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Rational design of a “sense and treat” system to target amyloid aggregates related to Alzheimer’s disease

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Abstract

The aggregation of amyloid-β peptide (Aβ) is implicated in the pathology of Alzheimer’s disease (AD), and Aβ oligomers are considered the most toxic species. Therefore, the detection and clearance of Aβ oligomers are crucial for the theranostic strategies for AD. However, effective methods for the detection of Aβ oligomers are rare, and only few of the oligomer-specific sensors have therapeutic functions as well. Recent studies have demonstrated that the toxicity of Aβ oligomers is related to the number of exposed hydrophobic residues. In this study, an oligomer-specific fluorescent probe, which was based on the hydrophobic regions that are exposed on Aβ oligomer surfaces was designed and synthesized. For improving the ability to recognize Aβ oligomers, the in situ treatment of AD symptoms and the ability to penetrate the blood-brain barrier, the probe and KLVFF peptide (an Aβ-target peptide) were modified on the surfaces of magnetic nanoparticles (MNP@NFP-pep). This complex could detect Aβ oligomers specifically, and achieve the wireless deep magnetothermally mediated disaggregation of Aβ aggregates with an alternating magnetic field. This work provides new insights into the development of a “sense and treat” system for AD therapy.

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References

  1. Blennow, K.; de Leon, M. J.; Zetterberg, H. Alzheimer’s disease. Lancet 2006, 368, 387–403.

    Article  Google Scholar 

  2. Rijal Upadhaya, A.; Kosterin, I.; Kumar, S.; von Arnim, C. A. F.; Yamaguchi, H.; Fä ndrich, M.; Walter, J.; Thal, D. R. Biochemical stages of amyloid-ß peptide aggregation and accumulation in the human brain and their association with symptomatic and pathologically preclinical Alzheimer’s disease. Brain 2014, 137, 887–903.

    Article  Google Scholar 

  3. Koffie, R. M.; Meyer-Luehmann, M.; Hashimoto, T.; Adams, K. W.; Mielke, M. L.; Garcia-Alloza, M.; Micheva, K. D.; Smith, S. J.; Kim, M. L.; Lee, V. M. et al. Oligomeric amyloid ß associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques. Proc. Nat. Acad. Sci. USA 2009, 106, 4012–4017.

    Article  Google Scholar 

  4. Li, S. M.; Hong, S.; Shepardson, N. E.; Walsh, D. M.; Shankar, G. M.; Selkoe, D. Soluble oligomers of amyloid ß protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron 2009, 62, 788–801.

    Article  Google Scholar 

  5. Haaßs, C.; Selkoe, D. J. Soluble protein oligomers in neurodegeneration: Lessons from the Alzheimer’s amyloid ß-peptide. Nat. Rev. Mol. Cell. Biol. 2007, 8, 101–112.

    Article  Google Scholar 

  6. Krishnan, R.; Goodman, J. L.; Mukhopadhyay, S.; Pacheco, C. D.; Lemke, E. A.; Deniz, A. A.; Lindquist, S. Conserved features of intermediates in amyloid assembly determine their benign or toxic states. Proc. Nat. Acad. Sci. USA 2012, 109, 11172–11177.

    Article  Google Scholar 

  7. Ladiwala, A. R.; Litt, J.; Kane, R. S.; Aucoin, D. S.; Smith, S. O.; Ranjan, S.; Davis, J.; Van Nostrand, W. E.; Teßsier, P. M. Conformational differences between two amyloid ß oligomers of similar size and dissimilar toxicity. J. Biol. Chem. 2012, 287, 24765–24773.

    Article  Google Scholar 

  8. Campioni, S.; Mannini, B.; Zampagni, M.; Pensalfini, A.; Parrini, C.; Evangelisti, E.; Relini, A.; Stefani, M.; Dobson, C. M.; Cecchi, C. et al. A causative link between the structure of aberrant protein oligomers and their toxicity. Nat. Chem. Biol. 2010, 6, 140–147.

    Article  Google Scholar 

  9. Cassagnes, L. E.; Hervé, V.; Nepveu, F.; Hureau, C.; Faller, P.; Collin, F. The catalytically active copper-amyloid-Beta state: Coordination site responsible for reactive oxygen species production. Angew. Chem., Int. Ed. 2013, 52, 11110–11113.

    Article  Google Scholar 

  10. Hamley, I. W. The amyloid beta peptide: A chemist’s perspective. Role in Alzheimer’s and fibrillization. Chem. Rev. 2012, 112, 5147–5192.

    Article  Google Scholar 

  11. Jakob-Roetne, R.; Jacobsen, H. Alzheimer’s disease: From pathology to therapeutic approaches. Angew. Chem., Int. Ed. 2009, 48, 3030–3059.

    Article  Google Scholar 

  12. Morgado, I.; Wieligmann, K.; Bereza, M.; Rönicke, R.; Meinhardt, K.; Annamalai, K.; Baumann, M.; Wacker, J.; Hortschansky, P.; Maleševic, M. et al. Molecular basis of ß-amyloid oligomer recognition with a conformational antibody fragment. Proc. Natl. Acad. Sci. USA 2012, 109, 12503–12508.

    Article  Google Scholar 

  13. Takahashi, T.; Mihara, H. FRET detection of amyloid ß-peptide oligomerization using a fluorescent protein probe presenting a pseudo-amyloid structure. Chem. Commun. 2012, 48, 1568–1570.

    Article  Google Scholar 

  14. Bruggink, K. A.; Jongbloed, W.; Biemans, E. A. L. M.; Veerhuis, R.; Claaßsen, J. A. H. R.; Kuiperij, H. B.; Verbeek, M. M. Amyloid-ß oligomer detection by ELISA in cerebrospinal fluid and brain tissue. Anal. Biochem. 2013, 433, 112–120.

    Article  Google Scholar 

  15. Teoh, C. L.; Su, D. D.; Sahu, S.; Yun, S. W.; Drummond, E.; Prelli, F.; Lim, S.; Cho, S.; Ham, S.; Wisniewski, T. et al. Chemical fluorescent probe for detection of aß oligomers. J. Am. Chem. Soc. 2015, 137, 13503–13509.

    Article  Google Scholar 

  16. Lv, G. L.; Sun, A. Y.; Wei, P.; Zhang, N.; Lan, H. C.; Yi, T. A spiropyran-based fluorescent probe for the specific detection of ß-amyloid peptide oligomers in Alzheimer’s disease. Chem. Commun. 2016, 52, 8865–8868.

    Article  Google Scholar 

  17. Chen, Q. W.; Wen, J.; Li, H. J.; Xu, Y. Q.; Liu, F. Y.; Sun, S. G. Recent advances in different modal imaging-guided photothermal therapy. Biomaterials 2016, 106, 144–166.

    Article  Google Scholar 

  18. Li, M.; Zhao, A. D.; Dong, K.; Li, W.; Ren, J. S.; Qu, X. G. Chemically exfoliated WS2 nanosheets efficiently inhibit amyloid ß-peptide aggregation and can be used for photothermal treatment of Alzheimer’s disease. Nano Res. 2015, 8, 3216–3227.

    Article  Google Scholar 

  19. Li, M.; Yang, X. J.; Ren, J. S.; Qu, K. G.; Qu, X. G. Using graphene oxide high near-infrared absorbance for photothermal treatment of Alzheimer’s disease. Adv. Mater. 2012, 24, 1722–1728.

    Article  Google Scholar 

  20. Bastus, N. G.; Kogan, M. J.; Amigo, R.; Grillo-Bosch, D.; Araya, E.; Turiel, A.; Labarta, A.; Giralt, E.; Puntes, V. F. Gold nanoparticles for selective and remote heating of ß-amyloid protein aggregates. Mater. Sci. Eng. C 2007, 27, 1236–1240.

    Article  Google Scholar 

  21. Weissleder, R. A clearer vision for in vivo imaging. Nat. Nanotechnol. 2001, 19, 316–317.

    Google Scholar 

  22. Chen, R.; Romero, G.; Christiansen, M. G.; Mohr, A.; Anikeeva, P. Wireless magnetothermal deep brain stimulation. Science 2015, 347, 1477–1480.

    Article  Google Scholar 

  23. Colombo, M.; Carregal-Romero, S.; Casula, M. F.; Gutiérrez, L.; Morales, M. P.; Böhm, I. B.; Heverhagen, J. T.; Prosperi, D.; Parak, W. J. Biological applications of magnetic nanoparticles. Chem. Soc. Rev. 2012, 41, 4306–4334.

    Article  Google Scholar 

  24. Riedinger, A.; Guardia, P.; Curcio, A.; Garcia, M. A.; Cingolani, R.; Manna, L.; Pellegrino, T. Subnanometer local temperature probing and remotely controlled drug release based on azo-functionalized iron oxide nanoparticles. Nano Lett. 2013, 13, 2399–2406.

    Article  Google Scholar 

  25. Huang, H.; Delikanli, S.; Zeng, H.; Ferkey, D. M.; Pralle, A. Remote control of ion channels and neurons through magnetic-field heating of nanoparticles. Nat. Nanotechnol. 2010, 5, 602–606.

    Article  Google Scholar 

  26. Reddy, L. H.; Arias, J. L.; Nicolas, J.; Couvreur, P. Magnetic nanoparticles: design and characterization, toxicity and biocompatibility, pharmaceutical and biomedical applications. Chem. Rev. 2012, 112, 5818–5878.

    Article  Google Scholar 

  27. Viola, K. L.; Sbarboro, J.; Sureka, R.; De, M.; Bicca, M. A.; Wang, J.; Vasavada, S.; Satpathy, S.; Wu, S.; Joshi, H. et al. Towards non-invasive diagnostic imaging of early-stage Alzheimer’s disease. Nat. Nanotechnol. 2015, 10, 91–98.

    Article  Google Scholar 

  28. Hu, B. B.; Dai, F. Y.; Fan, Z. M.; Ma, G. H.; Tang, Q. W.; Zhang, X. Nanotheranostics: Congo Red/Rutin-MNPs with enhanced magnetic resonance imaging and H2O2-responsive therapy of Alzheimer’s disease in APPswe/PS1dE9 transgenic mice. Adv. Mater. 2015, 27, 5499–5505.

    Article  Google Scholar 

  29. Duke, R. M.; Veale, E. B.; Pfeffer, F. M.; Kruger, P. E.; Gunnlaugsson, T. Colorimetric and fluorescent anion sensors: An overview of recent developments in the use of 1,8-naphthalimide-based chemosensors. Chem. Soc. Rev. 2010, 39, 3936–3953.

    Article  Google Scholar 

  30. Li, M.; Xu, C.; Wu, L.; Ren, J. S.; Wang, E. B.; Qu, X. G. Self-aßsembled peptide-polyoxometalate hybrid nanospheres: Two in one enhances targeted inhibition of amyloid ß-peptide aggregation associated with Alzheimer’s disease. Small 2013, 9, 3455–3461.

    Article  Google Scholar 

  31. Tang, Y. H.; Kong, X. Q.; Xu, A.; Dong, B. L.; Lin, W. Y. Development of a two-photon fluorescent probe for imaging of endogenous formaldehyde in living tissues. Angew. Chem., Int. Ed. 2016, 55, 3356–3359.

    Article  Google Scholar 

  32. Breul, A. M.; Hager, M. D.; Schubert, U. S. Fluorescent monomers as building blocks for dye labeled polymers: Synthesis and application in energy conversion, biolabeling and sensors. Chem. Soc. Rev. 2013, 42, 5366–5407.

    Article  Google Scholar 

  33. Huang, C. S.; Yin, Q.; Zhu, W. P.; Yang, Y.; Wang, X.; Qian, X. H.; Xu, Y. F. Highly selective fluorescent probe for vicinal-dithiol-containing proteins and in situ imaging in living cells. Angew. Chem., Int. Ed. 2011, 50, 7551–7556.

    Article  Google Scholar 

  34. Wang, J. S.; Zhao, C. Q.; Zhao, A. D.; Li, M.; Ren, J. S.; Qu, X. G. New insights in amyloid beta interactions with human telomerase. J. Am. Chem. Soc. 2015, 137, 1213–1219.

    Article  Google Scholar 

  35. Bolognesi, B.; Kumita, J. R.; Barros, T. P.; Esbjorner, E. K.; Luheshi, L. M.; Crowther, D. C.; Wilson, M. R.; Dobson, C. M.; Favrin, G.; Yerbury, J. J. ANS binding reveals common features of cytotoxic amyloid species. ACS Chem. Biol. 2010, 5, 735–740.

    Article  Google Scholar 

  36. Zhang, X. L.; Tian, Y. L.; Li, Z.; Tian, X. Y.; Sun, H. B.; Liu, H.; Moore, A.; Ran, C. Z. Design and synthesis of curcumin analogues for in vivo fluorescence imaging and inhibiting copper-induced cross-linking of amyloid beta species in Alzheimer’s disease. J. Am. Chem. Soc. 2013, 135, 16397–16409.

    Article  Google Scholar 

  37. Hamley, I. W. Peptide fibrillization. Angew. Chem., Int. Ed. 2007, 46, 8128–8147.

    Article  Google Scholar 

  38. Gao, N.; Sun, H. J.; Dong, K.; Ren, J. S.; Duan, T. C.; Xu, C.; Qu, X. G. Transition-metal-substituted polyoxometalate derivatives as functional anti-amyloid agents for Alzheimer’s disease. Nat. Commun. 2014, 5, 3422.

    Google Scholar 

  39. Li, M.; Liu, Z.; Ren, J. S.; Qu, X. G. Inhibition of metalinduced amyloid aggregation using light-responsive magnetic nanoparticle prochelator conjugates. Chem. Sci. 2012, 3, 868–873.

    Article  Google Scholar 

  40. Gao, N.; Sun, H. J.; Dong, K.; Ren, J. S.; Qu, X. G. Goldnanoparticle-based multifunctional amyloid-beta inhibitor against Alzheimer’s disease. Chem.— Eur. J. 2015, 21, 829–835.

    Article  Google Scholar 

  41. Geng, J.; Li, M.; Ren, J. S.; Wang, E. B.; Qu, X. G. Polyoxometalates as inhibitors of the aggregation of amyloid ß peptides associated with Alzheimer’s disease. Angew. Chem., Int. Ed. 2011, 50, 4184–4188.

    Article  Google Scholar 

  42. Hong, Y. N.; Meng, L. M.; Chen, S. J.; Leung, C. W. T.; Da, L. T.; Faisal, M.; Silva, D. A.; Liu, J. Z.; Lam, J. W. Y.; Huang, X. H. et al. Monitoring and inhibition of insulin fibrillation by a small organic fluorogen with aggregationinduced emission characteristics. J. Am. Chem. Soc. 2012, 134, 1680–1689.

    Article  Google Scholar 

  43. Li, C. X.; Born, A. K.; Schweizer, T.; Zenobi-Wong, M.; Cerruti, M.; Mezzenga, R. Amyloid-hydroxyapatite bone biomimetic composites. Adv. Mater. 2014, 26, 3207–3212.

    Article  Google Scholar 

  44. Bruce, I. J.; Sen, T. Surface modification of magnetic nanoparticles with alkoxysilanes and their application in magnetic bioseparations. Langmuir 2005, 21, 7029–7035.

    Article  Google Scholar 

  45. Guan, Y. J.; Li, M.; Dong, K.; Gao, N.; Ren, J. S.; Zheng, Y. C.; Qu, X. G. Ceria/POMs hybrid nanoparticles as a mimicking metallopeptidase for treatment of neurotoxicity of amyloid-ß peptide. Biomaterials 2016, 98, 92–102.

    Article  Google Scholar 

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Acknowledgements

Financial support was provided by the National Basic Research Program of China (973 Program) (No. 2012CB720602), the Project of Science and Technology Development Plan for Jilin Province (No. 20150520004JH) and the National Natural Science Foundation of China (NSFC) (Nos. 21210002, 21431007, 21402183 and 21533008).

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Authors and Affiliations

  1. Laboratory of Chemical Biology and State Key laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Changchun, 130022, China

    Zhi Du, Nan Gao, Yijia Guan, Chao Ding, Yuhuan Sun, Jinsong Ren & Xiaogang Qu

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  1. Zhi Du
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  2. Nan Gao
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  3. Yijia Guan
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  4. Chao Ding
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  5. Yuhuan Sun
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  6. Jinsong Ren
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  7. Xiaogang Qu
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Correspondence to Nan Gao or Xiaogang Qu.

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Du, Z., Gao, N., Guan, Y. et al. Rational design of a “sense and treat” system to target amyloid aggregates related to Alzheimer’s disease. Nano Res. 11, 1987–1997 (2018). https://doi.org/10.1007/s12274-017-1815-9

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  • DOI: https://doi.org/10.1007/s12274-017-1815-9

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