Oxidative damage and amyloid‐β metabolism in brain regions of the longest‐lived rodents

Abstract

Naked mole rats (NMRs) are the longest-lived rodents, with young individuals having high levels of Aβ in their brains. The purpose of this study was twofold: to assess the distribution of Aβ in key regions of NMR brains (cortex, hippocampus, cerebellum) and to understand whether the accumulation of Aβ 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 Aβ (soluble Aβ1–42). This was due not to increased Aβ 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 Aβ levels and its effects on the brain.

Age-related changes in the proteostasis network in the brain of the naked mole-rat: Implications promoting healthy longevity

“…While there are multiple β-subunits in eukaryotes, unlike in prokaryotes that have only one type, the reduced phosphorylated states in the oldest NMR brains could suggest that there is an increased affinity towards proteome assembly and therefore, an increased degradation of unwanted or damaged proteins, clearing the cell of detritus to promote healthy cellular function. This observation would be consistent with the observed high levels of proteasome activity reported for brain lysates of the NMR [8]. …”

“…Previously, we have shown that a particular UCH variant, UCHL1, is oxidized in AD brain, which could conceivably inhibit Aβ degradation [66, 67]. However, it has been reported that even though NMRs exhibit Aβ levels similar to that of 3xTg-AD mice, there is no accumulation of senile plaques in the NMR brain [8, 68]. Moreover, in mice ubiquitinylated proteins accumulate with age; however, in NMRs levels of ubiquitinylated proteins of 2 year-old and 26 year-old rodents were similar [12].…”

“…The proteasome cleaves damaged proteins into smaller peptide fragments by the proteolytic center that contains trypsin-like (T-L), post-glutamyl peptide-hydrolyzing (PGPH), and chymotrypsin-like (ChT-L) specificities [22, 23]. Liver and brain samples from NMRs when compared to mouse controls, have shown increased ChT-L and T-L activities, suggesting a more efficient UPS that may contribute to their inherent resistance to aging and age-related diseases [8, 14]. Moreover, human, mouse, and yeast proteasomes were demonstrated to have an increased activity when exposed to proteasome depleted cytosolic fractions containing a novel heat shock protein (HSP)-containing complex from NMR samples [23].…”

Divergent tissue and sex effects of rapamycin on the proteasome-chaperone network of old mice

“…In contrast to these declines in proteolytic degradation processes, the proteasome-mediated protein degradation system (PMDS), that includes both ubiquitin-dependent and independent proteasome machinery and associated molecular chaperones, is more robust in naturally long-lived species (Rodriguez et al, 2012; Edrey et al, 2014), long-lived mutants (Kruegel et al, 2011), calorically-restricted animals (Bonelli et al, 2008), and centenarians (Chondrogianni et al, 2000). As such it appears hard to reconcile a decline in proteasome function with rapamycin-induced extended longevity.…”

Physiological regulation of the heat shock response by glutamine: implications for chronic low-grade inflammatory diseases in age-related conditions

“…AD is the most common neurodegenerative disease causing dementia and having no treatment or cure as yet [158]. Although the exact physiopathology of AD is still unsettled, it is clear that brain dysfunctions and atrophy (due to neuronal loss) that accompany AD are correlated with the accumulation of unfolded proteins that tend to form neurotoxic protein aggregates, such as extracellular deposition of amyloid plaques, accumulation of intracellular neurofibrillary tangles (NFTs), inflammation, and oxidative stress [159][160][161]. Abundant extraneuronal deposits of amyloid-beta (Aβ) are the major pathological hallmark of AD and play an early pathologic role in the development of the disease [162].…”