New Mechanism Targets Alzheimer's Enzymes Without Harming Healthy Brain Cells
Senolytic compounds can selectively block disease-associated brain enzymes in Alzheimer's.
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A study published in the March 29 issue of Aging (Aging-US) suggests that certain senolytic compounds can inhibit specific forms of brain enzymes associated with Alzheimer’s disease (AD) without interfering with their healthy counterparts. The research, led by Sultan Darvesh at Dalhousie University, identifies a new mechanism for targeting the cholinesterase enzymes found near amyloid-beta plaques, a central feature of AD pathology.
Senolytics
Compounds that promote the clearance of senescent cells – non-dividing cells that accumulate with age and secrete inflammatory signals contributing to tissue dysfunction.Cholinesterases (AChE and BChE)
Enzymes that break down the neurotransmitter acetylcholine in the brain. Abnormal forms of these enzymes are linked to amyloid plaques in Alzheimer’s disease.
Amyloid-beta plaques
Aggregates of misfolded protein fragments found in the brains of individuals with Alzheimer’s disease. These plaques are associated with neural damage and memory decline.Distinguishing healthy from harmful enzyme activity
Cholinesterase inhibitors are a mainstay in AD treatment, primarily aimed at improving memory and cognition. These drugs act on two enzymes –acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) – which help regulate neurotransmission in the brain. However, current treatments do not discriminate between enzymes in normal brain tissue and those linked to disease, leading to side effects.
This new study addresses that limitation by showing that some senolytic compounds can selectively block the plaque-associated forms of AChE and BChE while sparing the normal variants. Senolytics are a class of compounds originally designed to eliminate senescent cells, which accumulate with age and contribute to inflammation and functional decline in tissues.
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Subscribe for FREEFindings from tissue and computer models
The researchers tested six known anti-aging or neuroactive compounds, including dasatinib and nintedanib, using brain tissue from patients with AD. Enzyme activity assays revealed that these two senolytics effectively inhibited the pathological variants of cholinesterase enzymes without affecting those in healthy neural tissue.
Structural modeling further indicated that cholinesterases near amyloid plaques undergo conformational changes that likely expose binding sites not present in their normal state. This structural difference may explain how some compounds achieve selective inhibition.
Implications for drug development
The ability to distinguish between normal and disease-associated enzyme forms offers a potential path to safer, more targeted AD therapies. By focusing on pathological enzyme variants, future treatments may improve cognitive function while reducing adverse effects linked to non-selective inhibition.
Not all tested compounds demonstrated selective activity, indicating that structural properties and binding specificity play crucial roles. The findings encourage further research into how aging and neurodegeneration intersect at the molecular level and how this knowledge can guide drug design.
Reference: Darvesh S, Cash MK, Forrestall K, Maillet H, Sands D. Differential senolytic inhibition of normal versus Aβ-associated cholinesterases: implications in aging and Alzheimer’s disease. Aging. 2025. doi: 10.18632/aging.206227
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