Sd. Webster et al., Antibody-mediated phagocytosis of the amyloid beta-peptide in microglia isdifferentially modulated by C1q, J IMMUNOL, 166(12), 2001, pp. 7496-7503
Microglial ingestion of the amyloid beta -peptide (A beta) has been viewed
as a therapeutic target in Alzheimer's disease, in that approaches that enh
ance clearance of A beta relative to its production are predicted to result
in decreased senile plaque formation, a proposed contributor to neuropatho
logy. In vitro, scavenger receptors mediate ingestion of fibrillar A beta (
fA beta) by microglia. However, the finding that cerebral amyloid depositio
n in a transgenic mouse model of Alzheimer's disease was diminished by inoc
ulation with synthetic A beta has suggested a possible therapeutic role for
anti-A beta Ab-mediated phagocytosis. Microglia also express C1qR(P),, a r
eceptor for complement protein Clq, ligation of which in vitro enhances pha
gocytosis of immune complexes formed with IgG levels below that required fo
r optimal FcR-mediated phagocytosis. The data presented here demonstrate Fc
R-dependent ingestion of A beta -anti-A beta complexes (IgG-fA beta) by mic
roglia that is a function of the amount of Ab used to form immune complexes
. In addition, Clq incorporated into IgG-fA beta enhanced microglial uptake
of these complexes when they contained suboptimal levels of anti-A beta Ab
. Mannose binding lectin and lung surfactant protein A, other ligands of C1
qR(P). also enhanced ingestion of suboptimally opsonized IgG-fA beta, where
as control proteins did not. Our data suggest that C1qR(P)-mediated events
may promote efficient ingestion of A beta at low Ab titers, and this may be
beneficial in paradigms that seek to clear amyloid via FcR-mediated mechan
isms by minimizing the potential for destructive Ab-induced complement-medi
ated processes.