Protein deposits perform vital functions within the human body; however, complications can arise, causing these aggregates to proliferate, which leads to neurodegeneration and conditions such as Parkinson’s and Alzheimer’s.
One such formation, amyloid beta peptide, is linked to dementia, but scientists were uncertain about the mechanisms through which these peptide structures “deteriorate” and the reasons behind their assembly.
Researchers at Washington University in St. Louis have discovered a significant role for the physical interfaces of these amyloid beta peptides in influencing the chemical behavior of their assemblies. This finding is essential for understanding the development of treatments that can interfere with the harmful pathways leading to Alzheimer’s or ALS.
Consider these protein deposits as structural frameworks that create “holes” and “nails” within themselves.
Previously, it was understood that amyloid aggregation undergoes a sequence of physical transformations that dictate its functionality. However, Yifan Dai, an assistant professor of biomedical engineering at the McKelvey School of Engineering at WashU, found that the function of the structure is also encoded in its “interfacial electrical field,” the surface that influences the chemical activities of surrounding molecules.
In findings published in the Journal of the American Chemical Society, Dai’s team, along with colleagues from Stanford and Columbia universities, demonstrated that these surfaces can generate an electric field that oxidizes water molecules, producing “highly reactive oxygen species” which propel the peptide along a toxic pathway.
Reactive oxygen species impose stress on the cell and DNA, leading to the degradation of that nanoscale framework. Through this electric field, amyloid beta peptides create a positive feedback loop that enhances the formation and aggregation of fibrils (a crucial element in the enlargement of that nanoscale structure).
“The beta amyloid monomer itself is chemically stable, but higher-order assemblies of these monomers become toxic,” Dai stated. This sparked researchers’ curiosity in how biological matter with varying length scales can encode distinct functions through the creation of a unique stable surface, he continued.
Previously, it was believed that highly reactive forms of molecular oxygen were produced through enzymatic mechanisms.
However, through current research, Dai observed that the electric field itself can stretch molecular bonds similarly to enzymatic activity, and once those bonds are elongated, the energy difference generates reactive oxygen species that render the environment toxic.
The main takeaway for biomedical researchers is that amyloid aggregation involves not just a physical process but also a chemical “crosslinking” mechanism—a process that researchers might have the potential to disrupt.
“This is the source of toxicity, originating directly from the assembly of amyloid during phase transitions,” remarked Michael W. Chen, a graduate student at McKelvey Engineering. Chen and postdoctoral researcher Xiaokang Ren are co-lead authors alongside Dai.
They also discovered small molecules capable of breaking the chemical feedback loop that drives this toxicity. These compounds operate by scavenging hydroxyl radicals—a variant of reactive oxygen molecules—or by disrupting the interface.
Such compounds are readily available in foods with antioxidant characteristics, further supporting the notion that proper nutrition can play a role in safeguarding against dementia.
“Consuming more coffee and incorporating more berries and nuts into the diet may assist in detoxifying this process,” Dai suggested.
Chen MW, Ren X, Song X, Qian N, Ma Y, Yu W, Yang L, Min W, Zare RN, Dai Y. Transition state-dependent spontaneous generation of reactive oxygen species by Aβ assemblies encodes a self-regulated positive feedback loop for aggregate formation. Journal of the American Chemical Society Feb. 25.
DOI: https://doi.org/10.1021/jacs.4c15532
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