Exposure to¹⁶O-Particle Radiation Causes Aging-Like Decrements in Rats through Increased Oxidative Stress, Inflammation and Loss of Autophagy

Abstract

Exposing young rats to particles of high energy and charge (HZE particles), a ground-based model for exposure to cosmic rays, enhances indices of oxidative stress and inflammation, disrupts the functioning of neuronal communication, and alters cognitive behaviors. Even though exposure to HZE particles occurs at low fluence rates, the cumulative effects of long-term exposure result in molecular changes similar to those seen in aged animals. In the present study, we assessed markers of autophagy, a dynamic process for intracellular degradation and recycling of toxic proteins and organelles, as well as stress and inflammatory responses, in the brains of Sprague-Dawley rats irradiated at 2 months of age with 5 and 50 cGy and 1 Gy of ionizing oxygen particles ((16)O) (1000 MeV/n). Compared to nonirradiated controls, exposure to (16)O particles significantly inhibited autophagy function in the hippocampus as measured by accumulation of ubiquitin inclusion bodies such as P62/SQSTM1, autophagosome marker microtubule-associated protein 1 beta light chain 3 (MAP1B-LC3), beclin1 and proteins such as mammalian target of rapamycin (mTOR). The molecular changes measured at short (36 h) and long (75 days) intervals after (16)O-particle exposure indicate that the loss of autophagy function occurred shortly after exposure but was recovered via inhibition of mTOR. However, HZE-particle radiation caused significant sustained loss of protein kinase C alpha (PKC-α), a key G protein modulator involved in neuronal survival and functions of neuronal trophic factors. Exposure to (16)O particles also caused substantial increases in the levels of nuclear factor kappa B (NF-κB) and glial fibrillary acidic protein (GFAP), indicating glial cell activation 75 days after exposure. This is the first report to show the molecular effects of (16)O-particle radiation on oxidative stress, inflammation and loss of autophagy in the brain of young rats.

The endocannabinoid system in normal and pathological brain ageing

“…It is generally observed that improving clearance with the induction of autophagy [10,106] or proteasome activity [107,108] slows down the ageing process and improves cognitive functions. Moreover, it was shown that reduced autophagy causes ageing-like decrements [109,110] and facilitates the development of neurodegenerative diseases [111]. Not surprising therefore that induction of autophagy was intensively tested in various models of neurodegenerative diseases.…”

Tart cherry supplementation improves working memory, hippocampal inflammation, and autophagy in aged rats

“…Autophagy is a well-regulated lysosomal degradation process whose disruption, which leads to neuronal dystrophy and death, is a potential mechanism of the aging process and the development of neurodegenerative diseases (Meijer and Codogno 2006;Rajawat et al 2009). Neuroinflammation has been identified as a cause of autophagal dysregulation in aged rats (Poulose et al 2011). Therefore, a potentially valuable approach to combat age-related deficits in behavior is to alter inflammation.…”

Protective effects of blueberry- and strawberry diets on neuronal stress following exposure to 56Fe particles

“…Exposing rats to 56 Fe particles has been shown to interfere with spatial learning and memory in the Morris water maze and is correlated with decreased hippocampal neurogenesis (Casadesus et al, 2005;Rola et al, 2004). Studies have also shown that exposing young animals to HZE particle radiation results in "accelerated aging" (Joseph et al, 1992;Poulose et al, 2011), a process where young animals exhibit behavioral and molecular changes similar to that of aged animals. Most of the studies support the role of OS and inflammation as mediators of the deficits observed in neuronal and cognitive functioning following exposure to HZE radiation; however, recent studies conclude that HZE radiation not only causes OS and inflammation, but also alters protective signaling, thereby unleashing a cascade of detrimental signals which ultimately leads to the death of neurons (Cherry et al, 2012;Huang et al, 2010).…”

“…One contributing molecular factor leading to a decrement in brain performance may be an increase in intracellular toxic proteins due to a failure of macroautophagy following exposure to HZE particles (Poulose et al, 2011). Autophagy is a wellregulated lysosomal process by which intracellular damaged toxic structures, such as protein/lipid complexes, protein oligomers/aggregates and cellular organelles, are identified, sequestered and/or recycled (Friedman et al, 2012;Komatsu et al, 2007).…”

“…In this regard, Hou and colleagues have shown that autophagy prevents irradiation injury through decreasing the generation of reactive oxygen species (ROS) in mesenchymal stem cells following exposure to a high dose (6 Gy) of 12 C ions (Hou et al, 2013). Studies in our laboratory using rats exposed to 16 O particles indicated an increased accumulation of p62/SQSTM1, an ubiquitin-binding sequestering protein; aggregation of p62 has been implicated in the dystrophy and degeneration of neurons (Poulose et al, 2011). While irradiation produces OS and inflammatory responses, the relationship between particle-induced OS and short long term effects of HZE particles is unknown.…”