The brain map that should help find the origin of Alzheimer's

BarcelonaResearchers at the prestigious Icahn School of Medicine at Mount Sinai in New York have developed the most comprehensive map of brain tissue proteins that may be associated with Alzheimer's disease. After examining how more than 12,000 protein molecules—which are a kind of nanorobot natural system that builds, repairs, and regulates vital processes within the brain, have identified up to 300 that experience communication failures and that could be linked to this neurodegeneration. These hundreds of proteins had barely been studied in the context of dementia, and among them stands out one alteration that researchers now want to understand in depth to find out if it could be one of the origins of the disease. If confirmed, they say, a window of research could open in the future that allows this type of error to be transformed into new therapeutic targets.

In a search published this Thursday in the journal Cell, a team led by Bin Zhang, director of the Center for Transformative Disease Modeling at the Icahn School of Medicine, examined brain tissue samples from nearly 200 individuals with and without Alzheimer's and found that disruptions in communication between neurons and the brain's supporting cells called microglia are closely linked to the disease. "Our study shows that the loss of healthy communication between neurons and glial cells could be a major driver of disease progression," said senior author Dr.

One protein in particular, called AHNAK, was identified as one of the main drivers of these harmful interactions. In healthy brains, neurons send and receive signals, while glial cells play a supporting role and protect them. But in Alzheimer's, this balance seems to be lost: glial cells become overactive and neurons less functional, causing an increase in inflammation in brain tissues. "This study opens up a new way of thinking about Alzheimer's, not just as a buildup of toxic proteins, but as a failure in the way brain cells communicate with each other," Bin Zhang summarizes.

Most research on Alzheimer's has focused on plaques of the protein beta-amyloid – a substance that accumulates in large quantities and that science considers either a major cause or a clear sign of Alzheimer's – and the buds of the neurofibromatosis cup. knots that prevent communication between neurons. But according to the New York researchers, these accumulations alone don't tell the whole story, which means that some of the currently available targeted treatments provide only modest benefits.

The point at which Alzheimer's occurs

In this sense, the innovation behind this study lies in the fact that, based on the enormous amount of proteins examined within the brain, it has been possible to quantify protein expression throughout the brain, which "allows us to have a complete view of proteomic alterations and interactions in Alzheimer's disease." Using advanced computational models, the Mount Sinai researchers built large-scale networks to map how proteins interact and, thus, identified at what point the connection breaks down and Alzheimer's disease occurs. "This allows us to discover entire systems that fail, rather than focusing on a single molecule," they insist. "And by knowing where they fail, we can begin to develop treatments that return the system to balance," adds Bin Zhang.

In these models, the researchers identified several proteins that they called "key driver proteins"—molecules that seemed to play a disproportionate role in triggering or accelerating the disease. AHNAK levels increase as Alzheimer's disease progresses, and this is associated with increased concentrations of other toxic proteins in the brain, such as amyloid beta and tau. To test its impact, they reduced the presence of AHNAK in stem cell-derived human brain cell models and observed decreased tau levels and improved neuronal function. In the lab, in fact, the tissues showed less toxicity and increased neuronal activity, two encouraging signs that the researchers argue could lead to restoring brain function.

"These results suggest that AHNAK could be a promising therapeutic target," says co-senior author Dongming Cai, professor of neurology and director of the Grossman Center for Memory Research and Care at the University of Minnesota. And because they have identified 300 proteins that have barely been studied in the context of the disease, the researchers say their exploitation could open up new avenues of research for the development of novel drugs.

The researchers themselves admit that further studies are needed to investigate AHNAK and other key proteins in living systems, but the full data from this study have already been made available to researchers worldwide.