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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Recent studies have demonstrated the involvement of oxidative stress in the pathogenesis of Alzheimer’s disease and Ab and apoE have been implicated as the key factors contributing to these oxidative events (Lyras et al. 1997; Sayre et al. 1997; Mattson, 1998; Mattson and Pedersen, 1998; Behl 1999a). ApoE are found in amyloid plaques, neurofibrillary tangles and vasculatures of autopsied AD brain. Lipoproteins (LP) in the central nervous system (CNS), particularly those associated with apolipoprotein E (apoE), are known to play important roles in support of many brain functions. For example, they are known for their ability to mediate intercellular lipid transport, promote neurite outgrowth, maintenance of cholesterol homeostasis and repair of membrane during injury (Ignatius et al. 1986; 1987; Holtzman et al., 1995; Fagan-Niven et al., 1996; Poirier et al., 1993; Beffert et al, 1998). Lipoproteins in cerebral spinal fluid (CSF) are of the high-density type and are different in lipid composition as compared to those in the circulatory system (Pitas et al., 1987a,b). Lipoproteins released from astrocytes contain high levels of phospholipids and cholesterol but low levels of triglycerides and cholesterylesters (LaDu et al., 1998). There is evidence that LP released from astrocytes are taken up by neurons through a receptor-mediated endocytotic process (Fagan-Niven et al., 1996).
We contemplate the possibility that in AD brain, the oxidative environment results in LP oxidation and exacerbates the progression of the disease. In our recent studies, we observed the ability of oxidized low-density lipoproteins (LDL) in serum to enhance oxidative stress and apoptotic cell death in PC12 cells (Draczynska-Lusiak et al. 1998 a,b). Oxidized LDL has also been implicated to cause cell differentiation, inflammation and cytotoxicity in embryonic neuronal cells (Keller et al, 1999a). Due to the high content of polyunsaturated fatty acids (PUFA) in brain membranes (Sun and Sun, 1976), it is possible that the phospholipids in brain LPs also contain high PUFA and are more susceptible to oxidative stress. In agreement with the increased oxidative stress in AD brain, there is evidence that LPs in cerebral spinal fluid of AD patients are more vulnerable to oxidation (Bassett et al., 1999). Therefore, an objective for this study is to test the hypothesis that oxidized LPs are more readily taken up and internalized by neurons and that oxidized LPs are cytotoxic and can induce neuron cell death.
Accumulation of neuritic plaques and amyloid beta peptides (Aß) are important pathological landmarks of AD (Strittmatter et al., 1993 a,b; Price et al., 1999). Amyloid beta peptides with 39 to 43 amino acid residues are derived from the amyloid precursor protein (APP) through cleavage by secretases. APP is a transmembrane protein present in both neurons and glial cells in the brain. While the cellular function of APP is still unknown, accumulation of Aß, especially in their aggregated form, is known to cause a number of cytotoxic events and exacerbate oxidative stress in the brain (Mattson and Pedersen, 1998). Under normal conditions, soluble Aß can be detected in the CSF and plasma at levels between 10-8 to 10-10 M. However, when Aß peptides (1-40 and 1-42) are converted to their fibrillar form, these peptides can enhance the production of reactive oxygen species (ROS), resulting in protein carbonyl formation and lipid peroxidation, and subsequent alteration of cellular functions (Yatin et al, 1999; Huang et al, 1999ab). Despite the pro-oxidative properties of aggregated Aß, whether this form of Ab can exacerbate the cytotoxic effect of oxidized LP on neurons has not been examined in detail. In this study, LPs were prepared using lipids extracted from the brain and subsequently enriched with apoE3 or apoE4. The brain LPs (BLP) were then subjected to oxidation and both native and oxidized BLPs were used to test their uptake by primary neurons in culture in the presence and absence of Ab (1-42) and their ability to induce cell death. These results provide evidence supporting the notion that aggregated Ab can exacerbate the cytotoxic effect of oxidized BLP.
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