Advertisement

Drug Delivery and Translational Research

, Volume 9, Issue 1, pp 394–403 | Cite as

The synthesized transporter K16APoE enabled the therapeutic HAYED peptide to cross the blood-brain barrier and remove excess iron and radicals in the brain, thus easing Alzheimer’s disease

  • Zhenyou Zou
  • Qiqiong Shen
  • Yanxia Pang
  • Xin Li
  • Yongfeng Chen
  • Xinjuan Wang
  • Xinhua Luo
  • Zhongmin Wu
  • Zhaosheng Bao
  • Juanli Zhang
  • Jiawei Liang
  • Lingjia Kong
  • Lunan Yan
  • Lijun Xiong
  • Tianjun Zhu
  • Shuaibin Yuan
  • Miaoyang Wang
  • Kewei Cai
  • Yinning Yao
  • Jianchao Wu
  • Yuding Jiang
  • Heng Liu
  • Jing Liu
  • Yan Zhou
  • Qianqian Dong
  • Wei Wang
  • Kangjie Zhu
  • Li Li
  • Yingjie Lou
  • Hongdian Wang
  • Yizi Li
  • Hong Lin
Methods Paper
  • 48 Downloads

Abstract

Alzheimer’s disease (AD) is currently incurable and places a large burden on the caregivers of AD patients. In the AD brain, iron is abundant, catalyzing free radicals and impairing neurons. The blood-brain barrier hampers antidementia drug delivery via circulation to the brain, which limits the therapeutic effects of drugs. Here, according to the method described by Gobinda, we synthesized a 16 lysine (K) residue-linked low-density lipoprotein receptor-related protein (LRP)-binding amino acid segment of apolipoprotein E (K16APoE). By mixing this protein with our designed therapeutic peptide HAYED, we successfully transported HAYED into an AD model mouse brain, and the peptide scavenged excess iron and radicals and decreased the necrosis of neurons, thus easing AD.

Keywords

Alzheimer’s disease Iron Radical Blood-brain barrier K16APoE HAYED peptide 

Notes

Funding information

This study was supported by the Public Welfare Technology Research Grant for Zhejiang Social Development [2015C33248], Natural Science Foundation of Zhejiang Province [Y17H160027], Open Object of the Key Laboratory of Shanghai Forensic Medicine [KF1606], Taizhou Science and Technology Program [1501KY32], Taizhou University Research Fund [0104010004], Taizhou University Talent Fostering Fund [2015PY028], and Public Applied Technology Research Project of Zhejiang Province [2015C37081].

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

References

  1. 1.
    Querfurth HW, LaFerla FM. Alzheimer’s disease. N Engl J Med. 2010;362(4):329–44.CrossRefGoogle Scholar
  2. 2.
    Thompson CA, Spilsbury K, Hall J, Birks Y, Barnes C, Adamson J. Systematic review of information and support interventions for caregivers of people with dementia. BMC Geriatr. 2007;7:18.CrossRefGoogle Scholar
  3. 3.
    Gumienna-Kontecka E, Pyrkosz-Bulska M, (2014). Iron chelating strategies in systemic metal overload, neurodegeneration and cancer, Curr Med Chem. [Epub ahead of print].Google Scholar
  4. 4.
    Hardy J, Allsop D. Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol Sci. 1991;12(10):383–8.CrossRefGoogle Scholar
  5. 5.
    Mudher A, Lovestone S. Alzheimer’s disease-do tauists and baptists finally shake hands? Trends Neurosci. 2002;25(1):22–6.CrossRefGoogle Scholar
  6. 6.
    Zou Z, Ma C, Zou R, Cheng L, Wang J, Zhi H, et al. Transitional metals distribution in tissues of transgenic Alzhemier’s disease model mice, and the involved roles of AD. Journal of Nanjing Agricultural University. 2007;30(2):116–21. ChineseGoogle Scholar
  7. 7.
    Liu G, Men P, Perry G, Smith MA. Nanoparticle and iron chelators as a potential novel Alzheimer therapy. Methods Mol Biol. 2010;610:123–44.CrossRefGoogle Scholar
  8. 8.
    Kontoghiorghes GJ. New concepts of iron and aluminium chelation therapy with oral L1 (deferiprone) and other chelators. A Rev Anal. 1995;120:845–85.Google Scholar
  9. 9.
    McLachlan DR, Kruck TP, Lukiw WJ, Krishnan SS. Would decreased aluminum ingestion reduce the incidence of Alzheimer’s disease? CMAJ. 1991;145:793–804.Google Scholar
  10. 10.
    Crowe A, Morgan EH. Effects of chelators on iron uptake and release by the brain in the rat. Neurochem Res. 1994;19:71–6.CrossRefGoogle Scholar
  11. 11.
    Gassen M, Youdim MB. The potential role of iron chelators in the treatment of Parkinson’s disease and related neurological disorders. Pharmacol Toxicol. 1997;80:159–66.CrossRefGoogle Scholar
  12. 12.
    Bergeron RJ, Brittenham GM. The development of iron chelators for clinical use. CRC; Boca Raton, 1994, 353–371.Google Scholar
  13. 13.
    Galanello R, Campus S. Deferiprone chelation therapy for thalassemia major. Acta Haematol. 2009;122(2–3):155–64.CrossRefGoogle Scholar
  14. 14.
    Levy M. Observational Study of Deferiprone (Ferriprox®) in the Treatment of Superficial Siderosis, https://clinicaltrials.gov/ct2/show/NCT01284127.
  15. 15.
    Vivekanandan S, Brender JR, Lee SY, Ramamoorthy A. A partially folded structure of amyloid-beta(1-40) in an aqueous environment. Biochem Biophys Res Commun. 2011;411(2):312–6.CrossRefGoogle Scholar
  16. 16.
    Bousejra-ElGarah F, Bijani C, Coppel Y, Faller P, Hureau C. Iron (II) binding to amyloid-β, the Alzheimer’s peptide. Inorg Chem. 2011;50(18):9024–30.CrossRefGoogle Scholar
  17. 17.
    Atwood CS, Scarpa RC, Huang X, Moir RD, Jones WD, Fairlie DP. Characterization of copper interactions with Alzheimer amyloid beta peptides: identification of an attomolar-affinity copper binding site on amyloid beta1–42. J Neurochem. 2000;75(3):1219–33.CrossRefGoogle Scholar
  18. 18.
    Zhang W, Johnson BR, Suri DE, Martinez J, Bjornsson TD. Immunohistochemical demonstration of tissue transglutaminase in amyloid plaques. Acta Neuropathol. 1998;96(4):395–400.CrossRefGoogle Scholar
  19. 19.
    Gobinda S, Geoffry LC, Eric M, Teresa D, Thomas M, Wengenack, et al. A carrier for non-covalent delivery of functional Beta-galactosidase and antibodies against amyloid plaques and IgM to the brain. PLoS One. 2001;6(12):e28881.Google Scholar
  20. 20.
    Deane R, Sagare A, Hamm K, Parisi M, LaRue B, Guo H, et al. IgG-assisted age dependent clearance of Alzheimer’s amyloid beta peptide by the blood-brain barrier neonatal Fc receptor. J Neurosci. 2005;25:11495–503.CrossRefGoogle Scholar
  21. 21.
    Jefferies WA, Brandon MR, Hunt SV, Williams AF, Gatter KC, Mason DY. Transferrin receptor on endothelium of brain capillaries. Nature. 1984;312:162–3.CrossRefGoogle Scholar
  22. 22.
    Zlokovic BV, Jovanovic S, Miao W, Samara S, Verma S, Farrell CL. Differential regulation of leptin transport by the choroid plexus and blood-brain barrier and high affinity transport systems for entry into hypothalamus and across the blood-cerebrospinal fluid barrier. Endocrinology. 2000;141:1434–41.CrossRefGoogle Scholar
  23. 23.
    Gabathuler R. Approaches to transport therapeutic drugs across the blood–brain barrier to treat brain diseases. Neurobiol Dis. 2010;37:48–57.CrossRefGoogle Scholar
  24. 24.
    Spencer BJ, Verma IM. Targeted delivery of proteins across the blood brain barrier. Proc Natl Acad Sci U S A. 2007;104:7594–9.CrossRefGoogle Scholar
  25. 25.
    Bush AI. Metal complexing agents as therapies for Alzheimer’s disease. Trends in Neurobiol Aging. 2003;25:1031–8.Google Scholar
  26. 26.
    Danielle GS, Roberto C, Kevin JB. The redox chemistry of the Alzheimer’s disease amyloid β peptide. Biochim Biophys Acta. 2007;1768:1976–90.CrossRefGoogle Scholar
  27. 27.
    Connor JR, Menzies SL, St. Martin SM, Mufson EJ. A histochemical study of iron, transferrin, and ferritin in Alzheimer’s disease brains. J Neurosci Res. 1992;31(1:75–83.CrossRefGoogle Scholar
  28. 28.
    Lahiri DK, Maloney B. Beyond the signaling effect role of amyloid–β 42 on the processing of AβPP, and its clinical implications. Exp Neurol. 2010;225(1):51–4.CrossRefGoogle Scholar

Copyright information

© Controlled Release Society 2018

Authors and Affiliations

  • Zhenyou Zou
    • 1
    • 2
  • Qiqiong Shen
    • 1
  • Yanxia Pang
    • 3
  • Xin Li
    • 1
  • Yongfeng Chen
    • 1
  • Xinjuan Wang
    • 1
  • Xinhua Luo
    • 4
  • Zhongmin Wu
    • 1
  • Zhaosheng Bao
    • 1
  • Juanli Zhang
    • 1
  • Jiawei Liang
    • 1
  • Lingjia Kong
    • 1
  • Lunan Yan
    • 1
  • Lijun Xiong
    • 1
  • Tianjun Zhu
    • 1
  • Shuaibin Yuan
    • 1
  • Miaoyang Wang
    • 1
  • Kewei Cai
    • 1
  • Yinning Yao
    • 1
  • Jianchao Wu
    • 1
  • Yuding Jiang
    • 1
  • Heng Liu
    • 1
  • Jing Liu
    • 1
  • Yan Zhou
    • 1
  • Qianqian Dong
    • 1
  • Wei Wang
    • 1
  • Kangjie Zhu
    • 1
  • Li Li
    • 5
  • Yingjie Lou
    • 1
  • Hongdian Wang
    • 1
  • Yizi Li
    • 1
  • Hong Lin
    • 1
  1. 1.Medical College of Taizhou UniversityTaizhouChina
  2. 2.Biochemistry Department of Purdue UniversityWest LafayetteUSA
  3. 3.Shanghai Key Laboratory of Forensic Medicine, Shanghai Forensic Service PlatformAcademy of Forensic ScienceShanghaiChina
  4. 4.Clinic Laboratory of Taizhou Municipal HospitalTaizhouChina
  5. 5.Oncogenomics Division of Netherlands Cancer InstituteAmsterdamNetherlands

Personalised recommendations