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Oxidative stress, an imbalance between pro-oxidant and antioxidant status, favouring the pro-oxidant state is a result of increased production of reactive oxygen species (ROS) or inadequate antioxidant protection. ROS are produced through several mechanisms in cells including during mitochondrial oxidative phosphorylation. Increased mitochondrialderived ROS are associated with mitochondrial dysfunction, an early event in age-related diseases such as Alzheimer's diseases (ADs) and in metabolic disorders including diabetes. AD post-mortem investigations of affected brain regions have shown the accumulation of oxidative damage to macromolecules, and oxidative stress has been considered an important contributor to disease pathology. An increase in oxidative stress, which leads to increased levels of superoxide, hydrogen peroxide and other ROS in a potentially vicious cycle is both causative and a consequence of mitochondrial dysfunction. Mitochondrial dysfunction may be ameliorated by molecules with antioxidant capacities that accumulate in mitochondria such as carotenoids. However, the role of carotenoids in mitigating mitochondrial dysfunction is not fully understood. A better understanding of the role of antioxidants in mitochondrial function is a promising lead towards the development of novel and effective treatment strategies for age-related diseases. This review evaluates and summarises some of the latest developments and insights into the effects of carotenoids on mitochondrial dysfunction with a focus on the antioxidant properties of carotenoids. The mitochondria-protective role of carotenoids may be key in therapeutic strategies and targeting the mitochondria ROS is emerging in drug development for agerelated diseases. [ABSTRACT FROM AUTHOR]

Elevated low-density lipoprotein (LDL) concentration in mid-life increases the risk of developing Alzheimer's disease (AD) in later life. Increased oxidized LDL (oxLDL) modification and nitration is observed during dementia and hypercholesterolaemia. We investigated the hypothesis that statin intervention in mid-life mitigates the inflammatory effects of oxLDL on the microvasculature. Human microvascular endothelial cells (HMVECs) were maintained in transwells to mimic the microvasculature and exposed to patient and control LDL. Blood was obtained from statin-naive, normo- and hyper-lipidaemic subjects, AD with vascular dementia (AD-plus) and AD subjects (n=10/group) at baseline. Only hyperlipidaemic subjects with normal cognitive function received 40 mg of simvastatin intervention/day for 3 months. Blood was re-analysed from normo- and hyper-lipidaemic subjects after 3 months. LDL isolated from statin-naive hyperlipidaemic, AD and AD-plus subjects was more oxidized (agarose gel electrophoretic mobility, protein carbonyl content and 8-isoprostane F2α) compared with control subjects. Statin intervention decreased protein carbonyls (2.5±0.4 compared with 3.95±0.2 nmol/mg; P<0.001) and 8-isoprostane F2α (30.4±4.0 pg/ml compared with 43.5±8.42 pg/ml; P<0.05). HMVEC treatment with LDL-lipids (LDL-L) from hyperlipidaemic, AD and AD-plus subjects impaired endothelial tight junction expression and decreased total glutathione levels (AD; 18.61±1.3, AD-plus; 16.5±0.7 nmol/mg of protein) compared with untreated cells (23.8±1.2 compared with nmol/mg of protein). Basolateral interleukin (IL)-6 secretion was increased by LDL-L from hyperlipidaemic (78.4±1.9 pg/ml), AD (63.2±5.9 pg/ml) and AD-plus (80.8±0.9 pg/ml) groups compared with healthy subject lipids (18.6±3.6 pg/ml). LDL-L isolated after statin intervention did not affect endothelial function. In summary, LDL-L from hypercholesterolaemic, AD and AD-plus patients are inflammatory to HMVECs. In vivo intervention with statins reduces the damaging effects of LDL-L on HMVECs. [ABSTRACT FROM AUTHOR]

Blood cholesterol levels are not consistently elevated in subjectswith age-related cognitive decline, although epidemiological studies suggest that Alzheimer's disease and cardiovascular diseases share common risk factors. These include the presence of an unusual genetic variant, the APOE4 (apolipoprotein E4) allele, which modulates LDL (low-density lipoproteins) metabolism, increases free radical formation and reduces plasma antioxidant concentrations. Together, these risk factors support a mechanism for increased LDL circulation time and free radical modification of LDL. Plasma oxycholesterols, hydroxylated metabolites of cholesterol, are carried by oxidized LDL, and elevated lipids in mid-life are associated with increased longterm risk of dementia. Although brain cholesterol metabolism is segregated from the systemic circulation, during oxidative stress, plasma oxycholesterols could have damaging effects on BBB (blood-brain barrier) function and consequently on neuronal cells. Cholesterol-lowering drugs such as statins may prevent the modifications to LDL in mid-life and might show beneficial effects in later life. [ABSTRACT FROM AUTHOR]