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The shape effect of reconstituted high-density lipoprotein nanocarriers on brain delivery and Aβ clearance

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Abstract

Accumulation of extracellular β-amyloid (Aβ) is crucial for the pathogenesis of Alzheimer’s disease (AD), and the development of novel therapeutic agents that can both accelerate Aβ clearance and inhibit the subsequent pathological cascades is regarded as a promising strategy for AD management. In our previous study, we have constructed discoidal apolipoprotein E3–reconstituted high-density lipoprotein (ApoE3-rHDL) as an efficient nanoplatform that can penetrate the blood–brain barrier and accelerate Aβ clearance for a combination treatment of AD. To further improve its drug loading capacity, we hypothesized that spherical rHDL might serve as a more powerful nanocarrier if it has the same brain delivery and Aβ clearance abilities as the discoidal rHDL does. To evaluate the potential of spherical rHDL as a promising alternative for the combination therapy for AD, here, we investigated the effect of the shape of rHDL on its brain delivery, Aβ clearance, and anti-AD efficacy. We found that spherical rHDL had stronger Aβ-binding affinity than discoidal rHDL did, more effectively facilitated microglial uptake and degradation of Aβ1–42, achieved better brain distribution after intravenous administration, and more powerfully reduced Aβ deposition, decreased microglia activation, attenuated neurological damage, and rescued memory deficits in a mouse model of AD. Among the rHDLs evaluated, monosialotetrahexosyl ganglioside–incorporated spherical rHDL exerted the best effect. The findings of this study for the first time show a shape effect of an rHDL nanocarrier on its biological functions and suggest that a spherical lipoprotein-mimic nanocarrier may serve as a more efficient multifunctional nanoplatform for AD therapy.

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References

  1. Kuai, R.; Li, D.; Chen, Y. E.; Moon, J. J.; Schwendeman, A. High-density lipoproteins: Nature’s multifunctional nanoparticles. ACS Nano 2016, 10, 3015–3041.

    Article  Google Scholar 

  2. Mo, Z. C.; Ren, K.; Liu, X.; Tang, Z. L.; Yi, G. H. A high-density lipoprotein-mediated drug delivery system. Adv. Drug Deliv. Rev. 2016, 106, 132–147.

    Article  Google Scholar 

  3. Damiano, M. G.; Mutharasan, R. K.; Tripathy, S.; McMahon, K. M.; Thaxton, C. S. Templated high density lipoprotein nanoparticles as potential therapies and for molecular delivery. Adv. Drug Deliv. Rev. 2013, 65, 649–662.

    Article  Google Scholar 

  4. Bricarello, D. A.; Smilowitz, J. T.; Zivkovic, A. M.; German, J. B.; Parikh, A. N. Reconstituted lipoprotein: A versatile class of biologically-inspired nanostructures. ACS Nano 2011, 5, 42–57.

    Article  Google Scholar 

  5. Thaxton, C. S.; Rink, J. S.; Naha, P. C.; Cormode, D. P. Lipoproteins and lipoprotein mimetics for imaging and drug delivery. Adv. Drug Deliv. Rev. 2016, 106, 116–131.

    Article  Google Scholar 

  6. Simonsen, J. B. Evaluation of reconstituted high-density lipoprotein (rHDL) as a drug delivery platform-a detailed survey of rHDL particles ranging from biophysical properties to clinical implications. Nanomedicine 2016, 12, 2161–2179.

    Article  Google Scholar 

  7. Huang, H.; Cruz, W.; Chen, J.; Zheng, G. Learning from biology: Synthetic lipoproteins for drug delivery. Wiley Interdiscip. Rev.: Nanomed. Nanobiotechnol. 2015, 7, 298–314.

    Google Scholar 

  8. Zhang, W. L.; He, H. L.; Liu, J. P.; Wang, J.; Zhang, S. Y.; Zhang, S. S.; Wu, Z. M. Pharmacokinetics and atherosclerotic lesions targeting effects of tanshinone II–A discoidal and spherical biomimetic high density lipoproteins. Biomaterials 2013, 34, 306–319.

    Article  Google Scholar 

  9. Zhang, W. L.; Xiao, Y.; Liu, J. P.; Wu, Z. M.; Gu, X.; Xu, Y. M.; Lu, H. Structure and remodeling behavior of drugloaded high density lipoproteins and their atherosclerotic plaque targeting mechanism in foam cell model. Int. J. Pharm. 2011, 419, 314–321.

    Article  Google Scholar 

  10. Hebert, L. E.; Weuve, J.; Scherr, P. A.; Evans, D. A. Alzheimer disease in the United States (2010–2050) estimated using the 2010 census. Neurology 2013, 80, 1778–1783.

    Article  Google Scholar 

  11. Wang, J.; Gu, B. J.; Masters, C. L.; Wang, Y. J. A systemic view of Alzheimer disease-insights from amyloid-β metabolism beyond the brain. Nat. Rev. Neurol. 2017, 13, 612–623.

    Article  Google Scholar 

  12. Kurochkin, I. V.; Guarnera, E.; Berezovsky, I. N. Insulindegrading enzyme in the fight against Alzheimer’s disease. Trends Pharmacol. Sci. 2018, 39, 49–58.

    Article  Google Scholar 

  13. Villemagne, V. L.; Doré, V.; Burnham, S. C.; Masters, C. L.; Rowe, C. C. Imaging tau and amyloid-β proteinopathies in Alzheimer disease and other conditions. Nat. Rev. Neurol. 2018, 14, 225–236.

    Article  Google Scholar 

  14. Lee, S. J. C.; Nam, E.; Lee, H. J.; Savelieff, M. G.; Lim, M. H. Towards an understanding of amyloid-β oligomers: Characterization, toxicity mechanisms, and inhibitors. Chem. Soc. Rev. 2017, 46, 310–323.

    Article  Google Scholar 

  15. Hyman, B. T. Amyloid-dependent and amyloid-independent stages of Alzheimer disease. Arch. Neurol. 2011, 68, 1062–1064.

    Article  Google Scholar 

  16. Heneka, M. T.; Golenbock, D. T.; Latz, E. Innate immunity in Alzheimer’s disease. Nat. Immunol. 2015, 16, 229–236.

    Article  Google Scholar 

  17. Reiss, A. B.; Arain, H. A.; Stecker, M. M.; Siegart, N. M.; Kasselman, L. J. Amyloid toxicity in Alzheimer’s disease. Rev. Neurosci., in press, DOI: 10.1515/revneuro-2017-0063.

  18. Sevigny, J.; Chiao, P.; Bussière, T.; Weinreb, P. H.; Williams, L.; Maier, M.; Dunstan, R.; Salloway, S.; Chen, T.; Ling, Y. et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 2016, 537, 50–56.

    Article  Google Scholar 

  19. Song, Q. X.; Huang, M.; Yao, L.; Wang, X. L.; Gu, X.; Chen, J.; Chen, J.; Huang, J. L.; Hu, Q. Y.; Kang, T. et al. Lipoprotein-based nanoparticles rescue the memory loss of mice with Alzheimer’s disease by accelerating the clearance of amyloid-beta. ACS Nano 2014, 8, 2345–2359.

    Article  Google Scholar 

  20. Song, Q. X.; Song, H. H.; Xu, J. R.; Huang, J. L.; Hu, M.; Gu, X.; Chen, J.; Zheng, G.; Chen, H. Z.; Gao, X. L. Biomimetic ApoE-reconstituted high density lipoprotein nanocarrier for blood-brain barrier penetration and amyloid beta-targeting drug delivery. Mol. Pharm. 2016, 13, 3976–3987.

    Article  Google Scholar 

  21. Huang, M.; Hu, M.; Song, Q. X.; Song, H. H.; Huang, J. L.; Gu, X.; Wang, X. L.; Chen, J.; Kang, T.; Feng, X. Y. et al. GM1-modified lipoprotein-like nanoparticle: Multifunctional nanoplatform for the combination therapy of Alzheimer’s disease. ACS Nano 2015, 9, 10801–10816.

    Article  Google Scholar 

  22. Huang, J. L.; Jiang, G.; Song, Q. X.; Gu, X.; Hu, M.; Wang, X. L.; Song, H. H.; Chen, L. P.; Lin, Y. Y.; Jiang, D. et al. Lipoprotein-biomimetic nanostructure enables efficient targeting delivery of siRNA to Ras-activated glioblastoma cells via macropinocytosis. Nat. Commun. 2017, 8, 15144.

    Article  Google Scholar 

  23. Schwendeman, A.; Sviridov, D. O.; Yuan, W. M.; Guo, Y. H.; Morin, E. E.; Yuan, Y.; Stonik, J.; Freeman, L.; Ossoli, A.; Thacker, S. et al. The effect of phospholipid composition of reconstituted HDL on its cholesterol efflux and anti-inflammatory properties. J. Lipid Res. 2015, 56, 1727–1737.

    Article  Google Scholar 

  24. Gentile, F.; Chiappini, C.; Fine, D.; Bhavane, R. C.; Peluccio, M. S.; Cheng, M. M. C.; Liu, X.; Ferrari, M.; Decuzzi, P. The effect of shape on the margination dynamics of non-neutrally buoyant particles in two-dimensional shear flows. J. Biomech. 2008, 41, 2312–2318.

    Article  Google Scholar 

  25. Molino, Y.; David, M.; Varini, K.; Jabès, F.; Gaudin, N.; Fortoul, A.; Bakloul, K.; Masse, M.; Bernard, A.; Drobecq, L. et al. Use of LDL receptor-targeting peptide vectors for in vitro and in vivo cargo transport across the blood-brain barrier. FASEB J. 2017, 31, 1807–1827.

    Article  Google Scholar 

  26. Basak, J. M.; Verghese, P. B.; Yoon, H.; Kim, J.; Holtzman, D. M. Low-density lipoprotein receptor represents an apolipoprotein E-independent pathway of Aβ uptake and degradation by astrocytes. J. Biol. Chem. 2012, 287, 13959–13971.

    Article  Google Scholar 

  27. Wang, D. R.; El-Amouri, S. S.; Dai, M.; Kuan, C. Y.; Hui, D. Y.; Brady, R. O.; Pan, D. Engineering a lysosomal enzyme with a derivative of receptor-binding domain of apoE enables delivery across the blood-brain barrier. Proc. Natl. Acad. Sci. USA 2013, 110, 2999–3004.

    Article  Google Scholar 

  28. Prévost, M.; Raussens, V. Apolipoprotein E-low density lipoprotein receptor binding: Study of protein-protein interaction in rationally selected docked complexes. Proteins 2004, 55, 874–884.

    Article  Google Scholar 

  29. Rajora, M. A.; Ding, L.; Valic, M.; Jiang, W.; Overchuk, M.; Chen, J.; Zheng, G. Tailored theranostic apolipoprotein E3 porphyrin-lipid nanoparticles target glioblastoma. Chem. Sci. 2017, 8, 5371–5384.

    Article  Google Scholar 

  30. Stine, W. B., Jr.; Dahlgren, K. N.; Krafft, G. A.; La Du, M. J. In vitro characterization of conditions for amyloid-β peptide oligomerization and fibrillogenesis. J. Biol. Chem. 2003, 278, 11612–11622.

    Article  Google Scholar 

  31. Robert, J.; Stukas, S.; Button, E.; Cheng, W. H.; Lee, M.; Fan, J. J.; Wilkinson, A.; Kulic, I.; Wright, S. D.; Wellington, C. L. Reconstituted high-density lipoproteins acutely reduce soluble brain Aβ levels in symptomatic APP/PS1 mice. Biochim. Biophys. Acta 2016, 1862, 1027–1036.

    Article  Google Scholar 

  32. Chiu, I. M.; Phatnani, H.; Kuligowski, M.; Tapia, J. C.; Carrasco, M. A.; Zhang, M.; Maniatis, T.; Carroll, M. C. Activation of innate and humoral immunity in the peripheral nervous system of ALS transgenic mice. Proc. Natl. Acad. Sci. USA 2009, 106, 20960–20965.

    Article  Google Scholar 

  33. Yao, L.; Gu, X.; Song, Q. X.; Wang, X. L.; Huang, M.; Hu, M.; Hou, L. N.; Kang, T.; Chen, J.; Chen, H. Z. et al. Nanoformulated alpha-mangostin ameliorates Alzheimer’s disease neuropathology by elevating LDLR expression and accelerating amyloid-beta clearance. J. Control. Release 2016, 226, 1–14.

    Article  Google Scholar 

  34. Portioli, C.; Bovi, M.; Benati, D.; Donini, M.; Perduca, M.; Romeo, A.; Dusi, S.; Monaco, H. L.; Bentivoglio, M. Novel functionalization strategies of polymeric nanoparticles as carriers for brain medications. J. Biomed. Mater. Res. A 2017, 105, 847–858.

    Article  Google Scholar 

  35. Ćurić, A.; Möschwitzer, J. P.; Fricker, G. Development and characterization of novel highly-loaded itraconazole poly(butyl cyanoacrylate) polymeric nanoparticles. Eur. J. Pharm. Biopharm. 2017, 114, 175–185.

    Article  Google Scholar 

  36. Calabuig-Navarro, M. V.; Jackson, K. G.; Kemp, C. F.; Leake, D. S.; Walden, C. M.; Lovegrove, J. A.; Minihane, A. M. A randomized trial and novel SPR technique identifies altered lipoprotein-LDL receptor binding as a mechanism underlying elevated LDL-cholesterol in APOE4s. Sci. Rep. 2017, 7, 44119.

    Article  Google Scholar 

  37. Tassa, C.; Duffner, J. L.; Lewis, T. A.; Weissleder, R.; Schreiber, S. L.; Koehler, A. N.; Shaw, S. Y. Binding affinity and kinetic analysis of targeted small molecule-modified nanoparticles. Bioconjug. Chem. 2010, 21, 14–19.

    Article  Google Scholar 

  38. Yin, T. T.; Yang, L. C.; Liu, Y.; Zhou, X. B.; Sun, J.; Liu, J. Sialic acid (SA)-modified selenium nanoparticles coated with a high blood-brain barrier permeability peptide-B6 peptide for potential use in Alzheimer’s disease. Acta Biomater. 2015, 25, 172–183.

    Article  Google Scholar 

  39. Li, Y.; Kröger, M.; Liu, W. K. Shape effect in cellular uptake of PEGylated nanoparticles: Comparison between sphere, rod, cube and disk. Nanoscale 2015, 7, 16631–16646.

    Article  Google Scholar 

  40. Goedert, M. NEURODEGENERATION. Alzheimer’s and Parkinson’s diseases: The prion concept in relation to assembled Aβ, tau, and α-synuclein. Science 2015, 349, 1255555.

    Google Scholar 

  41. Goldstein, L. E.; Muffat, J. A.; Cherny, R. A.; Moir, R. D.; Ericsson, M. H.; Huang, X. D.; Mavros, C.; Coccia, J. A.; Faget, K. Y.; Fitch, K. A. et al. Cytosolic β-amyloid deposition and supranuclear cataracts in lenses from people with Alzheimer’s disease. Lancet 2003, 361, 1258–1265.

    Article  Google Scholar 

  42. Jarrett, J. T.; Lansbury, P. T., Jr. Seeding “one-dimensional crystallization” of amyloid: A pathogenic mechanism in Alzheimer’s disease and scrapie? Cell 1993, 73, 1055–1058.

    Article  Google Scholar 

  43. Colvin, M. T.; Silvers, R.; Ni, Q. Z.; Can, T. V.; Sergeyev, I.; Rosay, M.; Donovan, K. J.; Michael, B.; Wall, J.; Linse, S. et al. Atomic resolution structure of monomorphic Aβ42 amyloid fibrils. J. Am. Chem. Soc. 2016, 138, 9663–9674.

    Article  Google Scholar 

  44. He, Z. H.; Guo, J. L.; McBride, J. D.; Narasimhan, S.; Kim, H.; Changolkar, L.; Zhang, B.; Gathagan, R. J.; Yue, C. Y.; Dengler, C. et al. Amyloid-β plaques enhance Alzheimer’s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat. Med. 2018, 24, 29–38.

    Article  Google Scholar 

  45. Dahlgren, K. N.; Manelli, A. M.; Stine, W.B., Jr.; Baker, L. K.; Krafft, G. A.; LaDu, M. J. Oligomeric and fibrillar species of amyloid-β peptides differentially affect neuronal viability. J. Biol. Chem. 2002, 277, 32046–32053.

    Article  Google Scholar 

  46. Jan, A.; Gokce, O.; Luthi-Carter, R.; Lashuel, H. A. The ratio of monomeric to aggregated forms of Abeta40 and Abeta42 is an important determinant of amyloid-beta aggregation, fibrillogenesis, and toxicity. J. Biol. Chem. 2008, 283, 28176–28189.

    Article  Google Scholar 

  47. Colvin, M. T.; Silvers, R.; Frohm, B.; Su, Y. C.; Linse, S.; Griffin, R. G. High resolution structural characterization of Aβ42 amyloid fibrils by magic angle spinning NMR. J. Am. Chem. Soc. 2015, 137, 7509–7518.

    Article  Google Scholar 

  48. Yu, J. T.; Tan, L.; Hardy, J. Apolipoprotein E in Alzheimer’s disease: An update. Annu. Rev. Neurosci. 2014, 37, 79–100.

    Article  Google Scholar 

  49. Tokuda, T.; Calero, M.; Matsubara, E.; Vidal, R.; Kumar, A.; Permanne, B.; Zlokovic, B.; Smith, J. D.; Ladu, M. J.; Rostagno, A. et al. Lipidation of apolipoprotein E influences its isoform-specific interaction with Alzheimer’s amyloid beta peptides. Biochem. J. 2000, 348, 359–365.

    Google Scholar 

  50. Kurz, A.; Perneczky, R. Amyloid clearance as a treatment target against Alzheimer’s disease. J. Alzheimers Dis. 2011, 24, 61–73.

    Article  Google Scholar 

  51. Feng, C. Z.; Yin, J. B.; Yang, J. J.; Cao, L. Regulatory factor X1 depresses ApoE-dependent Aβ uptake by miRNA-124 in microglial response to oxidative stress. Neuroscience 2017, 344, 217–228.

    Article  Google Scholar 

  52. 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 

  53. 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-β peptide. Biomaterials 2016, 98, 92–102.

    Article  Google Scholar 

  54. Butterfield, D. A.; Poon, H. F. The senescence-accelerated prone mouse (SAMP8): A model of age-related cognitive decline with relevance to alterations of the gene expression and protein abnormalities in Alzheimer’s disease. Exp. Gerontol. 2005, 40, 774–783.

    Article  Google Scholar 

  55. Akiguchi, I.; Pallàs, M.; Budka, H.; Akiyama, H.; Ueno, M.; Han, J. X.; Yagi, H.; Nishikawa, T.; Chiba, Y.; Sugiyama, H. et al. SAMP8 mice as a neuropathological model of accelerated brain aging and dementia: Toshio Takeda’s legacy and future directions. Neuropathology 2017, 37, 293–305.

    Article  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 81373351, 81573382, 81722043, and 81503174), the National Science and Technology Major Project (No. 2018ZX09734005-007), the National Youth Talent Support Program, grant from Shanghai Science and Technology Committee (No. 15540723700), and “Shu Guang” project supported by Shanghai Municipal Education Commission and Shanghai Education Development Foundation (No. 15SG14).

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  1. Huahua Song, Xinyi Ma, and Jianrong Xu contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology and Chemical Biology, Faculty of Basic Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China

    Huahua Song, Xinyi Ma, Jianrong Xu, Qingxiang Song, Meng Hu, Xiao Gu, Qian Zhang, Lina Hou, Lepei Chen, Ping Yu, Dayuan Wang, Gan Jiang, Meng Huang, Hongzhuan Chen & Xiaoling Gao

  2. Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai, 201203, China

    Yukun Huang & Jun Chen

  3. Department of Pharmacy, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China

    Meng Hu

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  1. Huahua Song
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Correspondence to Hongzhuan Chen or Xiaoling Gao.

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Song, H., Ma, X., Xu, J. et al. The shape effect of reconstituted high-density lipoprotein nanocarriers on brain delivery and Aβ clearance. Nano Res. 11, 5615–5628 (2018). https://doi.org/10.1007/s12274-018-2107-8

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