There is a growing body of evidence that iron in the brain may play a role in Alzheimer’s disease. Lending weight to that idea, a new imaging probe has for the first time shown that in the same regions of the brain where the amyloid beta plaques associated with Alzheimer’s occur, there is also an increase in iron redox, meaning the iron in these regions is more reactive in the presence of oxygen. Their imaging probe could yield even more details about the causes of Alzheimer’s and help in the search for new drugs to treat it.
A team from the University of Illinois at Urbana-Champaign and The University of Texas at Austin has published a study on the new imaging technique and findings in Science Advances.
Scientists in the lab of Liviu Mirica, William H. and Janet G. Lycan Professor of Chemistry, have been studying what happens in the brain at the onset of neurodegenerative disorders such as Alzheimer’s disease to develop novel therapeutic and diagnostic agents that can slow or halt disease progression.
The Mirica research group has been focusing on the role that the main oxidations states of iron, Fe(II) and Fe(III) and oxidative stress may play in the onset of such diseases. Lu’s group has developed DNA-based fluorescent sensors that can detect Fe(II) and Fe(III), which are important in the formation of reactive oxygen species (ROS) that lead to oxidative stress – basically cell and tissue damage due to an imbalance in the production and accumulation of ROS.
The two research groups established a collaboration to probe whether the ratio of Fe(II) and Fe(III) ions is different in mice with Alzheimer’s compared to healthy, wild type mice.
“Interestingly, we were able to detect that the areas of the mouse brain that are affected by the deposition of the amyloid plaques, the hallmark of Alzheimer’s disease, exhibit an increased amount of Fe(III) ions relative to the Fe(II) ions, confirming that those regions are directly affected by oxidative stress,” Mirica explained. “With these Fe oxidation state-specific fluorescent sensors in hand, we can now start screening for compounds that could target ROS and oxidative stress in Alzheimer’s, as a novel therapeutic target for fighting this debilitating disorder.”
Professor Yi Lu, corresponding author and professor of chemistry at the University of Texas Austin and former professor of chemistry at Illinois, said the link between iron redox and Alzheimer’s disease has been a black box.
“The most exciting part to me is that we now have a way to shine light into this black box so that we can begin to understand this whole process in much more detail,” he said.
About a decade ago, scientists discovered ferroptosis, a process in the body that is dependent on elevated iron levels, leads to cell death and plays a key role in neurodegenerative diseases, such as Alzheimer's. Using magnetic resonance imaging on living Alzheimer’s patients, scientists have observed that these patients tend to have elevated iron levels in the brain, although that method doesn’t differentiate between different forms of iron. Together, these findings suggested that iron might play a role in destroying brain cells in Alzheimer’s patients.
For the new study, the researchers developed DNA-based fluorescent sensors that can both forms of iron, Fe(II) and Fe(III), at the same time in cell cultures and in brain slices from mice genetically modified to mimic Alzheimer’s. One sensor glows green for Fe(II) and the other glows red for Fe(III). This is the first imaging technique that can simultaneously detect both forms of iron in cells and tissue while also indicating their quantity and spatial distribution.
“The best part about our sensor is that we can now visualize the changes of Fe(II) and Fe(III) and their ratios in each location,” said Yuting Wu, a co-first author of the study and a postdoctoral researcher in Lu’s lab at UT Austin. “We can change one parameter at a time to see if it changes the plaques or the oxidative states of iron.”
That ability could help them better understand why there is an increased ratio of Fe(III) to Fe(II) in the location of amyloid beta plaques and whether increased iron redox is involved in forming the plaques.
Another key question is whether the iron redox is directly involved in cell death in Alzheimer’s, or simply a byproduct. The researchers plan to explore this question in Alzheimer’s mice. If further research determines that iron and its redox changes indeed cause cell death in Alzheimer’s patients, that information could provide a potential new strategy for drug development. In other words, perhaps a drug that changes the ratio of Fe(III) to Fe(II) could help protect brain cells. The new imaging probe could be used to test how well drug candidates work at changing the ratio.
To develop the sensors, the scientists first hired a commercial lab to produce a library of 100 trillion short DNA strands, through a chemical process called oligonucleotide synthesis. They then conducted a screening process to find those strands that recognize — or in chemistry parlance “bind tightly to and conduct a catalytic reaction with” — a specific form of iron and not any other forms. To complete the sensors, other components were added including molecules called fluorophores that glow in a specific color when the probe recognizes the specific form of iron.
The research team also included Zhengxin Yu, a graduate student in the Mirica Group, and two recent graduates in Chemistry at Illinois — Ryan Lake (PhD, ’22) and Gregory Pawel (PhD, ’22).
This work was supported by the National Institutes of Health, the Alzheimer’s Association and the Robert A. Welch Foundation.
Editor’s notes:
To reach Liviu Mirica, email mirica@illinois.edu.
The paper “Simultaneous Fe2+/Fe3+ imaging shows Fe3+ over Fe2+ enrichment in Alzheimer’s disease mouse brain” is available online.
DOI: 10.1126/sciadv.ade7622
Related People
