The levels of neurotransmitters in the brain can serve as indicators of overall brain health and can signal neurodegenerative conditions like Alzheimer’s disease. However, the blood-brain barrier (BBB), a protective shield, complicates the process of delivering fluorescent sensors that can identify these small molecules into the brain. Recent research published in ACS Central Science reveals a novel method to package these sensors in a manner that facilitates their transport across the BBB in mice, enhancing brain imaging techniques. With further progress, this technology holds potential to improve the diagnosis and treatment of Alzheimer’s disease.
As people age, neurotransmitter levels typically decline, yet notably low levels of adenosine triphosphate (ATP) can signify the presence of Alzheimer’s disease. To accurately assess the location and quantity of ATP in the brain, scientists have crafted fluorescent sensors from short DNA sequences known as aptamers that emit light when they attach to a target molecule. Various strategies have been devised for delivering these sensors from the bloodstream into the brain; however, most involve synthetic materials that struggle to penetrate the BBB. To create sensors that can effectively visualize live brain activity, Yi Lu and his team have encapsulated an ATP aptamer sensor in microscopic vesicles called exosomes, derived from brain cells. They evaluated this new method of sensor delivery using lab models of the BBB as well as mouse models of Alzheimer’s disease.
The lab model of the BBB was formed by layering endothelial cells over a fluid containing brain cells. The researchers found that their exosome-loaded sensors showed nearly four times greater efficiency than traditional sensor delivery methods in crossing the endothelial barrier and releasing the fluorescent sensor into brain cells. This success was verified by measuring the fluorescence levels triggered by ATP binding. Subsequently, Lu’s team injected mouse models of Alzheimer’s disease with either the exosome-encapsulated sensors or standalone free-floating sensors. Their observations revealed that the free-floating sensors predominantly remained in the bloodstream, liver, kidneys, and lungs, whereas the exosome-delivered sensors successfully accumulated in the brain.
In the Alzheimer’s disease mouse models, the sensors delivered via exosomes were able to pinpoint the location and concentration of ATP in various brain regions. They notably detected decreased ATP levels in the hippocampus, cortex, and subiculum areas, which are associated with the disease. The researchers believe that these exosome-encapsulated ATP-sensitive sensors hold promise for non-invasive, real-time brain imaging and could be further refined to develop sensors for a wide array of clinically significant neurotransmitters.
The authors express gratitude for the support received from the U.S. National Institutes of Health (NIH), Welch Foundation, NIH Chemistry-Biology Interface Training Program at the University of Illinois Urbana-Champaign, and a National Science Foundation Graduate Research Fellowship.
