Lf. Lue et al., Involvement of microglial receptor for advanced glycation endproducts (RAGE) in Alzheimer's disease: Identification of a cellular activation mechanism, EXP NEUROL, 171(1), 2001, pp. 29-45
Receptor-mediated interactions with amyloid beta -peptide (A beta) could be
important in the evolution of the inflammatory. processes and cellular dys
function that are prominent in Alzheimer's disease (AD) pathology. One cand
idate receptor is the receptor for advanced glycation endproducts (RAGE), w
hich can bind A beta and transduce signals leading to cellular activation.
Data are presented showing a potential mechanism for A beta activation of m
icroglia that could be mediated by RAGE and macrophage colony-stimulating f
actor (M-CSF). Using brain tissue from AD and nondemented (ND) individuals,
RAGE expression was shown to be present on microglia and neurons of the hi
ppocampus, entorhinal cortex, and superior frontal gyrus. The presence of i
ncreased numbers of RAGE-immunoreactive microglia in AD led us to further a
nalyze RAGE-related properties of these cells cultured from AD and ND brain
s. Direct addition of A beta (1-42) to the microglia increased their expres
sion of M-CSF. This effect was significantly greater in microglia derived f
rom AD brains compared to those from ND brains. Increased M-CSF secretion w
as also demonstrated using a cell culture model of plaques whereby microgli
a were cultured in wells containing focal deposits of immobilized A beta (1
-42). In each case, the A beta stimulation of M-CSF secretion was significa
ntly blocked by treatment of cultures with anti-RAGE F(ab ')(2). Treatment
of microglia with anti-RAGE F(ab ')(2), also inhibited the chemotactic resp
onse of microglia toward A beta (1-42). Finally, incubation of microglia wi
th M-CSF and A beta increased expression of RAGE mRNA. These microglia also
expressed M-CSF receptor mRNA. These data suggest a positive feedback loop
in which A beta -RAGE-mediated microglial activation enhances expression o
f M-CSF and RAGE, possibly initiating an ascending spiral of cellular activ
ation. (C) 2001 Academic Press.