Molecular Imaging Laboratory, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129.
School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Proc Natl Acad Sci U S A. 2017 Nov 21;114(47):12384-12389. doi: 10.1073/pnas.1706248114. Epub 2017 Nov 6.
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.
阿尔茨海默病（AD）是一种不可逆的神经退行性疾病，其进展与氧化应激密切相关。长期以来，人们一直推测 AD 大脑中的活性氧（ROS）水平远高于健康大脑。然而，来自生物的证据很少。受“发光棒化学”的启发，我们设计了一种近红外荧光（NIRF）成像探针，称为 CRANAD-61，用于感测 ROS，以在微观和宏观层面提供证据。在 CRANAD-61 中，利用草酸盐部分与 ROS 反应，从而产生波长移动。我们的体外数据表明，CRANAD-61 对各种 ROS 高度敏感且快速响应。与 ROS 反应后，其激发和发射波长显著移至短波长，并且可以利用这种移动进行双色双光子成像和变革性的近红外荧光成像。在本报告中，我们表明 CRANAD-61 可用于通过双光子成像（微观水平）识别“活性”淀粉样β（Aβ）斑块和周围 ROS 水平高的脑淀粉样血管病（CAA），并通过全脑 NIRF 成像（宏观水平）提供 AD 大脑中的相对总 ROS 浓度。最后，我们表明可以使用我们的 NIRF 成像方法监测 AD 大脑中 ROS 水平随年龄的增加。我们相信，我们使用 CRANAD-61 进行的成像可以在微观和宏观水平上提供 ROS 的证据，并可用于监测各种 AD 病理条件下和药物治疗期间 ROS 的变化。
