Truncated apolipoprotein E (ApoE) causes increased intracellular calcium and may mediate ApoE neurotoxicity

Apolipoprotein E (apoE)-related synthetic peptides, the 22 kDa N-terminal t hrombin-cleavage fragment of apoE (truncated apoE), and full-length apoE ha ve all been shown to exhibit neurotoxic activity under certain culture cond itions. In the present study, protease inhibitors reduced the neurotoxicity and proteolysis of full-length apoE but did not block the toxicity of trun cated apoE or a synthetic apoE peptide, suggesting that fragments of apoE m ay account for its toxicity. Additional experiments demonstrated that both truncated apoE and the apoE peptide elicit an increase in intracellular cal cium levels and subsequent death of embryonic rat hippocampal neurons in cu lture. Similar effects on calcium were found when the apoE peptide was appl ied to chick sympathetic neurons. The rise in intracellular calcium and the hippocampal cell death caused by the apoE peptide were significantly reduc ed by receptor-associated protein, removal of extracellular calcium, or adm inistration of the specific NMDA glutamate receptor antagonist MK-801. Thes e results suggest that apoE may be a source of both neurotoxicity and calci um influx that involves cell surface receptors. Such findings strengthen th e hypothesis that apoE plays a direct role in the pathology of Alzheimer's disease.