Oxidative Damage and Amyloid-beta Metabolism in Brain Regions of the Longest-Lived Rodents

Naked mole rats (NMRs) are the longest-lived rodents, with young individuals having high levels of A in their brains. The purpose of this study was twofold: to assess the distribution of A in key regions of NMR brains (cortex, hippocampus, cerebellum) and to understand whether the accumulation of A is due to enhanced production or decreased degradation. Recent evidence indicates that lipid peroxides directly participate in induction of cytoprotective proteins, such as heat shock proteins (Hsps), which play a central role in the cellular mechanisms of stress tolerance. Amyloid precursor protein processing, lipid peroxidation, Hsps, redox status, and protein degradation processes were therefore assessed in key NMR brain regions. NMR brains had high levels of lipid peroxidation compared with mice, and the NMR hippocampus had the highest levels of the most toxic moiety of A (soluble A(1-42)). This was due not to increased A production but rather to low antioxidant potential, which was associated with low induction of Hsp70 and heme oxygenase-1 as well as low ubiquitin-proteasome activity. NMRs may therefore serve as natural models for understanding the relationship between oxidative stress and A levels and its effects on the brain. (c) 2013 Wiley Periodicals, Inc.