Amyloid-β peptide fragments p3 and p4 induce pro-inflammatory cytokine and chemokine production in vitro and in vivo

Alzheimer's disease (AD) pathology is characterized by senile plaques containing amyloid-beta (A beta) peptide, a protein with neurotoxic and glial immune activating potential. In addition to the highly amyloidogenic peptides A beta (1-40/42), plaques contain amino-terminal truncated A beta peptides including the alpha secretase-generated p3 fragments A beta (17-40/42). In the present study, A beta (17-40/42), A beta (1-40/42), A beta (1-16), and A beta (25-35) aged in different solvents exhibited varying capacity to activate the murine microglia cell line MG-7 depending on solvent, peptide 'aging', and peptide sequence that did not strictly correlate with beta -sheet formation. A beta (17-40/42) or A beta (1-42) stimulated production of the proinflammatory cytokines interleukin (IL)-1 alpha, IL-1 beta, IL-6 and tumor necrosis factor-alpha. (TNF-alpha), and the chemokine MCP-1 from differentiated human monocytes (THP-1) while little or no stimulation was observed with the other AP fragments. MG7 cells also produced these five pro-inflammatory proteins in response to A beta (1-42) whereas A beta (17-40/42) elicited mainly TNF-alpha and MCP-1. Murine and human astrocyte cell lines (D30 and U373, respectively) were generally less responsive to A beta fragments producing mainly IL-6 and MCP-1 in response to A beta (1-42) or A beta (17-40/42) fragments. In mice, an intracerebroventricular infusion of A beta (1-42) significantly increased IL-1 alpha, IL-1 beta, IL-6 and MCP-1 while A beta (17-40/42) increased MCP-1 and Ap(17-40) increased IL-1 beta. These results demonstrate that p3 and p4 A beta fragments are proinflammatory glial modulators and thus may play a role in development of the immunopathology observed in AD.