Oxidative stress status and RNA expression in hippocampus of an animal model of Alzheimer's disease after chronic exposure to aluminum

Abstract

It is well established that aluminum (Al) is a neurotoxic agent that induces the production of free radicals in brain. Accumulation of free radicals may cause degenerative events of aging such as Alzheimer's disease. On the other hand, melatonin (Mel) is a known antioxidant, which can directly act as free radical scavenger, or indirectly by inducing the expression of some genes linked to the antioxidant defense. In this study, AbetaPP female transgenic (Tg2576) (Tg) and wild-type mice (5 months of age) were fed with Al lactate supplemented in the diet (1 mg Al/g diet). Simultaneously, animals received oral Mel (10 mg/kg) dissolved in tap water until the end of the study at 11 months of age. Four treatment groups were included for both Tg and wild-type mice: control, Al only, Mel only, and Al+Mel. At the end of the period of treatment, hippocampus was removed and processed to examine the following oxidative stress markers: reduced glutathione (GSH), oxidized glutathione (GSSG), superoxide dismutase (SOD), glutathione reductase (GR), glutathione peroxidase (GPx), catalase (CAT), and thiobarbituric acid reactive substances (TBARS). Moreover, the gene expression of Cu-ZnSOD, GR, and CAT was evaluated by real-time RT-PCR. Aluminum concentration in hippocampus was also determined. The biochemical changes observed in this tissue suggest that Al acts as a pro-oxidant agent. Melatonin exerts an antioxidant action by increasing the mRNA levels of the antioxidant enzymes SOD, CAT, and GR evaluated in presence of Al and Mel, with independence of the animal model.

P3‐117: Progressive Inflammatory Pathology in the Retina of Aluminum‐Fed 5XFAD Transgenic Mice

“…The parallel and coordinated up-regulation of Aβ40 and Aβ42 peptides, COX-2 and CRP in aluminum-treated 5xFAD animals implicates an aluminum-orchestrated increase of pro-inflammatory signaling in both the brain cortex and retina of 5xFAD mice [3][4][5][6]. Indeed multiple previous studies have shown that aluminum exerts significant pro-inflammatory effects in a variety of embryologically-related cell types of the mammalian CNS [4,[10][11][12][13][14][15][16][17]25,32,33]. Interestingly, the common neuroectodermal origins of the mammalian cortex and retina may predispose these highly integrated, structurally similar, multi-layered cellular structures to AD-type dysfunction, including the involvement of shared pathogenic signaling pathways that drive amyloidogenesis, inflammatory neurodegeneration and the progressive deposition of aggregates of highly insoluble Aβ42-peptides.…”

“…The use of humanized murine Tg-AD models has significantly increased our understanding of the role of the pathological mechanisms that drive amyloidogenesis and inflammatory degeneration characteristic of the AD phenotype [6][7][8][9][10]. In the AD brain Aβ42 peptides progressively accumulate and self-aggregate, evolving into higher order proinflammatory senile plaque deposits; in progressive neurodegenerative diseases of the retina such as agerelated macular degeneration (AMD), Aβ42 peptides accumulate with age and selfaggregate into highly insoluble pro-inflammatory lesions called drusen [27][28][29][30][31][32].…”

“…Whether amyloidogenesis originates independently in the brain and retina, or whether amyloidogenic signals originate in the brain and spread via the primary visual cortex and thalamus to the retina is open to question, but current data now favor the latter possibility [4][5][6][7][8]. Several laboratories have independently studied the effects of supplementing the diets of amyloidoverexpressing Tg-AD murine models (Tg-2576, APP/PS1, 5xFAD, etc.,) with aluminum (as chloride, lactate, maltolate or sulfate) and have evaluated the impact of ingested aluminum with pathological outcome [9][10][11][12][13][14][15][16][17]. The general consensus is that the presence of aluminum in the diets of Tg-AD murine models enhances AD-type neuropathology: (1) by up-regulating the abundance of pro-inflammatory microRNAs [3], (2) by progressively exacerbating the incidence of oxidative stress [9][10][11][12]; (3) by hastening the appearance of Aβ42 peptides, accelerating Aβ42 oligomerization, amyloidogenesis and senile plaque deposition [11][12][13]; and (4) by increasing apoptosis in brain cells that temporally correlate to deficits in memory, cognition and spatial learning [14][15][16][17], all of which are features characteristic of AD neuropathology [9][10][11][12][13][14][15][16][17].…”

Alzheimer’s Disease: Focus on the Neuroprotective Role of Melatonin

“…Melatonin enhanced Bcl-2 expression with consequent inhibition of Aβ-induced cell death [60]. Caspase-3 is known to be directly linked to cytochrome c release and is related to cell death in AD [61,62], and this is down regulated by melatonin [63]. Thus, the apoptosis-inducing factors liberated during mitochondrial damage are effectively inhibited by melatonin through a variety of mechanisms, thereby preventing the neuronal cell death seen in AD.…”

The Prevention of Alzheimer's Disease and Parkinson’s Disease by Monascus purpureus NTU 568-Fermented Compounds

“…An important cause for AD is currently the deposition of amyloid β (Aβ) in the brain, leading to severe oxidative stress and inflammation, as well as neuronal death and memory damage in patients with AD [1]. In a number of in vitro and in vivo studies, it has been found that the use of antioxidants can effectively prevent the memory disability due to nerve impairment, caused by Aβ [1][2][3]. Epidemiology data also indicate the reduction in occurrence rate of AD by non-steroidal anti-inflammatory drugs [4].…”