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Every three seconds someone in the world develops dementiaAlzheimer’s disease is the most common type dementiaWhich is between 60 percent to 70 percent in all cases.
Although scientists have made significant progress in understanding the disease, there is still no cure. This is partly because Alzheimer’s disease has many causes – many of which are still not fully understood.
Two proteins that are believed to play a central role in Alzheimer’s disease are amyloid-beta and tau. Amyloid-beta forms sticky plaques outside brain cells. This disrupts communication between neurons. Tau accumulates inside brain cells, where it forms tangles. This ultimately leads to cell death. These plaques and tangles are the hallmarks of Alzheimer’s disease.
This understanding, known as the amyloid hypothesis, has shaped research for decades and led to treatments that aim to clear amyloid from the brain. Monoclonal antibody drugs have been approved in recent years for this purpose.
But they work only in the early stages of the disease. They do not reverse existing damage and can cause serious side effects such as swelling and bleeding in the brain. Most importantly, they only target amyloid-beta, tau is not treated.
But in a surprising twist, recently published research by my colleagues and I found that a protein from Helicobacter pylori – a bacteria known to cause stomach ulcers – can prevent the toxic buildup of both amyloid-beta and tau. This unexpected finding may point to a new strategy for the fight against Alzheimer’s disease.
Our search began with a completely different question. We were initially studying how H. pylori interacted with other microbes. Some bacteria form protective communities called biofilms, which rely on amyloid assemblies (similar in structure to the plaques that form in the brain) as a structural scaffold. This led us to wonder: could H. pylori affect bacterial biofilms by interfering with amyloid assembly in humans?
We turned our attention to a well-known H. pylori protein called CagA. While half of the protein is known to cause harmful effects in human cells (known as the C-terminal region), the other half (the N-terminal region of the protein) may have protective properties. To our surprise, this N-terminal fragment, called CAGAN, dramatically reduced both bacterial amyloid and biofilm formation in the bacterial species Escherichia coli and Pseudomonas.
Encouraged by these results, we tested whether the same protein fragment could prevent the formation of human amyloid-beta protein. To do this, we incubated amyloid-beta molecules in the laboratory: some were treated with CagAN, while others were left as normal. We then tracked amyloid formation using a fluorescence reader and an electron microscope.
We found that the treated samples had little formation of amyloid clumps during the testing period. Even at very low concentrations, CagAN almost completely prevented amyloid-beta from forming amyloid aggregates.
To understand how CAGAN works, we used nuclear magnetic resonance (which allows us to see how molecules interact with each other) to investigate how the protein interacts with amyloid-beta. We also used computer modeling to investigate possible mechanisms. Remarkably, CagAN also blocked tau aggregation – suggesting that it acts on multiple toxic proteins involved in Alzheimer’s disease.
prevent disease
Our study shows that a fragment of Helicobacter pylori protein can effectively block the formation of two proteins involved in Alzheimer’s disease. This suggests that bacterial proteins – or drugs based on them – may someday prevent early symptoms of Alzheimer’s.
Moreover, the benefits may extend beyond Alzheimer’s disease.
In additional experiments, the same bacterial fragment blocked the aggregation of IAPP (a protein involved in type 2 diabetes) and alpha-synuclein (linked to Parkinson’s disease). All of these conditions are induced by the accumulation of toxic amyloid aggregates.
That a bacterial fragment can interfere with so many proteins suggests exciting therapeutic potential. Although these conditions affect different parts of the body, they may be linked through cross-talk between amyloid proteins – a shared mechanism that CagAN may help disrupt.
Of course, it’s important to be clear: This research is still in its early stages.
All of our experiments were conducted in a laboratory setting, not yet in animals or humans. Still, the findings open a new path.
Our study also uncovered the underlying mechanism of how CAGAN blocked amyloid-beta and tau from forming amyloid aggregates. One of the ways CagAN did this was by preventing the proteins from coming together and forming clumps. They also prevented small, premature amyloid aggregates from forming. In the future, we will continue detailed mechanism studies and evaluate the effects in animal models.
These results also raise a question: Could H. pylori, long thought to be merely harmful, also have a protective side? Some studies have indicated an association between H. pylori infection and Alzheimer’s disease, although this relationship is not clear. Our discovery adds a new layer to this discussion, suggesting that part of H. pylori may actually interfere with the molecular events that lead to Alzheimer’s disease.
This means that in the future, we may need to take a more precise and personalized approach. Rather than aiming to completely eliminate H. pylori with antibiotics, it may be more important to understand in different biological contexts which parts of the bacterium are harmful, and which may actually be beneficial.
As medicine moves toward greater precision, the goal is no longer to eradicate every microbe, but to understand how some of them may work with us rather than against us.
Gefei Chen is Associate Professor at Karolinska Institutet.
This article is republished from The Conversation under a Creative Commons license. read the original article,