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Alzheimer’s disease (AD) is the most common neurodegenerative disorder affecting the elderly population worldwide. Brain inflammation plays a key role in the progression of AD. Deposition of senile plaques in the brain stimulates an inflammatory response with the overexpression of pro-inflammatory mediators, such as the neuroinflammatory cytokine. interleukin-6. Curcumin has been revealed to be a potential agent for treating AD following different neuroprotective mechanisms, such as inhibition of aggregation and decrease in brain inflammation. We synthesized new curcumin derivatives with the aim of providing good anti-aggregation capacity but also improved anti-inflammatory activity. Nine curcumin derivatives were synthesized by etherification and esterification of the aromatic region. From these derivatives, compound 8 exhibited an anti-inflammatory effect similar to curcumin, while compounds 3, 4, and 10 were more potent. Moreover, when the anti-aggregation activity is considered, compounds 3, 4, 5, 6, and 10 showed biological activity in vitro. Compound 4 exhibited a strong anti-aggregation effect higher than curcumin. Monofunctionalized curcumin derivatives showed better bioactivity than difunctionalized compounds. Moreover, the presence of bulky groups in the chemical structure of curcumin derivatives decreased bioactivity.
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This content will become publicly available on December 1, 2025
Artificial Intelligence-Assisted Comparative Analysis of the Overlapping Molecular Pathophysiology of Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, and Frontotemporal Dementia
The overlapping molecular pathophysiology of Alzheimer’s Disease (AD), Amyotrophic Lateral Sclerosis (ALS), and Frontotemporal Dementia (FTD) was analyzed using relationships from a knowledge graph of 33+ million biomedical journal articles. The unsupervised learning rank aggregation algorithm from SemNet 2.0 compared the most important amino acid, peptide, and protein (AAPP) nodes connected to AD, ALS, or FTD. FTD shared 99.9% of its nodes with ALS and AD; AD shared 64.2% of its nodes with FTD and ALS; and ALS shared 68.3% of its nodes with AD and FTD. The results were validated and mapped to functional biological processes using supervised human supervision and an external large language model. The overall percentages of mapped intersecting biological processes were as follows: inflammation and immune response, 19%; synapse and neurotransmission, 19%; cell cycle, 15%; protein aggregation, 12%; membrane regulation, 11%; stress response and regulation, 9%; and gene regulation, 4%. Once normalized for node count, biological mappings for cell cycle regulation and stress response were more prominent in the intersection of AD and FTD. Protein aggregation, gene regulation, and energetics were more prominent in the intersection of ALS and FTD. Synapse and neurotransmission, membrane regulation, and inflammation and immune response were greater at the intersection of AD and ALS. Given the extensive molecular pathophysiology overlap, small differences in regulation, genetic, or environmental factors likely shape the underlying expressed disease phenotype. The results help prioritize testable hypotheses for future clinical or experimental research.
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- Award ID(s):
- 1944247
- PAR ID:
- 10615486
- Publisher / Repository:
- MDPI
- Date Published:
- Journal Name:
- International Journal of Molecular Sciences
- Volume:
- 25
- Issue:
- 24
- ISSN:
- 1422-0067
- Page Range / eLocation ID:
- 13450
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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