Presentation
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6th Internet World Congress for Biomedical Sciences |
Albert Sun(1), Bozena Draczynska-Lusiak(2), Grace Sun(3)
(1)(2)(3)Department of Pharmacology. University of Missouri - Columbia. United States
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It is recognized that oxidative stressors such as ionizing radiation, inflammatory agents, excitotoxic insults, stroke and ischemia, or release of transition metal ions (Fe3+, Cu2+), may cause production of reactive oxygen species (ROS) in the brain (Sun and Chen, 1998). Lipoproteins are likely targets of the oxidative insult. For example, increase in oxidized LPs was found associated with traumatic brain injury (Borovic et al., 1995). Our previous studies further demonstrated that oxidized low-density lipoproteins (LDL) from human plasma could damage these cells and cause apoptotic cell death (Draczynska-Lusiak et al. 1998ab; Sun and Chen, 1998). In this study, we tested LPs prepared with lipids extracted from the brain and enriched with human recombinant apoE (Resen et al. 1997). Ultracentrifugation of the BLP preparation showed that these LP had the characteristic high density similar to those isolated from CSF (Pitas et al., 1987a,b). Our results show that regardless of enrichment with apoE3 or apoE4, BLP could be taken up by primary neurons. However, oxidized BLPs were more effectively taken up by neurons that the native BLPs. Furthermore, the greater uptake of oxidized BLP is associated with their ability to induce neuron cell death. Taken together, studies by our laboratory (Draczynska-Lusiak et al. 1998ab) as well as those from others (Keller et al., 1999a, b, c) well indicate the ability of oxidized LPs to be taken up by neurons and subsequently cause cytotoxicity to these cells.
An important pathological landmark of Alzheimer’s disease is the accumulation of neuritic plaques surrounded with activated glial cells and degenerating neurons (Price et al. 1998). There is immense interest to understand mechanisms that can regulate the production of Ab and its interaction with apoE. Aßs have been shown to disrupt neuronal ion homeostasis (Yankner 1996), increase ROS production and cause oxidative damage to neurons (Butterfield 1997; Mark et al., 1999). Aß peptides (39 to 43 amino acids) are derived from the amyloid precursor protein (APP) present in both neurons and glial cells in the brain. While the cellular function of APP is yet to be elucidated, this protein is comprised of a hydrophobic membrane-spanning domain, N-glycosylation sites, and sites for binding Zn2+ and Cu2+ with high affinity (Hesse et al. 1994). Copper is present at substantial levels in the brain and its release as a result of synaptic activation can reach as high as 100 mM in the synaptic cleft (Kardos et al. 1989). The interaction between APP and Cu2+ may result in the reduction of Cu2+ to Cu+ and the formation of an intra-molecular disulfide bond (Mucke et al., 1994). In the presence of oxidant stressors such as H2O2, the APP-Cu interaction may cause APP fragmentation and increase in the production of Ab (Smith et al. 1997). Under normal conditions, Abs appear to be normal products of APP metabolism and are present in CSF and plasma. Although the exact molecular mechanism underlying neurotoxicity of Aß is still unknown, Abin their fibrillar form have been shown as a direct source for ROS production (Huang et al. 1997; 1999). Studies by these investigators gave evidence for a direct interaction between Aß and Fe3+/Cu2+ to create a strong positive formal reduction potential, which can rapidly reduce Fe3+ and Cu2+ ions and trap molecular oxygen to generate H2O2. These results suggest that Aß, in the order of Aß 1-42> Aß 1-40, may directly contribute to the oxidative stress in the AD brain. In this study, we examined the effects of aggregated Aß (1-42) on the survivability of neuronal cells. Our data are in agreement with the notion that aggregated Aßs are cytotoxic and can cause neuron cell death (Fig 5). Furthermore, more extensive neuronal damage can be observed when aggregated Aßs were added to neurons together with oxidized BLPs. Lipoprotein oxidation is known to result in the generation of a number of products such as 17 oxycholesterol, acylhydroperoxide, malonyldialdehyde, and 4-hydroxynonenal. In our study, oxidation of BLP resulted in the decrease in phospholipids, particularly, ethanolamine plasmalogen, as well as the PUFA content of these phospholipids (data not shown). These lipid peroxidation products are likely the major factors underlying neuronal cell death induced by oxidized LP (Chanvitayapongs et al 1997; Sun and Chen 1998; Neely et al., 1999; Keller et al., 1999b).
Antioxidants such as Vitamin E have been used to ameliorate oxidative damage in AD brain (Behl 1999; Mattson and Goodman, 1995). Our recent studies have focused on the polyphenolic flavonoid compound, resveratrol, which is an amphipathic molecule capable of ameliorating oxidative stress in both cytosol and membrane compartments in the cells. This molecule is effective in scavenging free radicals due to its ability to form a stable resonance structure. Resveratrol has been the active ingredient in red wine that provides protective effects on cardiovascular diseases (Fremont, 2000). In the peripheral system, resveratrol has been shown to inhibit LDL oxidation and to prevent the cytotoxicity of modified LDL (Frankel et al., 1993). In our recent studies with PC12 cells, resveratrol was shown to protect oxidative injury due to t-butyl hydroperoxide (Chanvitayapongs et al., 1997). Resveratrol can also inhibit NF-kB/AP-1 activation and apoptotic cell death induced by oxidized lipoproteins (Draczynska-Lusiak et al., 1998b; Sun et al., 1998). Thus, it is not surprising that resveratrol can rescue neurons from cell death due to oxidized BLP. Based on these data, it is reasonable to consider resveratrol as a possible therapeutic agent to ameliorate progression of neurodegenerative diseases in general and Alzheimer’s disease in particular.
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