According to the authors, the research opens up new possibilities for developing the next generation of ChE inhibitors that specifically target AChE and BChE linked to Alzheimer’s disease pathology.
In a new study published in the journal Aging, a research team from Dalhousie University, led by Sultan Darvesh, discovered that certain anti-aging compounds, known as senolytics, can block harmful brain enzymes linked to Alzheimer’s disease (AD) without affecting healthy ones. Senolytics are compounds that help clear out damaged or “zombie” cells that build up with age and contribute to inflammation and tissue dysfunction. This work provides new insight into how AD-related damage can be precisely targeted, leading the way for safer treatments that protect memory and brain health in older adults.
Alzheimer’s disease is one of the most common causes of memory loss and dementia. A hallmark of the disease is the buildup of sticky protein clumps in the brain, known as amyloid-beta plaques. Two enzymes—acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)—are found near these plaques. While these enzymes play important roles in brain function, they can also contribute to AD progression when they attach to plaques. Drugs that target these enzymes are already used to help with memory, but they often block both harmful and healthy forms, which can cause unwanted side effects.
Testing Compounds for Selectivity
To investigate a better solution, researchers tested six compounds that are known for their anti-aging or brain-boosting properties. They wanted to know if these compounds could block only the harmful AChE and BChE enzymes forms linked to Alzheimer’s disease. Using brain tissue samples from AD patients and enzyme activity assays, they discovered that compounds such as dasatinib and nintedanib, both senolytics, were able to block the forms of AChE and BChE associated with amyloid-beta plaques. These compounds did not affect normal brain enzymes, though.
“We show that the selected senolytics and nootropic inhibit ChEs associated with plaques but not the enzymes associated with normal neural elements.”
Computer Modeling and Drug Targeting
The study also used computer modeling to explore how these compounds interact with the enzymes. The models showed that the enzymes change shape when near plaques, making them easier for certain compounds to target. This change may explain how the drugs can selectively affect only the diseased areas of the brain.
While not all compounds worked equally well, the findings offer a new strategy for treating AD. By focusing on the differences between healthy and diseased enzyme forms, researchers may be able to design more precise and effective therapies. This selective approach could improve memory, reduce inflammation, and avoid the side effects of AD’s current treatments.
In summary, this research opens new possibilities for treating Alzheimer’s disease in a more targeted way. It also highlights how discoveries in aging and brain health can work together to create better therapies for neurodegenerative diseases.
Reference: “Differential senolytic inhibition of normal versus Aβ-associated cholinesterases: implications in aging and Alzheimer’s disease” by Sultan Darvesh, Meghan K. Cash, Katrina Forrestall, Hillary Maillet and Dane Sands, 29 March 2025, Aging.
DOI: 10.18632/aging.206227
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