APOLIPOPROTEIN E4 INDUCES NEURONAL CELL-DEATH UNDER CONDITIONS OF SUPPRESSED DE-NOVO CHOLESTEROL-SYNTHESIS

The presence of the apolipoprotein E (apoE) allele epsilon 4 is a majo r risk factor for the development of Alzheimer's disease (AD); however , the molecular mechanism underlying the acceleration of AD developmen t in individuals with epsilon 4 remains to be determined. To investiga te the isoform-specific effects of apoE on neurons, primary neuron cul tures were prepared from fetal rat cerebral cortices, Inhibition by co mpactin, a 3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitor of de novo cholesterol synthesis, induced premature neuronal cell deat h in a dose-dependent manner. In the presence of compactin at a sublet hal dose to the cells, rabbit beta-migrating very low density lipoprot ein (beta-VLDL) with human apoE4 (the product of E4) induced premature neuronal cell death, while that with apoE3 (the product of epsilon 3) did not. Neurons cultured in the presence of apoE4, beta-VLDL, and co mpactin were shrunken and spherical, containing condensed chromatin an d fragmented DNA, features characteristic of apoptosis, The addition o f intermediate metabolites of the cholesterol biosynthetic pathway, in cluding mevalonate and squalene, rescued neuronal cells incubated with apoE4 and beta-VLDL, in the presence of compactin, These results stro ngly suggest that a reduction in the level of endogenously synthesized cholesterol is a prerequisite for apoE4-induced neuronal cell death. J. Neurosci. Res. 54:58-67, 1998. (C) 1998 Wiley-Liss, Inc.