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Oxalate-curcumin–based probe for micro- and macroimaging of reactive oxygen species in Alzheimer’s disease

  1. Chongzhao Rana,2
  1. aMolecular Imaging Laboratory, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129;
  2. bSchool of Pharmacy, China Pharmaceutical University, Nanjing 210009, China;
  3. cDepartment of Neurology, Yale University, New Haven, CT 06520;
  4. dDepartment of Biology, Stanford University, Stanford, CA 94304;
  5. eSchool of Pharmaceutical Sciences, Soochow University, Suzhou 215006, China;
  6. fDepartment of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019
  1. Edited by Gregory A. Petsko, Weill Cornell Medical College, New York, NY, and approved October 6, 2017 (received for review April 14, 2017)

Significance

It has long been speculated that Alzheimer’s disease (AD) is tightly associated with oxidative stress and high concentrations of reactive oxygen species (ROS) in the brain. However, comprehensive evidence from living beings is rare. In this report, inspired by the “chemistry of glow stick,” we designed oxalate-curcumin–based imaging probes to provide evidence of high ROS concentrations in AD brains in animal studies at micro- and macrolevels. At the microlevel, our imaging method identified “active” amyloid beta plaques and cerebral amyloid angiopathy via dual-color two-photon imaging. At the macrolevel, our probe could detect relatively high ROS concentrations in AD brains using near-IR fluorescence imaging. We believe that our method will be an indispensable tool for investigating ROS in living beings.

Abstract

Alzheimer’s disease (AD) is an irreversible neurodegenerative disorder that has a progression that is closely associated with oxidative stress. It has long been speculated that the reactive oxygen species (ROS) level in AD brains is much higher than that in healthy brains. However, evidence from living beings is scarce. Inspired by the “chemistry of glow stick,” we designed a near-IR fluorescence (NIRF) imaging probe, termed CRANAD-61, for sensing ROS to provide evidence at micro- and macrolevels. In CRANAD-61, an oxalate moiety was utilized to react with ROS and to consequentially produce wavelength shifting. Our in vitro data showed that CRANAD-61 was highly sensitive and rapidly responsive to various ROS. On reacting with ROS, its excitation and emission wavelengths significantly shifted to short wavelengths, and this shifting could be harnessed for dual-color two-photon imaging and transformative NIRF imaging. In this report, we showed that CRANAD-61 could be used to identify “active” amyloid beta (Aβ) plaques and cerebral amyloid angiopathy (CAA) surrounded by high ROS levels with two-photon imaging (microlevel) and to provide relative total ROS concentrations in AD brains via whole-brain NIRF imaging (macrolevel). Lastly, we showed that age-related increases in ROS levels in AD brains could be monitored with our NIRF imaging method. We believe that our imaging with CRANAD-61 could provide evidence of ROS at micro- and macrolevels and could be used for monitoring ROS changes under various AD pathological conditions and during drug treatment.

Footnotes

  • ?1Jian Yang, X.Z., and P.Y. contributed equally to this work.

  • ?2To whom correspondence should be addressed. Email: cran{at}nmr.mgh.harvard.edu.
  • Author contributions: Jian Yang, X.Z., P.Y., and C.R. designed research; Jian Yang, X.Z., P.Y., Jing Yang, Y.S., and C.R. performed research; Jian Yang, X.Z., P.Y., and C.R. contributed new reagents/analytic tools; Jian Yang, X.Z., P.Y., Y.S., and C.R. analyzed data; and Jian Yang, X.Z., P.Y., Jing Yang, Y.X., J.G., Y.S., A.M., and C.R. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.danielhellerman.com/lookup/suppl/doi:10.1073/pnas.1706248114/-/DCSupplemental.

Published under the PNAS license.

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