The presence of elemental iron and copper embedded in brain samples from Alzheimer’s patients is an unexpected twist in known human biochemistry. “These metal forms have never been seen in human biology,” says Neil Telling of Keele University in the UK, who led the study. “We see something beyond what we understand in relation to the biochemical world.”
Metals like copper and iron are essential for normal brain function, but they also interact with amyloid plaque proteins. The plaques are variants of the amyloid beta peptide, which is formed by enzymatic cleavage of a precursor protein in the brain. Their exact role in pathology is controversial, but they have been linked to features of Alzheimer’s disease, neurotoxicity, and high levels of iron and iron deposition.
However, like copper, iron has always been found as positively charged ions – until now. Using synchrotron-based scanning transmission x-ray microscopy (STXM), Telling’s team observed elemental copper and iron in the nuclei of amyloid plaques taken from two deceased Alzheimer’s patients.
The STXM method captures chemically specific images with a spatial resolution of 20 nm and at the same time provides X-ray absorption spectra that localize the exact chemical state of the metal deposits. Great care has been taken to exclude possible artifacts. The x-rays were carefully controlled and kept below thresholds that would potentially alter the samples. Attempts to simulate the result artificially with significantly higher amounts of radiation were unsuccessful.
The team is also careful about interpreting how the metals got there and the potential impact on neurodegenerative diseases. “At that point, we made an observation and put together a number of plausible mechanisms,” says Joanna Collingwood, co-investigator for Telling at the University of Warwick, UK.
For Ashley Bush, neuroscientist and director of the Melbourne Dementia Research Center in Australia, “this is very clear evidence of aggressive redox changes in the brain in Alzheimer’s disease”. According to Bush, the study offers several interesting possibilities for investigation. For example, higher levels of iron in the brain have been linked to the likelihood of Alzheimer’s disease getting worse, and this work suggests that iron quality may also be important. Changes in the valency of iron and copper can also intensify oxidative damage through the formation of free radicals and oxidative stress.
Determining the chemical pathway responsible for these elemental metals is critical to understanding their roles in disease and potential drug targets, but no one hypothesis is currently ranked higher, Collingwood says. “The exciting thing for us is, I think, to say:“ Okay, do we need a new biology for this? Or is it taken into account by one of the existing mechanisms? And is that related to the disease process or, in general, to what we might expect if we happened to look at amyloid plaque nuclei? “