Elevated Oxidative Stress in the Brain of Senescence-accelerated Mice at 5 Months of Age

Abstract

The senescence-accelerated mouse (SAM) is a useful animal model to study aging or age-associated disorder. In the present study, we have used a multidisciplinary approach to the characterization of changes that occur in aging and in the modelling of brain aging. The SAMP8 mouse at 5 months of age exhibited an increase in gliosis and molecular oxidative damage. Likewise, we found that superoxide dismutase activity decreased compared with age-matched SAMR1 while there were no differences in activity of catalase and glutathione reductase. These results indicate that the decrease of superoxide dismutase may be involved in the increase of oxidative stress in brain of SAMP8 at younger stages. This suggestion is supported by an increase in the expression of alpha-synuclein together with phosphorylated tau protein, which is concurrent with the decline of that antioxidant enzyme. Alpha-synuclein aggregates are invariably associated with tau pathologies and our results demonstrate that alpha-synuclein accumulation is a potent inducer of tau pathologies not only in neurodegenerative diseases but also in normal aging. These results also imply that SAMP8 are exposed to elevated levels of oxidative stress from an early age, and that could be a very important cause of the senescence-related impairments and degeneration in the brain seen in this strain.

Senescence-Accelerated Mice P8: A Tool to Study Brain Aging and Alzheimer's Disease in a Mouse Model

“…The higher oxidative stress status observed in SAMP mice is partly due to mitochondrial dysfunction and may be a cause of the senescence acceleration and age-dependent alterations in cell structure and function [21]. As expected, SAMP8 exhibited higher levels of lipid peroxides and protein carbonyls than SAMR1 [22,26]. Carbonyl modification of Cu,Zn-superoxide dismutase (Cu,Zn-SOD) in liver at 3 months and hippocampal cholinergic neurostimulating peptide precursor protein (HCNP-pp) in brain at 9 months were higher in SAMP8 than in control SAMR1 [23].…”

“…Indeed, recent studies provide a more in-depth understanding of tau phosphorylation dynamics in the SAMP8. As such, the data indicates that various forms of hyperphosphorylated tau are more present in SAMP8 than in SAMR1 [22,55].…”

“…However, the literature on oxidative stress in SAMP8 is not always unequivocal. For example, Alvarez-Garcia et al [22] found no differences in the activity of catalase and glutathione reductase. A different study in animals of the same age showed the opposite result: glutathione-S-transferase was not affected, but glutathione reductase and catalase were significantly inhibited compared to SAMR1 [31].…”

“…SAMP8 brains overproduce amyloid precursor protein (APP) and have increased phosphorylation of tau [36]. Notably, tau hyperphosphorylation increases occur as early as 5 months of age in SAMP8 [22,55], which suggests that this process is an integral part of aging and, like oxidative stress, an early event in AD. Indeed, recent studies provide a more in-depth understanding of tau phosphorylation dynamics in the SAMP8.…”

Dysfunction of astrocytes in senescence‐accelerated mice SAMP8 reduces their neuroprotective capacity

“…In addition, chronic administration of antioxidants, such as melatonin, α -lipoic acid, N-acetylcysteine and acetyl-L-carnitine, to SAMP8 mice not only reduced oxidative damage to neural lipids and proteins, but also lessened cognitive deficits (Okatani et al ., 2002;Yasui et al ., 2002;Farr et al ., 2003;Poon et al ., 2005). Decreases in superoxide dismutase, catalase, glutathione reductase and glutathione peroxidase activities, as well as increases in acyl-CoA oxidase, which have been detected early in SAMP8 mice (1-12 months) compared with age-matched SAMR1 controls (Sato et al ., 1996b;Kurokawa et al ., 2001;Okatani et al ., 2002;Alvarez-García et al ., 2006;Sureda et al ., 2006), may cause elevated generation of ROS. On the other hand, ROS generated by mitochondria or from other cell sites not only cause damage to mitochondrial components and DNA, but also trigger degradative processes that contribute to the aging process (Cadenas & Davies, 2000;Manczak et al ., 2005).…”