REGULATION OF PHOSPHOLIPID SYNTHESIS IN RAT BRAIN UNDER OXIDATIVE STRESS IN UTERO BY ALZHEIMER'S AMYLOID BETA
N.V. Koudinova1,2; A.R. Koudinov1,2 and E. Yavin1
1. Weizmann Institute of Science, Department of Neurobiology, Rehovot 76100, Israel
2. Russian Academy of Medical Sciences, National Mental Health Research Center, Institute of Biomedical Chemistry, Timoshenko 38-27, Moscow 121359, Russian Federation
Amyloid b (Ab) is a major constituent of Alzheimer's (AD) brain amyloid and a normal soluble protein of plasma and CSF where it appears to be involved in lipid metabolism. To further investigate the effect of Ab on phospholipid (PL) metabolism, we used a fetal rat model which is characterized by active de novo lipid synthesis due to rapid intrauterine growth. When subjected to transient obstruction of the maternal-fetal blood supply (global ishemia), the fetuses are rendered growth-retarded and lipid metabolism is impaired. This offers an in vivo model to study the effect of ischemic stress and Ab on the newly synthesized PL. On day 18 of gestation, the Ab1-40 (5 mg) was administered intraperitonealy into the fetus along with [14C ]-acetate (2 mCi/fetus). After 24h the does were subjected to ischemic conditions and 30 min thereafter, fetuses were killed and liver and brain subjected to lipid extraction, TLC analysis and radioactivity counting as well as brain sections autoradiography. An overall increase (17-44%) in the radioactivity of brain, in contrast to a 20-30% in discrete liver PL species, was observed in the Ab-treated fetuses. After ischemia, a reduction of 15-30% in brain and 15-46% in liver PL species was noticed in Ab-treated fetuses. These data suggest that Ab contributes to the regulation of neuronal PL biosynthesis, and to amplification of stress consequences of ischemia. The latter finding confirms the oxidative stress etiology in AD and suggests that Ab modulation of PLbiosynthesis may have AD pathological relevance, particularly at high peptide concentration.
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