Chemotactic-like receptors and Aβ peptide induced responses in Alzheimer’s Disease

Evidence suggests that β-amyloid (Aβ) has chemokine-like properties and may act through formyl chemotactic receptors (FPR) to induce pathophysiologically important functional changes in Alzheimer’s disease (AD) microglia. We have shown that Aβ 1-42, fibrillar Aβ 1-40, and Aβ 25-35 potentiate the release of interleukin-1β (IL-1β) from LPS activated human THP-1 monocytes [26] and LPS primed rat microglia. Moreover, Aβ-stimulated IL-1β secretion seems to be receptor mediated because it is calcium dependent and requires activation of specific G-proteins [27]. Thus, we have evaluated the ability of Aβ 1-42 to mimic formyl chemotactic peptides in stimulating IL-1β release from THP-1 monocytes. Several of the formyl chemotactic peptides and Aβ 1-42 significantly enhanced IL-1β production in THP-1 monocytes. In contrast, a formyl chemotactic receptor antagonist inhibited Aβ 1-42-induced IL-1β release from both human THP-1 monocytes and primary rat microglia. Further, primary rat microglia grown in culture expressed FPR as demonstrated by immunocytochemistry. Given the multiple pathophysiologic roles IL-1β may play in AD, agents that block Aβ interactions with formyl chemotactic receptors on microglia might be important antiinflammatory therapeutic targets.