzheimer\u2019s Amyloid Beta\u201d, Physical Chemistry Chemical Physics, 24, 86-97 (2022) doi: 10.1039\/D1CP04246G<\/p>\n

23. N. Andrikopoulos, Z. Song, X. Wan, A. Douek, I. Javed, C. Fu, X. Changkui, Y. Xing, F. Xin, Y. Li, A. Kakinen, K. Koppel, R. Qiao, A. Whittaker, J. Kaslin, T. Davis*, Y. Song*, F. Ding*, P.C. Ke*, \u201cInhibition of Amyloid Aggregation and Toxicity with Janus Iron Oxide Nanoparticles\u201d, Chem. Mater., 33, 16, 6484\u20136500 (2021) doi: 10.1021\/acs.chemmater.1c01947<\/p>\n

22. Y. Li, H. Tang, H. Zhu, A. Kakinen, D. Wang, N. Andrikopoulos, Y. Sun, A. Nandakumar, E. Kwak, T. Davis, D. Leong, F. Ding, P. C. Ke, \u201cUltrasmall Molybdenum Disulfide Quantum Dots Cage Alzheimer\u2019s Amyloid Beta to Restore Membrane Fluidity\u201d, ACS Appl. Mater. Interfaces, 13(25): 29936\u201329948 (2021) doi: 10.1021\/acsami.1c06478<\/p>\n

21. Chen P, Ding F, Cai R, Javed I, Yang W, Zhang Z, Li Y, Davis TP, Ke PC, Chen C., \u201cAmyloidosis Inhibition, a New Frontier of the Protein Corona\u201d, Nano Today, 35:100937 (2020) doi: 10.1016\/j.nantod.2020.100937<\/p>\n

20. Y. Sun, F. Ding, \u201c\u03b1B-Crystallin Chaperone Inhibits A\u03b2 Aggregation by Capping the \u03b2-Sheet-Rich Oligomers and Fibrils\u201d, J. Phys. Chem. B, 124:10138-10146 (2020) doi: 10.1021\/acs.jpcb.0c07256.<\/p>\n

19. Z Huma,I Javed, Z Zhang, H Bilal, Y Sun, SZ Hussain, TP Davis, DE Otzen, CB Landersdorfer, F Ding, I Hussain and PC Ke, \u201cNano Silver Mitigates Biofilm Formation via FapC Amyloidosis Inhibition\u201d, Small, 1906674-1906683 (2019) DOI: 10.1002\/smll.201906674<\/p>\n

18. A Faridi, Y Sun, M Mortimer, RR Aranha, A Nandakumar, Y Li, I Javed, A Kakinen, Q Fan, AW Purcell, TP Davis,* F Ding,* P Faridi,* and P Ke*, \u201cGraphene quantum dots rescue protein dysregulation of pancreatic \u03b2-cells exposed to human islet amyloid polypeptide\u201d, Nano Research, 12(11), 2827\u20132834 (2019) DOI: 10.1007\/s12274-019-2520-7<\/p>\n

17. P.C. Ke, E.H. Pilkington, Y. Sun, I. Javed, A. Kakinen, G. Peng, F. Ding, T.P. Davis, \u201cMitigation of Amyloidosis with Nanomaterials\u201d, Advanced Materials, 32(18):e1901690, (2020) DOI: 10.1002\/adma.201901690<\/p>\n

16. M. Wang, Y. Sun, X. Cao, G. Peng, I. Javed, A. Kakinen, T.P. Davis, S. Lin, J. Liu, F. Ding, and P. Ke, \u201cGraphene Quantum Dots against Human IAPP Aggregation and Toxicity in Vivo\u201d, Nanoscale 10, 19995, DOI: 10.1039\/C8NR07180B (2018)<\/p>\n

15. A. Faridi,Y. Sun, Y. Okazaki, G. Peng, J. Gao, A. Kakinen, P. Faridi, M. Zhao, I. Javed, A.W. Purcell, T.P. Davis, S. Lin, R. Oda, F. Ding, P. Ke, \u201cMitigating Human IAPP Amyloidogenesis in Vivo with Chiral Silica Nanoribbons\u201d, Small, 14, 1802825, DOI: 10.1002\/smll.201802825 (2018)<\/p>\n

14. A. Kakinen, J. Adamcik, B. Wang, X. Ge, R. Mezzenga, T.P. Davis, F. Ding, and P. Ke, \u201cNanoscale inhibition of polymorphic and ambidextrous IAPP amyloid aggregation with small molecules\u201d, Nano Research, 11(7): 3636\u20133647 (2018)[download] DOI: 10.1007\/s12274-017-1930-7<\/p>\n

13. Y. Xing, E. H. Pilkington, M. Wang, C. Nowell, A. Kakinen, Y. Sun, B. Wang, T. P. Davis, F. Ding and P. C. Ke, \u201cLysophosphatidylcholine modulates the aggregation of human islet amyloid polypeptide\u201d, Phys. Chem. Chem. Phys., 19, 30627-30635, 2017, DOI: 10.1039\/C7CP06670H<\/p>\n

12. E. Pilkington, M. Lai, X. Ge, W. Stanley, B. Wang, M. Wang, A. Kakinen, M. Sani, M. Whittaker, E. Gurzov, F. Ding, J. Quinn, T. Davis, P. Ke, \u201cStar Polymers Reduce IAPP Toxicity via Accelerated Amyloid Aggregation\u201d, Biomacromolecules, 18 4249\u20134260, (2017) DOI: 10.1021\/acs.biomac.7b01301<\/p>\n

11. I. Javed, Y. Sun, J. Adamcik, B. Wang, A. Kakinen, E. Pilkington, F. Ding, R. Mezzenga, T. Davis, Thomas; P. Ke, \u201cCo-fibrillization of pathogenic and functional amyloid proteins with gold nanoparticles against amyloidogenesis\u201d, Biomacromolecules, 18, 4316\u20134322 (2017) DOI: 10.1021\/acs.biomac.7b01359<\/p>\n

10. B. Wang, E.H. Pilkington, Y. Sun, T.P. Davis, P.C. Ke and F. Ding, \u201cModulating protein amyloid aggregation with nanomaterials\u201d, Environmental Science Nano, 4, 1772-1783 (2017) DOI: 10.1039\/C7EN00436B<\/p>\n

9. X. Ge, A. Kakinen, E.N. Gurzov, W. Yang, L. Pang, E.H. Pilkington, P. Govindan-Nedumpully, P. Chen, F. Separovic, T.P. Davis, P. C. Ke, and F. Ding, \u201cZinc-coordination and C-peptide complexation: a potential mechanism for the endogenous inhibition of IAPP aggregation\u201d, Chem. Comm., 53(68):9394-9397 (2017) DOI: 10.1039\/C7CC04291D<\/p>\n

8. Pilkington E.H., Xing Y., Wang B., Kakinen A., Wang M., Davis T.P., Ding F., Ke P.C., \u201cEffects of Protein Corona on IAPP Amyloid Aggregation, Fibril Remodelling, and Cytotoxicity\u201d, Scientific Reports, 7(1):2455 (2017)<\/p>\n

7. E.N. Gurzov, B. Wang, E.H. Pilkington, P. Chen,A. Kakinen, W.J. Stanley, S.A. Litwak, E.G. Hanssen,T.P. Davis, F. Ding, and P.Chun Ke, \u201cInhibition of hIAPP Amyloid Aggregation and Pancreatic \u03b2-cell Toxicity by OH-terminated PAMAM Dendrimer\u201d, Small, 12(12):1615\u20131626 (2016)<\/p>\n

6. P. Nedumpully-Govindan, E.N. Gurzov, P. Chen, E.H. Pilkington, W.J. Stanley, S.A. Litwak, T.P. Davis, P.C. Ke, and F. Ding, \u201cGraphene Oxide Inhibits hIAPP Amyloid Fibrillation and Toxicity in Insulin-Producing NIT-1 Cells\u201d, Phys. Chem. Chem. Phys., 18:94-100 (2016) <\/p>\n

5. P. Nedumpully-Govindan, A. Kakinen, E.H. Pilkington, T.P. Davis, P.C. Ke and F. Ding, \u201cStabilizing Off-pathway Oligomers by Polyphenol Nanoassemblies for IAPP Aggregation Inhibition\u201d, Scientific Reports 6: 19463 (2016)<\/p>\n

4. S. Radic, T.P. Davis, P.C. Ke and F. Ding, \u201cContrasting effects of nanoparticle-protein attraction on amyloid aggregation\u201d, RSC Advances, 5, 105489-105498 (2015)<\/p>\n

3. P. Nedumpully-Govindan, Y. Yang, R. Andorfer, W. Cao, and F. Ding, \u201cPromotion or Inhibition of IAPP Aggregation by Zinc Coordination Depends on Its Relative Concentration\u201d, Biochemistry, 54:7335-44 (2015)<\/p>\n

2. Nedumpully-Govindan P. and Ding F., \u201cInhibition of IAPP aggregation by insulin depends on the insulin oligomeric state regulated by zinc ion concentration\u201d, Scientific Reports 5, (2015) <\/p>\n

1. S. Radic, P. Nedumpully-Govindan,R. Chen, E. Salonen, J.M. Brown, P.C. Ke, and F. Ding, \u201cEffect of Fullerenol Surface Chemistry on Nanoparticle Binding-induced Protein Misfolding\u201d, Nanoscale, 6 (14), 8340 \u2013 8349 (2014)<\/p>\n","protected":false},"excerpt":{"rendered":"

Amyloid aggregation is associated with an increasing list of degenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and type-2 diabetes. The hallmark common to all amyloid diseases is the deposition of beta-sheet rich fibrils formed of by misfolding and aggregation of otherwise soluble proteins and peptides. Mounting experiments suggest that soluble oligomers instead of mature … <\/p>\n

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