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

Abstract

Alzheimer's disease (AD) pathology is characterized by senile plaques containing amyloid‐β (Aβ) peptide, a protein with neurotoxic and glial immune activating potential. In addition to the highly amyloidogenic peptides Aβ(1–40/42), plaques contain amino‐terminal truncated Aβ peptides including the alpha secretase‐generated p3 fragments Aβ(17–40/42). In the present study, Aβ(17–40/42), Aβ(1–40/42), Aβ(1–16), and Aβ(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 β‐sheet formation. Aβ(17–40/42) or Aβ(1–42) stimulated production of the pro‐inflammatory cytokines interleukin (IL)‐1α, IL‐1β, IL‐6 and tumor necrosis factor‐α (TNF‐α), and the chemokine MCP‐1 from differentiated human monocytes (THP‐1) while little or no stimulation was observed with the other Aβ fragments. MG7 cells also produced these five pro‐inflammatory proteins in response to Aβ(1–42) whereas Aβ(17–40/42) elicited mainly TNF‐α and MCP‐1. Murine and human astrocyte cell lines (D30 and U373, respectively) were generally less responsive to Aβ fragments producing mainly IL‐6 and MCP‐1 in response to Aβ(1–42) or Aβ(17–40/42) fragments. In mice, an intracerebroventricular infusion of Aβ(1–42) significantly increased IL‐1α, IL‐1β, IL‐6 and MCP‐1 while Aβ(17–40/42) increased MCP‐1 and Aβ(17–40) increased IL‐1β. These results demonstrate that p3 and p4 Aβ fragments are pro‐inflammatory glial modulators and thus may play a role in development of the immunopathology observed in AD.