title: Near-infrared fluorescence molecular imaging of amyloid beta species and monitoring therapy in animal models of Alzheimer's disease.
abstract: Near-infrared fluorescence (NIRF) molecular imaging has been widely applied to monitoring therapy of cancer and other diseases in preclinical studies; however, this technology has not been applied successfully to monitoring therapy for Alzheimer's disease (AD). Although several NIRF probes for detecting amyloid beta (Aβ) species of AD have been reported, none of these probes has been used to monitor changes of Aβs during therapy. In this article, we demonstrated that CRANAD-3, a curcumin analog, is capable of detecting both soluble and insoluble Aβ species. In vivo imaging showed that the NIRF signal of CRANAD-3 from 4-mo-old transgenic AD (APP/PS1) mice was 2.29-fold higher than that from age-matched wild-type mice, indicating that CRANAD-3 is capable of detecting early molecular pathology. To verify the feasibility of CRANAD-3 for monitoring therapy, we first used the fast Aβ-lowering drug LY2811376, a well-characterized beta-amyloid cleaving enzyme-1 inhibitor, to treat APP/PS1 mice. Imaging data suggested that CRANAD-3 could monitor the decrease in Aβs after drug treatment. To validate the imaging capacity of CRANAD-3 further, we used it to monitor the therapeutic effect of CRANAD-17, a curcumin analog for inhibition of Aβ cross-linking. The imaging data indicated that the fluorescence signal in the CRANAD-17-treated group was significantly lower than that in the control group, and the result correlated with ELISA analysis of brain extraction and Aβ plaque counting. It was the first time, to our knowledge, that NIRF was used to monitor AD therapy, and we believe that our imaging technology has the potential to have a high impact on AD drug development.
authors.affiliation: Molecular Imaging Laboratory, Massachusetts General Hospital/Massachusetts Institute of Technology/Harvard Medical School Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School, Charlestown, MA 02129; School of Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China; Department of Pharmacy, ZhongDa Hospital, Southeast University, Nanjing 210009, People's Republic of China;
authors.forename: Xueli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Molecular Imaging Laboratory, Massachusetts General Hospital/Massachusetts Institute of Technology/Harvard Medical School Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School, Charlestown, MA 02129; Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, People's Republic of China;
authors.forename: Yanli
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129;
authors.forename: Can
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Center for Drug Discovery, Northeastern University, Boston MA 02115.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Tian
authors.affiliation: Molecular Imaging Laboratory, Massachusetts General Hospital/Massachusetts Institute of Technology/Harvard Medical School Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School, Charlestown, MA 02129;
authors.forename: Alana W
authors.initials: AW
authors.lastname: Ross
authors.affiliation: Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129;
authors.forename: Robert D
authors.initials: RD
authors.lastname: Moir
authors.affiliation: School of Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China;
authors.forename: Hongbin
authors.initials: H
authors.lastname: Sun
authors.affiliation: Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129;
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
authors.affiliation: Molecular Imaging Laboratory, Massachusetts General Hospital/Massachusetts Institute of Technology/Harvard Medical School Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School, Charlestown, MA 02129; amoore@helix.mgh.harvard.edu cran@nmr.mgh.harvard.edu.
authors.forename: Anna
authors.initials: A
authors.lastname: Moore
authors.affiliation: Molecular Imaging Laboratory, Massachusetts General Hospital/Massachusetts Institute of Technology/Harvard Medical School Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School, Charlestown, MA 02129; amoore@helix.mgh.harvard.edu cran@nmr.mgh.harvard.edu.
authors.forename: Chongzhao
authors.initials: C
authors.lastname: Ran
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D052160:Benzothiazoles; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D004195:Disease Models, Animal; D016903:Drug Monitoring; D005456:Fluorescent Dyes / Q000138:chemical synthesis / Q000737:chemistry; D006801:Humans; D008822:Mice, Transgenic; D057054:Molecular Imaging / Q000379:methods*; D017785:Photons; D053764:Presenilin-1 / Q000378:metabolism; D066244:Proton Magnetic Resonance Spectroscopy; D013050:Spectrometry, Fluorescence; D019265:Spectroscopy, Near-Infrared; D013844:Thiazoles / Q000378:metabolism; D014020:Tissue Extracts; D017186:Titrimetry
chemical_list: D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D005456:Fluorescent Dyes; D053764:Presenilin-1; D013844:Thiazoles; D014020:Tissue Extracts; C009462:thioflavin T
keywords: Alzheimer's; amyloid; curcumin; fluorescence; imaging