Revealing the Interplay of Intraorganellar O₂^•- and ATP in Brain Aging-Related Alzheimer’s Disease via Unimolecular Dual-Responsive Probes.

Researchers developed tools to observe the interplay of a damaging molecule called superoxide and the cell’s energy currency, ATP, within brain cell compartments, finding that aging cells affected by Alzheimer’s-related proteins experience an imbalance where damaging superoxide increases before ATP decreases.

Brain aging is a significant risk factor for Alzheimer’s disease, yet the precise mechanisms behind this connection are still not fully understood. Recent research has shed light on how two crucial molecules, superoxide anion and adenosine triphosphate (ATP), interact within our brain cells, contributing to this complex disease. Superoxide anion (O2•–) is a type of reactive oxygen species, an unstable molecule that can cause damage to cells and is associated with cellular stress. On the other hand, adenosine triphosphate (ATP) is the primary energy currency of the cell, essential for powering almost all cellular activities.

Scientists have developed innovative tools called unimolecular dual-responsive probes, specifically named Mito-SA and Lyso-SA, which can simultaneously detect and monitor the levels of both superoxide anion and ATP within specific cell compartments: mitochondria, often called the “powerhouses” of the cell, and lysosomes, the cell’s “recycling centers.”

Using these probes, the study observed coordinated changes in the levels of superoxide anion and ATP within the mitochondria and lysosomes of mouse hippocampal neuronal cells, which are crucial for memory. It was discovered that both normal organelle functions and the process of neuronal aging lead to fluctuations in these molecules. More importantly, brain cells that were aged (senescent cells) were found to be more vulnerable to the adverse effects of the amyloid-beta (Aβ) protein, a protein notoriously linked to Alzheimer’s disease. This vulnerability resulted in a significant burst of superoxide anion and a simultaneous depletion of ATP. Interestingly, the increase in superoxide anion occurred earlier than the decrease in ATP during this process. The researchers also confirmed these age-dependent alterations in superoxide anion and ATP levels in the brains of AD mice, providing valuable insights into how these two biomarkers contribute to the disease.

This work not only demonstrates a clever way to design probes that can target specific cell compartments and detect multiple substances but also unravels the pivotal interplay of superoxide anion and ATP in the development of age-related Alzheimer’s disease.