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<p>Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders. The accumulation of amyloid-beta (Aβ) deposits in the brain is considered a major cause of the disease. Acetylcholinesterase (AChE) plays a unique role in AD pathogenesis: (1) its overactivity reduces acetylcholine (ACh) levels, leading to degeneration of the cholinergic system, and (2) it is consistently colocalized with amyloid deposits, where it may promote amyloid fibril formation. AChE binds to Aβ, thereby facilitating both fibril assembly and the resulting neurotoxicity. It is widely accepted that compounds inhibiting AChE activity or binding to the enzyme may serve as effective therapeutic agents for AD. A new group of AChE inhibitors—N-substituted amino acid dialkyl-aminoalkylamides—has been developed. In this study, we evaluated the neuroprotective properties of three novel cholinesterase (ChE) inhibitors: TVA (N-benzoyl-DL-valine-dimethylaminoethylamine iodometilate), TVS (1-diethylaminoethyl-2-phenyl-4-benzylidene-5-imidazolone), and TVV (2-phenyl-4-(p-toluenesulfonyloxybenzylidene)-5-imidazolone) using a primary rat hippocampal neuron culture model treated with Aβ25–35. We investigated the concentration-dependent effects of these compounds. The resulting dose–response curves had two distinct phases: lower concentrations (&lt; 10⁻² mg/ml) exhibited anti-amyloid or therapeutic activity, while higher concentrations (&gt; 10⁻² mg/ml) were toxic to hippocampal neurons. The beneficial effects were confirmed by multiple assays, including LDH activity, lactate content, cresyl violet staining, Calcein AM/PI double staining, and NF/GFAP immunostaining. TVA and TVV at 10⁻² mg/ml effectively attenuated Aβ25–35-induced (20&#xa0;µg/ml) neuronal damage. Our findings demonstrate that members of the newly synthesized N-substituted amino acid dialkyl-aminoalkylamide family—particularly TVA and TVV—possess strong protective activity against Aβ25–35-induced toxicity in primary rat hippocampal neurons. Interaction with AChE, leading to either enzyme inhibition or conformational changes, is proposed as the primary mechanism underlying their neuroprotective effects.</p>

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Targeting Amyloid Toxicity: Novel Cholinesterase Inhibitors Protect Hippocampal Cells from Amyloid Peptide-Derived Death

  • 期刊论文

  • 发表日期：

    2025年10月30日

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  • Sona Buloyan,
  • Anahit Poghosyan,
  • Hayk Harutyunyan,
  • Hermine Yeritsyan,
  • Marina Sargsyan,
  • Armen Hovhannisyan,
  • Vigen Topuzyan,
  • Hrachik Gasparyan

摘要

Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders. The accumulation of amyloid-beta (Aβ) deposits in the brain is considered a major cause of the disease. Acetylcholinesterase (AChE) plays a unique role in AD pathogenesis: (1) its overactivity reduces acetylcholine (ACh) levels, leading to degeneration of the cholinergic system, and (2) it is consistently colocalized with amyloid deposits, where it may promote amyloid fibril formation. AChE binds to Aβ, thereby facilitating both fibril assembly and the resulting neurotoxicity. It is widely accepted that compounds inhibiting AChE activity or binding to the enzyme may serve as effective therapeutic agents for AD. A new group of AChE inhibitors—N-substituted amino acid dialkyl-aminoalkylamides—has been developed. In this study, we evaluated the neuroprotective properties of three novel cholinesterase (ChE) inhibitors: TVA (N-benzoyl-DL-valine-dimethylaminoethylamine iodometilate), TVS (1-diethylaminoethyl-2-phenyl-4-benzylidene-5-imidazolone), and TVV (2-phenyl-4-(p-toluenesulfonyloxybenzylidene)-5-imidazolone) using a primary rat hippocampal neuron culture model treated with Aβ25–35. We investigated the concentration-dependent effects of these compounds. The resulting dose–response curves had two distinct phases: lower concentrations (< 10⁻² mg/ml) exhibited anti-amyloid or therapeutic activity, while higher concentrations (> 10⁻² mg/ml) were toxic to hippocampal neurons. The beneficial effects were confirmed by multiple assays, including LDH activity, lactate content, cresyl violet staining, Calcein AM/PI double staining, and NF/GFAP immunostaining. TVA and TVV at 10⁻² mg/ml effectively attenuated Aβ25–35-induced (20 µg/ml) neuronal damage. Our findings demonstrate that members of the newly synthesized N-substituted amino acid dialkyl-aminoalkylamide family—particularly TVA and TVV—possess strong protective activity against Aβ25–35-induced toxicity in primary rat hippocampal neurons. Interaction with AChE, leading to either enzyme inhibition or conformational changes, is proposed as the primary mechanism underlying their neuroprotective effects.