Amyloid beta peptides trigger CD47-dependent mast cell secretory and phagocytic responses.
Mast cells are found in the brain, where they contribute to immune responses. They have been implicated in multiple sclerosis, but their potential role in Alzheimers disease (AD), another inflammatory disease of the central nervous system, remains elusive. In the present study, we examined mast cell responses to amyloid beta (Abeta) peptides 1-40 and 1-42, the major components of the Alzheimer amyloid plaques. Rat peritoneal mast cells were used as experimental model for human brain serosal mast cells. Fibrillar Abeta1-40 and Ami1-42 peptides induced concentration-dependent exocytosis, as assessed by measurement of histamine secretion; exocytosis was reduced by pre-treatment with pertussis toxin and with antibodies against the CD47 receptor and the beta1-integrin subunit. Fibrillar Abeta1-40 and Abeta1- 42 peptides coated on heat-inactivated yeast particles and soluble fibrillar Abeta1-40 and Abeta1-42 peptides were also recognized and phagocyted by mast cells. Uptake of the peptides was decreased in the presence of 4N1, a peptide agonist of the CD47 receptor, but remained unchanged in the presence of 4NGG, a peptide derived from 4N1 which does not bind to CD47. Non-fibrillar forms of Abeta1-40 and 1-42 peptides were unable to elicit mast cell responses. These results show that fibrillar Abeta peptides can trigger mast cells and elicit exocytosis and phagocytosis. The Abeta-induced activation of mast cells operates through a CD47/beta1-integrin membrane complex coupled with Gi-protein. The present data support the hypothesis that mast cells, similarly to microglial cells, could play a major role in AD pathogenesis.
Niederhoffer
N
N
Université de Strasbourg, CNRS UMR 7213, Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, Illkirch, France. Nathalie.niederhoffer@pharma.u-strasbg.fr
Levy
R
R
Sick
E
E
Andre
P
P
Coupin
G
G
Lombard
Y
Y
Gies
J P
JP
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000906:Antibodies; D051928:CD47 Antigen / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D005089:Exocytosis / Q000187:drug effects; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008856:Microscopy, Fluorescence; D010446:Peptide Fragments / Q000378:metabolism*; D037342:Pertussis Toxin / Q000494:pharmacology; D010587:Phagocytosis / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D016229:Amyloid beta-Peptides; D000906:Antibodies; D051928:CD47 Antigen; D019012:Integrin beta1; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go