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Smart Chemiluminescence Probe Facilitates Optical Imaging of Amyloid-Beta

Key findings

  • The low tissue penetration of near-infrared fluorescence makes it problematic for optical imaging of the brain; chemiluminescence imaging can provide much better penetration by reducing background noise
  • Researchers at Massachusetts General Hospital have created ADLumin-1, the first chemiluminescence probe that binds to amyloid-beta, one of the pathologic hallmarks of Alzheimer's disease
  • In vitro, ADLumin-1 proved to be "smart"—it amplified chemiluminescence intensity 216-fold when mixed with amyloid-beta in saline solution
  • After injection of ADLumin-1, signals from the brain area were 1.8 times greater in a mouse model of Alzheimer's disease than in wild-type mice
  • When ADLumin-1 was used alone or combined with a smart near infrared fluorescence probe, luminescence signals from mouse brains, eyes and noses were higher in a mouse model of Alzheimer's disease than in wild-type mice

Optical imaging, such as with near-infrared fluorescence (NIRF), is widely used for pathology studies and drug development. Over the past decade, Massachusetts General Hospital researchers have developed a series of NIRF probes that are "smart"—that increase the intensity of the signal—for imaging amyloid-beta (Aβ), one of the pathologic hallmarks of Alzheimer's disease (AD) (described in PNAS).

However, the low tissue penetration of NIRF makes it problematic for imaging the brain. Chemiluminescence imaging can provide much better penetration at the same emission wavelength. Chongzhao Ran, PhD, director of the Chongzhao Ran Lab at the Martinos Center for Biomedical Imaging at Mass General, postdoctoral fellows Jing Yang, PhD, and Wei Yin, PhD, and colleagues have now created the first smart chemiluminescence probe for Aβ, called ADLumin-1. They describe preclinical results in Nature Communications.

In Vitro Results

When ADLumin-1 was mixed with Aβ in saline solution, the chemiluminescence intensity was amplified by 216-fold. The researchers then incubated ADLumin-1 with mouse brain homogenate in the presence and absence of Aβ. The signal strength was about 11.6-fold higher with Aβ.

In Vivo Imaging

The researchers used an IVIS® system to image transgenic 5xFAD mice, a common model of AD, and age-matched wild-type mice (WT). Thirty minutes after the injection of ADLumin-1, signals from the brain area were 1.8 times greater in 5xFAD mice than in WT mice.

DAS-CRET

To try for even better tissue penetration, the researchers injected 5xFAD and WT mice with both ADLumin-1 and CRANAD-3, one of their smart NIRF probes for Aβ created by Dr. Chongzhao's group. They dubbed this method dual amplification of signal via chemiluminescence resonance energy transfer (DAS-CRET). When a 640 nm filter was used, the 5xFAD mice showed a 2.25-fold higher signal than the control group.

Both with ADLumin-1 alone and with DAS-CRET, luminescence signals from mouse eyes were higher in the 5xFAD group than in the WT group. Those findings are consistent with a previous report in Molecular Imaging and Biology that NIRF ocular imaging can differentiate AD mice from WT mice and monitor the effect of Aβ-lowering treatment. Signals from noses were also stronger in 5xFAD mice than in WT mice using both methods.

Looking Ahead

DAS-CRET can be expected to have applications for studying other aggregating-prone proteins, including tau, another pathologic hallmark of AD. Considering the tissue penetration of DAS-CRET, it should be possible to use it for brain studies on larger animals. The new method might also prove suitable for translational clinical studies via ocular imaging.

There are a few reports of higher Aβ levels in the noses of AD patients than in controls. Investigation of ocular imaging for AD is ongoing at Mass General, and the potential benefit of imaging noses deserves further work as well.

216x
greater chemiluminescence intensity when ADLumin-1 was mixed with Aβ in solution

12x
greater chemiluminescence intensity when ADLumin-1 was mixed with Aβ in mouse brain homogenates

1.8x
greater chemiluminescence intensity in a mouse model of Alzheimer's disease than in wild-type mice when ADLumin-1 was used

2.25x
greater chemiluminescence intensity in a mouse model of Alzheimer's disease than in wild-type mice when ADLumin-1 was combined with a near infrared fluorescence probe

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