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<p>Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) aggregation, tau hyperphosphorylation, synaptic dysfunction and neuroinflammation. The study investigates bergapten (BGN) as a potential AD treatment. Computational analysis revealed strong binding affinity of BGN with Filamin A (FLNA) and glycogen synthase kinase-3β (GSK3β). In vitro assays demonstrated acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition suggesting cholinergic modulation. In intracerebroventricular (i.c.v) streptozotocin (STZ) induced AD mice model, BGN (25&#xa0;mg/kg, 50&#xa0;mg/kg and 100&#xa0;mg/kg i.p) was administered daily for 23&#xa0;days. The blood and brain tissues samples were collected for biochemical and histopathological analysis. BGN showed dose-dependent cognitive improvements, with biochemical tests indicating renal and hepatic safety. Reduced C-reactive protein and lactate dehydrogenase levels suggested minimal systemic toxicity and neuroinflammation. Histology revealed preserved neurons, decreased amyloid deposits, and improved brain structure. Immunohistochemical analyses indicated BGN was associated with lower Tau, NF-κB, TLR4, and Caspase-3 expression and restored redox homeostasis. Critically, ELISA confirmed reduced FLNA along with Aβ and GSK-3β levels and thus highlights BGN novel modulation of this unexplored AD target. RT-PCR analysis showed downregulated expression of amyloid precursor protein, tau, discs large scaffold protein 4 and glial fibrillary acidic protein, while enhanced synaptic plasticity markers. Collectively, these findings suggest BGN as a promising multi-target neuroprotective and safer agent for AD.</p> Graphical abstract <p></p>

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Mechanistic Insights into Bergapten by Modulation of Filamin A and GSK3β in STZ Induced Alzheimer’s Disease: An Integrated In Silico, In Vitro and In Vivo Study

  • 期刊论文

  • 发表日期：

    2026年4月7日

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  • Muhammad Riaz,
  • Halima Qadir,
  • Muhammad Noman,
  • Sagheer Ahmed,
  • Fawad Ali Shah,
  • Muhammad Usman Malik,
  • Kashif Bashir,
  • Umar Farooq,
  • Nadeem Irshad

摘要

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) aggregation, tau hyperphosphorylation, synaptic dysfunction and neuroinflammation. The study investigates bergapten (BGN) as a potential AD treatment. Computational analysis revealed strong binding affinity of BGN with Filamin A (FLNA) and glycogen synthase kinase-3β (GSK3β). In vitro assays demonstrated acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition suggesting cholinergic modulation. In intracerebroventricular (i.c.v) streptozotocin (STZ) induced AD mice model, BGN (25 mg/kg, 50 mg/kg and 100 mg/kg i.p) was administered daily for 23 days. The blood and brain tissues samples were collected for biochemical and histopathological analysis. BGN showed dose-dependent cognitive improvements, with biochemical tests indicating renal and hepatic safety. Reduced C-reactive protein and lactate dehydrogenase levels suggested minimal systemic toxicity and neuroinflammation. Histology revealed preserved neurons, decreased amyloid deposits, and improved brain structure. Immunohistochemical analyses indicated BGN was associated with lower Tau, NF-κB, TLR4, and Caspase-3 expression and restored redox homeostasis. Critically, ELISA confirmed reduced FLNA along with Aβ and GSK-3β levels and thus highlights BGN novel modulation of this unexplored AD target. RT-PCR analysis showed downregulated expression of amyloid precursor protein, tau, discs large scaffold protein 4 and glial fibrillary acidic protein, while enhanced synaptic plasticity markers. Collectively, these findings suggest BGN as a promising multi-target neuroprotective and safer agent for AD.

Graphical abstract