The long-term objective of this proposal is to determine the functional role that dietary aluminum (Al) plays in vivo in Alzheimer's disease (AD)-like amyloidosis. Epidemiological studies have implicated Al exposure in AD pathogenesis, and its known capacity to exacerbate oxidative events has been suggested as a possible mechanism of its neurotoxicity. However, conflicting results have also been reported. Isoprostanes are sensitive and specific markers of in vivo lipid peroxidation and oxidative stress. Recently, the investigators have shown that isoprostane biosynthesis is increased in a transgenic mouse model of AD amyloidosis, the Tg2567, and that this increase precedes the onset of detectable amount of brain amyloid Beta (ABeta) levels and plaque deposition.
In Specific Aim 1, the researchers will investigate whether or not dietary Al exacerbates in vivo oxidative stress and lipid peroxidation in Tg2567 mice, and whether this will lead to an earlier development of the AD-like amyloidosis and behavioral changes.
In Specific Aim 2, they will test the hypothesis that dietary antioxidant, vitamin E, by suppressing isoprostane biosynthesis, will delay the accumulation of amyloid B and the onset of amyloid plaque deposition and ameliorate the behavioral impairment in Tg2567 mice. In summary, these studies will elucidate the controversial role of dietary Al as a potential pathogenetic factor in AD development. These studies will investigate its role as modulator of brain oxidative damage and lipid peroxidation and subsequent amyloid deposition in a model of AD amyloidosis. Such data will provide new insights into the relationship between Al exposure and AD. These studies are a necessary prelude to understand some of the mechanisms by which this nutritional factor may contribute to the initiation and progression of AD. This could lead to future novel therapeutic approaches for this devastating disease.
| Pratico, Domenico; Yao, Yuemang; Rokach, Joshua et al. (2004) Reduction of brain lipid peroxidation by CSF drainage in Alzheimer's disease patients. J Alzheimers Dis 6:385-9; discussion 443-9 |
| Rokach, Joshua; Kim, Seongjin; Bellone, Sophie et al. (2004) Total synthesis of isoprostanes: discovery and quantitation in biological systems. Chem Phys Lipids 128:35-56 |
| Pratico, Domenico; Rokach, Joshua; Lawson, John et al. (2004) F2-isoprostanes as indices of lipid peroxidation in inflammatory diseases. Chem Phys Lipids 128:165-71 |
| Yao, Y; Zhukareva, V; Sung, S et al. (2003) Enhanced brain levels of 8,12-iso-iPF2alpha-VI differentiate AD from frontotemporal dementia. Neurology 61:475-8 |
