RAPID ELEVATION OF NEURONAL CYTOPLASMIC CALCIUM BY APOLIPOPROTEIN-E PEPTIDE

Apolipoprotein E (apoE) and certain peptides derived from it have been shown to exert neurotoxic effects in vitro, and apoE has been linked to the etiology of Alzheimer's disease. The mechanisms underlying thes e toxic and pathological effects are, however, not known. To approach this question, we have studied the effects of apoE peptides on the cyt oplasmic calcium ([Ca2+](i)) homeostasis of cultured cortical neurons. A tandem dimer repeat peptide (apoE(dp)) derived from the receptor bi nding domain of apoE was found to have a potent effect on elevation of [Ca2+](i) calcium. The pathway by which apoE(dp) exerted this effect was shown to involve both the mobilization of intracellular calcium an d the influx of extracellular calcium, although the effect on influx w as more pronounced. Calcium mobilization occurs via a G-protein-linked phospholipase C (PLC) pathway, whereas calcium influx appears to invo lve a novel Co2+-sensitive channel. Both the mobilization and the infl ux of calcium require the binding of the apoE peptide to a membrane re ceptor because both pathways are blocked by antibody to low-density-li poprotein receptor-related protein. The data suggest that the neurotox ic effects of apoE may be mediated by a persistent elevation of [Ca2+] (i). (C) 1997 Wiley-Liss, Inc.