J Neurochem 1996 Sep 01;673:1172-82. doi: 10.1046/j.1471-4159.1996.67031172.x.

Neurotoxicity of a carboxyl-terminal fragment of the Alzheimer's amyloid precursor protein.

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We have previously shown that a recombinant carboxyl-terminal 105-amino-acid fragment (CT105) of the amyloid precursor protein (APP) induced strong non-selective inward currents in Xenopus oocytes. Here we investigated the toxic effect of CT105 peptide on the cultured mammalian cells. The CT105 peptide induced a significant lactate dehydrogenase (LDH) release from cultured rat cortical neurons and PC12 cells in a concentration (from 10 microM)- and time (from 48 h)-dependent manner. The toxic effect of CT105 was more potent than that of any fragments of amyloid beta protein (A beta). However, CT105 peptide did not affect the viability of U251 human glioblastoma cells. In contrast to CT105, A beta increased LDH release only slightly even at 50 microM but significantly inhibited 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction at submicromolar concentrations. Among the various neuroprotective drugs tested, only cholesterol, which alters membrane fluidity, could attenuate the cytotoxicity of CT105 significantly. The CT105 peptide formed multiple self-aggregates on solubilization. Pretreatment with a sublethal concentration of CT105 did not significantly alter the susceptibility of cells to hydrogen peroxide and glutamate. Endogenous CT peptides were found not only in the cell lysates but also in the conditioned medium of PC12 cells. These results imply that CT peptide can directly attack the cell membrane probably by making pores or nonselective ion channels, whereas A beta impairs the intracellular metabolic pathway first. Thus, it is thought that both CT and A beta, which are formed during the processing of APP, may participate in the neuronal degeneration in Alzheimer's disease by different mechanisms.

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Species referenced: Xenopus
Genes referenced: app