P2-110: Aβ(pE3-42) potently stimulates CCL2 (MCP-1) secretion

A major proportion of amyloid-beta (Aβ)-aggregates in Alzheimer's disease (AD) is truncated at the N-terminus. In addition, modifications of Aβ have been described such as isoaspartate or pyroglutamate (pE) formation. It is well known that full-length Aβ peptides (Aβ1-42) may stimulate the secretion of cytokines such as CCL2 (MCP-1) from glial cells. The process is mediated by interaction with, e.g., the LPS-receptor CD14. In this study, we investigated the potential of N-truncated and modified Aβ to stimulate chemokine secretion. We used synthetic Aβ peptides to stimulate human neuroblastoma cells line SH-SY5Y, primary neurons, primary glial cell cultures and organotypic brain slices from mice. Among the peptides tested, pE-Aβ(3-42) displays a higher potency to stimulate CCL2 (MCP-1) secretion compared to other Aβ-species. The N-terminal modification leads to a faster oligomer formation of Aβ-peptides. The high hydrophobicity of the oligomers could result in binding of oligomers on the cell surface and therewith higher expression of cytokines. The enhanced expression of CCL2 is accompanied by upregulation of the enzyme glutaminyl cyclase (QC). QC is also responsible for pE-modification of Aβ-peptides. We could show that N-terminal truncated and pE-modified Aβ peptides increase the chemokine secretion in cell culture. The correlation between stimulation of chemokines and an increase of QC could explain upregulation of CCL2 and pE-Aβ in the human AD pathogenesis.