image: Figure 10. Structural components and amino acid residues that are essential for the catalytic activity of acetylcholinesterase (AChE) and butyrylcholinesterse (BChE). (A) 2D depiction of the entry/exit routes (“doors”) to the active site gorge of AChE. Amino acids are labelled and arranged according to their structural placement around the gorge, with those located on the opposite side to the viewing plane shown through the transparent green gorge wall. (B) AChE (PDB: 4M0E, 2.00 Å) [91] and BChE (BChE; PDB: 4TPK, 2.70 Å) [92] enzyme ribbon structures are overlayed to show structural conservation between the two enzymes. The catalytic triad residues are shown in yellow. (C, D) The five main compound binding site pockets (I-V) of AChE (C) and BChE (D) are identified as the enzyme active site gorge (lime green, I), pocket behind ChE acyl loop (pink, II), pocket behind ChE catalytic glutamate (orange, III), pocket behind ChE active site tryptophan (Back Door, blue, IV), and other binding pocket (teal, V). Structural features of AChE and BChE including the acyl loop (pink), Ω-loop (blue), and ε-helix (orange) are shown throughout each panel. Figures were generated using Microsoft PowerPoint for Microsoft 365 MSO (version 2409 build 18025.20104; Microsoft Corporation, Redmond, WA, USA) and Molecular Operating Environment 2022.02 (Chemical Computing Group ULC, Montreal, Quebec, Canada).
Credit: Copyright: © 2025 Darvesh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
“This work provides new opportunities for the development of the next generation of ChE inhibitors that specifically target AChE and BChE associated with AD pathology.”
BUFFALO, NY — April 1, 2025 — A new research paper was published in Aging (Aging-US) on March 29, 2025, as the cover of Volume 17, Issue 3, titled “Differential senolytic inhibition of normal versus Aβ-associated cholinesterases: implications in aging and Alzheimer’s disease.”
In this study, 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.
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.”
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.
Read the full paper: DOI: https://doi.org/10.18632/aging.206227
Corresponding author: Sultan Darvesh- sultan.darvesh@dal.ca
Keywords: aging, cellular senescence, β-amyloid, acetylcholinesterase, butyrylcholinesterase, cholinesterase inhibitors
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Journal
Aging-US
Method of Research
News article
Subject of Research
Not applicable
Article Title
Differential senolytic inhibition of normal versus Aβ-associated cholinesterases: implications in aging and Alzheimer’s disease
Article Publication Date
29-Mar-2025
COI Statement
Sultan Darvesh is a scientific co-founder and stockholder in the Treventis Corporation, a biotech company focused on the development of diagnostic and therapeutic agents for Alzheimer’s disease. Sultan Darvesh is listed as an inventor on patents assigned to Treventis Corporation. Also, Sultan Darvesh is an Associate Editor of Current Alzheimer Research. All other authors do not have financial disclosures or conflicts of interest to declare.