C-terminal fragments of APP: Its neurotoxic mechanisms and involvement in gene transcription



Several lines of evidence suggest that some neurotoxicity in AD is due to proteolytic fragments of APP. In this study, we compared the potency of neurotoxicity induced by CT with that of A-beta neurotoxicity and our results showed that various CT peptide fragments (CTFs; CTF99, AICD, CTF31) caused neurotoxicity in cultured cells and primary cortical neurons, induced strong non-selective inward currents in Xenopus oocytes, planar lipid bilayers, Purkinje cells, and blocked the later phase of LTP in rat hippocampus in vivo. And also we showed that CT peptide impaired calcium homeostasis, learning and memory impairment. Our results also suggest that CTF peptides triggered inflammatory reaction through MAPKs- and NF-kB dependent astrocytosis and iNOS induction. In addition, we found that CTF translocated into nucleus binding with Fe65 and CP2 and then affected transcription of genes, such as GSK-3beta, suggesting that neurotoxicities exerted by CTFs may be mediated by interactions of CTF with CP2 and Fe65 in the nucleus and their involvement in transcription of genes including GSK-3beta, leading to increase in tau phosphorylation and their inducing NFT and cell death. However, A-beta didn’t enter the nucleus to affect gene transcription. Collectively these results imply that CT peptides themselves can much more greatly damage the neurons both in vitro and in vivo than A-beta and it is thought that both CT and A-beta may participate in the neuronal degeneration in Alzheimer’s disease by different mechanisms.