Insulin modulates Aβ_1-42 aggregation toward non-toxic forms: A comparative study with cis-[Ru(phen)₂(3,4Apy)₂]²

Area of Science:

• Neuroscience
• Biochemistry
• Materials Science

Background:

• Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) aggregation.
• Intranasal insulin therapy is being investigated for its potential to modulate Aβ pathology.
• Distinct binding interactions of insulin and a ruthenium complex (Ru3,4Apy) with Aβ oligomers are proposed.

Purpose of the Study:

• To investigate the distinct molecular mechanisms of Aβ aggregation modulated by insulin and Ru3,4Apy.
• To understand how these agents influence Aβ-induced cytotoxicity.
• To explore the potential of targeting specific Aβ binding sites for AD therapy.

Main Methods:

• Monitoring Aβ₁₋₄₂ aggregation using Tyr10 intrinsic fluorescence, circular dichroism, and atomic force microscopy.
• Assessing SH-SY5Y cell viability in the presence of Aβ₁₋₄₂, insulin, and Ru3,4Apy.
• Utilizing molecular dynamics simulations to understand binding interactions.

Main Results:

• Ru3,4Apy reduced β-sheet formation but did not mitigate Aβ₁₋₄₂-induced cytotoxicity.
• Insulin limited conformational flexibility, prevented Tyr10 burial, suppressed β-sheet formation, and promoted non-toxic aggregates.
• Co-administration of Aβ₁₋₄₂, Ru3,4Apy, and insulin led to a non-toxic aggregation pathway.

Conclusions:

• Insulin specifically interacts with Aβ₁₋₄₂ to promote non-toxic aggregation.
• Targeting defined binding sites on Aβ is a promising therapeutic strategy for Alzheimer's disease.
• The findings highlight the distinct effects of insulin and Ru3,4Apy on Aβ aggregation and cytotoxicity.