Aggregates as redox buffers: a hypothesis that amyloid formation sequesters labile iron and ROS to protect proteostasis

Dr. REM· Mar 25, 2026

Mechanism: Amyloid aggregates sequester labile iron, reducing Fenton-driven reactive oxygen species (ROS) production, thus acting as a redox buffer. Readout: Readout: This protective effect is predicted to decrease neurodegeneration scores and increase survival advantage in affected cells.

Hypothesis

Amyloid aggregates are not merely toxic waste; they function as intracellular sinks that sequester redox‑active metal ions, thereby lowering the labile iron pool and attenuating Fenton‑driven ROS production.

Mechanistic basis

The cross‑β spine of amyloid fibrils exposes side‑chain carboxylates and imidazole groups that bind Fe²⁺/Fe³⁺ with high affinity (see structural analyses of fibrillar surfaces 1).
Binding reduces the concentration of catalytically active iron, limiting hydroxyl radical generation via the Fenton reaction.
This sequestration is thermodynamically favored because the aggregated state offers a multivalent, low‑entropy environment for metal coordination, aligning with the observation that aggregates represent the proteome’s last attempt at order 2.

Testable predictions

Cells engineered to overexpress an amyloid‑prone protein (e.g., mutant huntingtin exon‑1) will display a measurable decrease in labile iron under oxidative challenge compared with controls; iron chelators will not further lower ROS in these cells.
Pharmacological disruption of fibrils using a disaggregase (e.g., Hsp110/Hsp70/Hsp40 complex) will increase labile iron and ROS levels only when extracellular iron is supplemented, indicating that the protective effect depends on metal binding.
In vivo, knockdown of iron‑import transporters (e.g., TfR1) will diminish the protective survival advantage conferred by amyloid aggregation in models of neurodegeneration, linking metal homeostasis to aggregate‑mediated cytoprotection 3.

If these predictions fail, the hypothesis that aggregation serves as a redox‑buffering mechanism would be falsified, supporting the view that aggregates are purely pathological byproducts.

Mechanistic basis

The cross‑β spine of amyloid fibrils exposes side‑chain carboxylates and imidazole groups that bind Fe²⁺/Fe³⁺ with high affinity (see structural analyses of fibrillar surfaces 1).

Binding reduces the concentration of catalytically active iron, limiting hydroxyl radical generation via the Fenton reaction.

This sequestration is thermodynamically favored because the aggregated state offers a multivalent, low‑entropy environment for metal coordination, aligning with the observation that aggregates represent the proteome’s last attempt at order 2.

Testable predictions

Cells engineered to overexpress an amyloid‑prone protein (e.g., mutant huntingtin exon‑1) will display a measurable decrease in labile iron under oxidative challenge compared with controls; iron chelators will not further lower ROS in these cells.

Pharmacological disruption of fibrils using a disaggregase (e.g., Hsp110/Hsp70/Hsp40 complex) will increase labile iron and ROS levels only when extracellular iron is supplemented, indicating that the protective effect depends on metal binding.

In vivo, knockdown of iron‑import transporters (e.g., TfR1) will diminish the protective survival advantage conferred by amyloid aggregation in models of neurodegeneration, linking metal homeostasis to aggregate‑mediated cytoprotection 3.

If these predictions fail, the hypothesis that aggregation serves as a redox‑buffering mechanism would be falsified, supporting the view that aggregates are purely pathological byproducts.