The elucidation of the intriguing relationship between oxidative stress and Alzheimer's disease is crucial to understand the pathogenesis of the disease as also to design a suitable drug trial with antioxidants against this condition. We begin by reviewing the basic facts about Alzheimer's disease and the chemistry and biology of oxygen free radicals with particular reference to the cellular adaptive response through redox-signalling pathways. The post-mortem evidence of oxidative damage in the brain of Alzheimer's disease patients is overwhelming which is also supported by the similar changes in transgenic mice models of this disease. However, the causal relationship of oxidative stress with amyloid beta pathology or the genesis of Alzheimer's disease is not clear. Considering the available evidence the review suggests that the oxidative stress could be an early event in the disease process and may trigger various adaptive responses such as the alterations of amyloid beta metabolism and the activation of stress responsive kinases which can subsequently lead to neuronal degeneration and AD pathology. Further, we have presented a large body of evidence from various studies to highlight the beneficial effects of antioxidants against amyloid beta toxicity or AD pathology in animal or cell based models of AD. The failure of clinical trials with antioxidants against AD has been mentioned and the possible causes of such failures have been analysed.

The present study has attempted to understand how oxidative stress contributes to the development of proinflammatory state in the brain during aging. Three groups of rats have been used in this study: young (4-6 months, Group I), aged (22-24 months, Group II) and aged with dietary antioxidant supplementation (Group III). The antioxidants were given daily from 18 months onwards in the form of a combination of N-acetyl cysteine (50 mg/100 g body weight), α-lipoic acid (3 mg/100 g body weight), and α-tocopherol (1.5 mg/100 g body weight) till the animals were used for the experiments between 22 and 24 months. Several measurements have been made to evaluate the ROS (reactive oxygen species) production rate, the levels of proinflammatory cytokines (IL-1β, IL-6 and TNF-α) and the activation status of NF-κβ (p65 subunit) in brain of the three groups of rats under the study. Our results reveal that brain aging is accompanied with a significant increase in NADPH oxidase activity and mitochondrial ROS production, a distinct elevation of IL-1β, IL-6 and TNF-α levels along with increased nuclear translocation of NF-κβ (p65 subunit) and all these phenomena are partially but significantly prevented by the long-term dietary antioxidant treatment. The results imply that chronic dietary antioxidants by preventing oxidative stress and proinflammatory state may produce beneficial effects against multiple age-related deficits of the brain.

A combination of antioxidants (N-acetyl cysteine, α-lipoic acid, and α-tocopherol) was selected for long term oral supplementation study in rats for protective effects on age-related mitochondrial alterations in the brain. Four groups of rats were chosen: young control (6-7 months); aged rats (22-24 months); aged rats (22-24 months) on daily antioxidant supplementation from 18 month onwards and young rats (6-7 months) on daily antioxidant supplementation from 2 month onwards. The brain mitochondrial functional parameters, status of antioxidant enzymes and accumulation of oxidative damage markers were measured in the four groups of rats. A significant decrease in complex IV activity and a loss of transmembrane potential and phosphorylation capacity along with an increased accumulation of oxidative damage markers and compromised antioxidant enzyme status were noticed in aged rat brain mitochondria as compared to that in young controls, but in aged rats supplemented with oral antioxidants the mitochondrial alterations were largely prevented. Antioxidant supplementation in young rats had no effect on mitochondrial parameters investigated in this study. The results have implications in biochemical and functional deficits of brain during aging as well as in neurodegenerative disorders.

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phosphorylation of amyloid precursor protein (APP). When phosphorylated at threonine 668 (T668), APP undergoes conformational changes affecting its intracellular sorting and trafficking, which in turns impact proteolytic cleavage and increases A b production. The role of APP T668 phosphorylation and obesity in AD are not well understood and indicate a critical need to understand the mechanism(s) linking obesity and cognitive decline. Methods: Obesity is induced in C57Bl/6 mice using a high fat diet (54% kCal from fat) for 24 wk. APP and tau phosphorylation is examined from cortex lysates. Cortical neurons are prepared from E15 rat embryo and cultured in vitro for 7 days before insulin and/or IGF-I treatment. Results: Obese mice displayed significant cognitive impairment at 24 wk in parallel with the increased tau and T668-APP phosphorylation in the cortex. We previously reported that embryonic cortical neurons (eCN) develop neuronal IR with decreased insulin and IGF-I signaling following chronic insulin treatment. IGF-I treatment of eCN decreased T668-APP phosphorylation. Insulin also decreased APP phosphorylation but the effect was much weaker compared to IGF-I. Chronic treatment of eCN with insulin increased basal T668-APP phosphorylation. IGF-I was still able to reduce T668 phosphorylation after chronic insulin treatment; insulin itself was unable to reduce APP phosphorylation. These effect was reversed with the simultaneous treatment of chronic insulin with PI3-K inhibitor, suggesting chronic hyperactivation of Akt is responsible for IR-induced APP phosphorylation. Conclusions: Our results suggest IR-induced increases in T668 phosphorylation of APP as a possible link between obesity and cognitive impairment. Furthermore our data reveal a potential and beneficial effect of IGF-I signaling as a therapeutic target.