Age related memory loss and the role of the ubiquitin proteasome system

Abstract

The hippocampus is a vital region of the brain directly involved in memory formation and spatial processing. As individuals age, this area undergoes significant structural changes, including a reduction in volume and modifications in molecular processes. These transformations are an inevitable aspect of the natural aging process, occurring in individuals regardless of the presence of neurodegenerative diseases or neurological injuries. At the molecular level, the aging brain encounters challenges, such as the accumulation of damaged proteins. The ubiquitin-proteasome system (UPS), responsible for breaking down damaged proteins, exhibits dysfunction in neurodegenerative disorders like Alzheimer's disease or dementia. While we acknowledge that proteasome function declines with age, its specific alterations in the hippocampus, a key area for memory and learning, remain unexplored and urgently need further investigation. I investigated age-related memory loss across the lifespan. Two ubiquitin molecules that I studied are K48 and M1/linear ubiquitin: K48 is the canonical protein degradation marker, while M1 is an atypical ubiquitin marker that is independent of the proteasome. My findings revealed that there were age-dependent changes in proteasome activity, and degradation-specific K48 polyubiquitin protein targeting in the hippocampus and retrosplenial cortex of male and female rats across their lifespan. In terms of targeted protein degradation in the hippocampus, altered protein degradation targets were involved in transcription, astrocyte structure, G-protein, and interferon signaling in males and females, respectively. Further, using a contextual fear conditioning paradigm I found that learning increased proteasome activity and K48 polyubiquitin protein targeting in the hippocampus of aged male rats, contrasting with previous findings in young adult animals. My findings revealed age-dependent alterations in the protein degradation function of the ubiquitin proteasome system (UPS) in male and female rats throughout their lifespan. These discoveries suggest that protein degradation in the hippocampus may contribute to age-related memory decline. In terms of M1/linear polyubiquitination in aging, there was an increase in the aged hippocampus in linear polyubiquitin levels at rest but reduced levels of linear polyubiquitin in response to learning. CRISPR-dCas9 manipulation of Rnf31 levels to increase linear polyubiquitination in the aged hippocampus did not improve memory. However, it enhanced memory in young animals. These findings suggest that more processes are dysregulated in the aging brain, and further research into these areas is needed to understand and potentially treat age-related cognitive decline.