PA28α overexpressing female mice maintain exploratory behavior and capacity to prevent protein aggregation in hippocampus as they age

With age, protein damage accumulates and increases the risk of age‐related diseases. The proteasome activator PA28αβ is involved in protein damage clearance during early embryogenesis and has demonstrated protective effects against proteinopathy. We have recently discovered that adult female mice overexpressing PA28α (PA28αOE) have enhanced learning and memory, and protein extracts from their hippocampi prevent aggregation more efficiently than wild type. In this study, we investigated the effect of overexpressing PA28α on aging using C57BL/6N×BALB/c F2 hybrid mice. We found that the hippocampal anti‐aggregation effect was maintained in young adult (7 months) to middle‐aged (15 months) and old (22 months) PA28αOE females. While the PA28αOE influence on learning and memory gradually decreased with aging, old PA28αOE females did not display the typical drop in explorative behavior—a behavioral hallmark of aging—but were as explorative as young mice. PA28αOE lowered PA28‐dependent proteasome capacity in both heart and hippocampus, and there was no indication of lower protein damage load in PA28αOE. The life span of PA28αOE was also similar to wild type. In both wild type and PA28αOE, PA28‐dependent proteasome capacity increased with aging in the heart, while 26S and 20S proteasome capacities were unchanged in the timepoints analyzed. Thus, PA28αOE females exhibit improved hippocampal ability to prevent aggregation throughout life and enhanced cognitive capabilities with different behavioral outcomes dependent on age; improved memory at early age and a youth‐like exploration at old age. The cognitive effects of PA28αβ combined with its anti‐aggregation molecular effect highlight the therapeutical potential of PA28αβ in combating proteinopathies.