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The Journal of Neuroscience, January 1, 1998, 18(1):195-204
Isoform-Specific Effect of Apolipoprotein E on Cell Survival and
 -Amyloid-Induced Toxicity in Rat Hippocampal Pyramidal Neuronal
Cultures
Joaquín
Jordán1,
María F.
Galindo1,
Richard J.
Miller1,
Catherine A.
Reardon2,
Godfrey S.
Getz2, and
Mary Jo
LaDu2
Departments of 1 Pharmacological and Physiological
Sciences and 2 Pathology, University of Chicago, Chicago,
Illinois 60637
Although the genetic link between the  4 allele of apolipoprotein
E (apoE) and Alzheimer's disease is well established, the isoform-specific activity of apoE underlying this correlation remains
unclear. To determine whether apoE influences the neurotoxic actions of
 -amyloid (A), we examined the effect of native preparations of
apoE3 and E4 on A-induced toxicity in primary cultures of rat
hippocampal pyramidal neurons. The source of apoE was conditioned medium from HEK-293 cells stably transfected with human apoE3 or E4
cDNA. ApoE4 (10 µg/ml) alone was toxic to the cultures, whereas apoE3
had no effect. ApoE3 treatment prevented the toxicity induced by 10 µM A(1-40) or A(25-35). The apoE3 protective
effect appears to be specific to A-induced toxicity, because apoE3
did not protect against the cytotoxicity produced by NMDA or
staurosporine, nor did apoE3 affect the increase in intracellular
calcium induced by either NMDA or KCl. ApoE3 had no effect on the
toxicity produced by A in the presence of receptor-associated
protein, an inhibitor of apoE receptors, particularly the
LDL-receptor-related protein. Interaction with apoE receptors may not
mediate the toxic actions of apoE4, because receptor-associated protein
did not affect apoE4-induced neurotoxicity. Consistent with our
previous biochemical experiments, analysis of the culture medium
revealed that SDS-stable apoE3:A complex is present in greater
abundance than apoE4:A complex. Thus, the protection from
A-induced neurotoxicity afforded by apoE3 treatment may result from
clearance of the peptide by apoE3:A complex formation and uptake by
apoE receptors.
Key words:
apolipoprotein E; -amyloid; neurotoxicity; primary
hippocampal neuron cultures; LDL receptor-related protein; receptor-associated protein; Alzheimer's disease
Copyright © 1998 Society for Neuroscience 0270-6474/98/181195-10$05.00/0
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