Rationally designed divalent caffeic amides inhibit amyloid-β fibrillization, induce fibril dissociation, and...

Area of Science:

• Neuroscience
• Biochemistry
• Pharmacology

Background:

• Alzheimer's disease (AD) is characterized by extracellular senile plaques formed by amyloid-β (Aβ) fibrils.
• Therapeutic strategies for AD include inhibiting Aβ self-assembly or disassembling existing Aβ aggregates using small molecules.

Purpose of the Study:

• To synthesize and evaluate rationally designed divalent compounds for their effects on Aβ fibrillization.
• To investigate the therapeutic potential of a potent Aβ inhibitor in cellular and organismal models of AD.

Main Methods:

• Synthesis of divalent amide compounds, including a potent candidate (2) with a propylenediamine linker.
• Assessment of compound effects on Aβ(1-42) fibrillization and dissociation of preformed fibrils.
• Evaluation of compound 2's efficacy in reducing Aβ(1-42) cytotoxicity in human neuroblastoma cells and rescuing paralysis in Aβ transgenic C. elegans.
• Characterization of compound 2 binding to Aβ(1-40) using electrospray ionization-traveling wave ion mobility-mass spectrometry (ESI-TWIMS-MS) and molecular dynamics (MD) simulations.

Main Results:

• A divalent amide (2), derived from caffeic acid with a specific linker length, potently inhibited Aβ(1-42) fibrillization.
• Compound 2 effectively dissociated preformed Aβ(1-42) fibrils and reduced Aβ-induced cytotoxicity in neuroblastoma cells.
• Administration of compound 2 to Aβ transgenic C. elegans rescued the paralysis phenotype, demonstrating in vivo efficacy.
• ESI-TWIMS-MS and MD simulations provided insights into the binding and structural interactions of compound 2 with Aβ(1-40).

Conclusions:

• The rationally designed divalent compound 2 demonstrates significant potential as a therapeutic agent for Alzheimer's disease.
• Compound 2 effectively targets key pathological features of AD, including Aβ fibril formation, aggregation, and associated neurotoxicity.
• Further investigation into compound 2 and similar molecules is warranted for developing novel AD treatments.