# Near infrared fluorescence imaging of reactive oxygen species in Alzheimer's disease

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $419,880

## Abstract

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder, whose progression 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 rare. Studies
suggest that a vicious cycle revolves around amyloid beta (Aβ) and Tau production/aggregation, microglia
responses, inflammatory responses, and ROS production. In this cycle, ROS species play a central role. Many
clinical trials indicate that drugs can effectively engage with Aβ and remove Aβ plaques, but none of the trials
have shown clear benefits of improving cognition. Nonetheless, it is not clear whether the removal of Aβs can
lead to the changes of ROS levels in brains during the therapy. To answer these fundamental and critically
important questions, in this application, we propose to use Near Infrared Fluorescence (NIRF) imaging to
monitor ROS changes in living AD brains during disease progression and therapy in preclinical animal models.
Inspired by the chemistry of glow sticks, we have designed a NIRF probe, termed CRANAD-61 for detecting
ROS. In glow sticks, oxalate esters react with H2O2 to produce chemiluminescence. 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. Upon reacting with
ROS, its excitation and emission wavelengths significantly shifted, and this shifting could be harnessed for
dual-wavelength imaging. We showed that, for the first time, age-related increases in ROS levels in AD brains
could be monitored with our NIRF imaging method.
In this application, we propose to further structurally optimize CRANAD-61 by extending excitation/emission to
make them suitable for dual-wavelength imaging in the NIR window. We will then use the optimized probe to
monitor the changes of ROS during the progression of AD in transgenic mice, and during therapy with an Aβ
antibody. We will investigate whether Aβ-lowering treatment can lead to a decrease of ROS, and whether a
combination of Aβ-reduction and anti-oxidant or anti-inflammation therapies should be considered for AD
treatment. The answers from our studies will improve and guide the paradigm of AD therapy regimens.

## Key facts

- **NIH application ID:** 9829520
- **Project number:** 5R01AG055413-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Chongzhao Ran
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $419,880
- **Award type:** 5
- **Project period:** 2018-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9829520

## Citation

> US National Institutes of Health, RePORTER application 9829520, Near infrared fluorescence imaging of reactive oxygen species in Alzheimer's disease (5R01AG055413-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9829520. Licensed CC0.

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