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.Alzheimer's | amyloid | imaging | fluorescence | curcumin

Protease-resistant modified human β-hexosaminidase B ameliorates symptoms in GM2 gangliosidosis model

“…In recent years, the molecular imaging with fluorescent probes has been widely applied to monitoring therapy of cancer and other diseases in preclinical studies (12,48,49). In this study, we firstly established an enzyme replacement imaging system to visualize the intracellular β-Hex activity of modified HexBs incorporated into living cultured SD fibroblasts with a newly developed fluorescent substrate, HMDER-βGlcNAc specific for the β-Hex, based on the design of previous report (48,50).…”

“…This fluorescent probe will also be useful for imaging or chase of other lysosomal enzymes and related proteins in acidic cellular compartments (late endosomes/lysosomes). Near-infrared fluorescence molecular imaging of amyloid β species and monitoring therapy in animal models of AD was reported (49). Such monitoring methods with fluorescent probes capable of assisting drug development is highly desirable for monitoring therapy of neurological disorders for not only preclinical studies using animal disease models, but also clinical trials and applications to disease patients.…”

Layer-by-layer assembled fluorescent probes in the second near-infrared window for systemic delivery and detection of ovarian cancer

“…F luorescence-based optical imaging is a broadly applied imaging technique that provides a nondestructive means for detecting disease, monitoring disease progression, and evaluating treatment outcome (1)(2)(3)(4). Compared with tomographic imaging techniques, such as magnetic resonance imaging and computed tomography, fluorescence imaging yields quicker results at a lower cost (5).…”

P1‐104: Imaging Hydrogen Peroxide in Alzheimer’s Disease Via Cascade Signal Amplification

“…However, utilizing this method for cascade signal amplification has not been explored. In our previous studies, we demonstrated that CRANAD-58 was a "smart" NIRF probe for Aβ s, and displayed about a 100-fold intensity increase after binding to Aβ s [28][29][30][31] . To achieve cascade signal amplification, we integrated our previous Aβ "smart" probe strategy into the design of an H 2 O 2 responsive probe.…”

“…To quantitatively calculate the relative H 2 O 2 changes during ageing and longitudinal therapy monitoring, we will use the ratio between CRANAD-88 and CRANAD-3 (R H 2 O 2 = R (CRANAD-88) /R (CRANAD-3) ). For CRANAD-3, our previous data showed that it could reflect the changes in Aβ s during ageing and treatment 31 . Using the ratio of the two probes, we will be able to reliably calculate relative H 2 O 2 changes in the longitudinal studies.…”