Proteins with cognition-associated structural changes in a rat model of aging exhibit reduced refolding capacity.

Cognitive decline during aging represents a major societal burden, causing both personal and economic hardship in an increasingly aging population. Many studies have found that the proteostasis network, which functions to keep proteins properly folded, is impaired with age, suggesting that there may be many proteins that incur structural alterations with age. Here, we used limited proteolysis mass spectrometry, a structural proteomic method, to globally interrogate protein conformational changes in a rat model of cognitive aging. Specifically, we compared soluble hippocampal proteins from aged rats with preserved cognition to those from aged rats with impaired cognition. We identified a couple hundred proteins as having undergone cognition-associated structural changes (CASCs). We report that CASC proteins are substantially more likely to be nonrefoldable than non-CASC proteins, meaning that they typically cannot spontaneously refold to their native conformations after being chemically denatured. These findings suggest that noncovalent, conformational alterations may be general features in cognitive decline.