Chemotactic-like receptors and Abeta peptide induced responses in Alzheimer's disease.
Evidence suggests that beta-amyloid (Abeta) 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 Abeta 1-42, fibrillar Abeta 1-40, and Abeta 25-35 potentiate the release of interleukin-1beta (IL-1beta) from LPS activated human THP-1 monocytes [26] and LPS primed rat microglia. Moreover, Abeta-stimulated IL-1beta 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 Abeta 1-42 to mimic formyl chemotactic peptides in stimulating IL-1beta release from THP-1 monocytes. Several of the formyl chemotactic peptides and Abeta 1-42 significantly enhanced IL-1beta production in THP-1 monocytes. In contrast, a formyl chemotactic receptor antagonist inhibited Abeta 1-42-induced IL-1beta 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-1beta may play in AD, agents that block Abeta interactions with formyl chemotactic receptors on microglia might be important antiinflammatory therapeutic targets.
Lorton
D
D
Hoover Arthritis Research Center, Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City, AZ 85351, USA. dlorton@mail.sunhealth.org
Schaller
J
J
Lala
A
A
De Nardin
E
E
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002630:Chemotactic Factors / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D002630:Chemotactic Factors; D007375:Interleukin-1; D010455:Peptides; D019707:Receptors, Chemokine; D009240:N-Formylmethionine Leucyl-Phenylalanine; D007770:L-Lactate Dehydrogenase