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The Journal of Neuroscience, April 1, 2003, 23(7):2665
A Cell Surface Receptor Complex for Fibrillar -Amyloid
Mediates Microglial Activation
Maria E.
Bamberger1, 2,
Meera E.
Harris2,
Douglas
R.
McDonald3,
Jens
Husemann4, and
Gary E.
Landreth2
Alzheimer Research Laboratory, 1 Program in Cell
Biology and 2 Departments of Neurosciences and Neurology,
Case Western Reserve University School of Medicine, Cleveland, Ohio
44106, 3 Department of Immunology, Children's Hospital,
Boston, Massachusetts 02115, and 4 Department of Physiology
and Cellular Biophysics, Columbia University College of Physicians and
Surgeons, New York, New York 10032
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ABSTRACT |
Senile plaques found in the Alzheimer's disease brain are foci of
local inflammatory reactions mediated by plaque-associated microglia.
The interaction of microglia with compacted deposits of -amyloid
(A ) fibrils results in the stimulation of intracellular Tyr
kinase-based signaling cascades and cellular activation, leading to the
secretion of proinflammatory molecules. This study identifies a cell
surface receptor complex that mediates the binding of microglia to A
fibrils and the subsequent activation of intracellular signaling pathways leading to a proinflammatory response. The receptor complex includes the B-class scavenger receptor CD36, the integrin-associated protein/CD47, and the 6 1-integrin.
Antagonists of scavenger receptors, CD36, CD47, and
6 1 inhibited the adhesion of THP-1 monocytes to A fibrils. In addition, peptide competitors of A fibril interactions with CD36, scavenger receptors, CD47, and the
6 1-integrin inhibited A stimulation of
Tyr kinase-based signaling cascades in both THP-1 monocytes and murine
microglia as well as interleukin 1 production. A scavenger receptor
antagonist and antibodies specific for CD36 and the
1-integrin subunit also inhibited the A -stimulated
generation of reactive oxygen species. Importantly, the principal
components of this receptor complex are shared with those for other
fibrillar proteins and thus represent general elements through which
myeloid lineage cells recognize complex fibrillar proteins.
Identification of the cell surface molecules that interact with A
fibrils and mediate their activation of intracellular signaling
cascades represents a potential intervention point in the treatment of
Alzheimer's disease.
Key words:
Alzheimer's disease; -amyloid; 6 1-integrin; CD36; CD47; microglia; THP-1
monocytes; scavenger receptor; signal transduction; receptors; Tyr
kinase
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Introduction |
The contribution of an inflammatory
component to the pathogenesis of Alzheimer's disease (AD) has been
well documented (Akiyama et al., 2000 ). Microglia are the principal
immune effector cells in the brain and undergo a conversion into a
reactive proinflammatory phenotype after their association with
fibrillar -amyloid (A ) deposits comprising the senile plaques in
the AD brain. Epidemiological studies have demonstrated the decreased
incidence and severity of AD in patient populations treated with
nonsteroidal anti-inflammatory drugs (Rich et al., 1995 ; Breitner,
1996 ; Stewart et al., 1997 ; in't Veld et al., 2001 ), which were
correlated with a 65% reduction in plaque-associated reactive
microglia (Mackenzie and Munoz, 1998 ). These data support a role for
microglia in the pathophysiology of AD and as a target of
anti-inflammatory therapy.
The interaction of microglia with fibrillar forms of A peptides
initiates cellular activation, as evidenced by the enhanced expression
of immune cell markers by these cells, including CD45, major
histocompatibility complex class I and II antigens, Fc receptors,
and complement receptors 3 and 4 (Akiyama et al., 2000 ). The
plaque-associated microglia also exhibit increased levels of
intracellular phospho-Tyr staining (Wood and Zinsmeister, 1991 ), which
is a consequence of the activation of Tyr kinase-based signaling pathways on exposure of the cells to A fibrils (McDonald et al., 1997 , 1998 ; Combs et al., 1999 ). Significantly, these A -stimulated microglial signaling events lead to the production and secretion of a
broad range of proinflammatory molecules and neurotoxic factors that
contribute to the sustained inflammatory response and neuronal loss
observed in AD (Combs et al., 2000 , 2001 ; Yates et al., 2000 ).
There has been considerable interest in the identity of the cell
surface receptor(s) that mediates microglial activation on interaction
with A fibrils. A number of receptors have been reported to bind
A , namely scavenger receptor class A (SR-A; El Khoury et al., 1996 ;
Paresce et al., 1996 ), SR-B1 (Husemann et al., 2001 ), the neuronal 7
nicotinic acetylcholine receptor (Dineley et al., 2001 ; Pettit et al.,
2001 ), the receptor for advanced glycation end products (RAGE; Yan et
al., 1996 ), the serpin enzyme complex (Boland et al., 1996 ), the formyl
peptide chemotactic receptor (FPR; Lorton, 1997 ; Le et al., 2001 ),
heparan sulfate proteoglycans (Giulian et al., 1998 ; Scharnagl et al.,
1999 ), and the
5 1-integrin (Matter
et al., 1998 ). However, only SR-A and RAGE have been shown to interact
with fibrillar forms of A , and neither of these receptors is linked
to activation of intracellular signaling cascades leading to a
proinflammatory response. Recently, while this work was in progress,
the B class scavenger receptor CD36 was also shown to act as a receptor
for fibrillar A (Coraci et al., 2002 ; Moore et al.,
2002 ).
Our approach to the identification of putative A receptors arose
from the recognition that myeloid lineage cells use multiple cell
surface receptors to bind fibrillar proteins, and the assembly of
ensembles of receptors is necessary for cellular activation (Ishibashi
et al., 1994 ; Bornstein, 1995 ; Wong et al., 1996 ). We evaluated the
involvement of a number of such receptors by monitoring their ability
to induce intracellular signaling events and generation of
proinflammatory molecules such as interleukin 1 (IL-1 ) and
reactive oxygen species (ROS). We report the identification of a
multireceptor complex comprising the B-class scavenger receptor CD36,
6 1-integrin, and the
integrin-associated protein CD47. This complex mediates activation of
microglia and other myeloid cells (e.g., THP-1 monocytes) on
interaction with fibrillar A peptides.
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Materials and Methods |
Materials. The
anti- 1-integrin antibody Lia1/2 used for
intracellular signaling assays was from Immunotech
(Marseille, France). The 1-integrin antibody
used for adhesion assays and all subunit integrin antibodies were
from Chemicon (Temecula, CA).
Anti- 2-integrin antibody was from Roche
Molecular Biochemicals (Indianapolis, IN). The anti-Fyn JD3
antibody was from Dr. S. Brady-Kalnay (Case Western Reserve
University). The glutathione S-transferase
(GST)-CD36-(93-120) peptide was a gift from Dr. S. Frieda Pearce
(Cornell University, Ithaca, NY). The anti-CD36 monoclonal antibody
OKM5 was from Ortho-Clinical Diagnostics (Raritan, NJ).
Mouse IgG was from Sigma (St. Louis, MO). The 4N1K and RHD
peptides were purchased from Bachem (Philadelphia, PA) and
reconstituted in sterile distilled water. Fucoidan, pertussis toxin,
and N-formyl-Met-Leu-Phe (fMLP) were purchased from
Sigma and reconstituted in sterile distilled water. A
peptides corresponding to human A amino acids 25-35 and 1-42 were
purchased from American Peptide Co. (Sunnyvale, CA), and
that corresponding to amino acids 1-40 was from California
Peptide Research, Inc. (Napa, CA). The peptides were resuspended
in sterile distilled water followed by incubation at 37°C for 1 week
to allow fibrillarization. The method used to fibrillarize A 25-35,
1-40, and 1-42 has been well characterized (Burdick et al., 1992 ;
Lorenzo and Yankner, 1994 ; Terzi et al., 1994 ); however, the
composition of the fibrillar solutions was not tested and may have
included A oligomers as well as fibrils. Nonfibrillar A 1-40 was
prepared by resuspending the peptide in sterile distilled water and
used immediately. Soluble RAGE (sRAGE) was a gift from Dr. Mark Kindy
(University of Kentucky). The anti-phospho-Tyr antibody 4G10 was
obtained from Upstate Biotechnology (Lake Placid, NY).
Anti-phospho-extracellular-regulated kinase (ERK) antibody was obtained
from New England Biolabs (Beverly, MA). Anti-ERK2 antibody
was from Santa Cruz Biotechnology (Santa Cruz, CA).
Anti-IL-1 was obtained from the National Cancer Institute (Frederick, MD). Affinity-purified horseradish peroxidase-conjugated sheep anti-mouse and donkey anti-rabbit antibodies were from
Amersham Biosciences (Piscataway, NJ).
Tissue culture. Human THP-1 monocytes (American Type
Culture Collection, Manassas, VA) were grown in RPMI 1640 medium
(Whittaker Bioproducts, Walkersville, MD) containing 10%
heat-inactivated fetal bovine serum (FBS), 5 × 10 5 M
2-mercaptoethanol, 5 mM HEPES, and 15 µg/ml
gentamycin in 5% CO2. Microglia were derived
from postnatal day 1-2 mouse brains (C57BL/6J) as described previously
(McDonald et al., 1997 ).
Cell stimulation. THP-1 cells and microglia were collected
and resuspended in 37°C HBSS for 30 min at 37°C in the absence or
presence of sRAGE, pertussis toxin, fucoidan, GST-CD36-(93-120), 4N1K,
or the RHD peptide or at 4°C in the presence of anti- 1,
2, 4, 5, 6, v or
anti- 1 antibody for intracellular signaling
analysis. Cells were then stimulated by the addition of 60 µM A peptides for 3 min at 37°C, collected
by centrifugation, and lysed at 4°C in Triton buffer (1% Triton
X-100, 20 mM Tris, pH 7.5, 100 mM NaCl, 40 mM NaF, 1 mM EDTA, 1 mM EGTA, and 1 mM
Na3VO4). All experiments were performed a minimum of three times.
IL-1 assay. THP-1 cells were plated 48 hr
before stimulation in 2% FBS. The cells (3 × 106) were collected and resuspended in
37°C 0.5% FBS with 0.5 µg/ml lipopolysaccharide for 4 hr in
the presence of fucoidan, 4N1K, and RHD peptide and stimulated with 60 µM A 25-35. Cells were collected by
centrifugation and lysed at 4°C in radioimmunoprecipitation assay
(RIPA) buffer (1% Triton X-100, 20 mM Tris, pH
7.5, 100 mM NaCl, 40 mM
NaF, 0.2% SDS, 0.5% deoxycholate, 1 mM EDTA, 1 mM EGTA, and 1 mM
Na3VO4).
Immunoprecipitation and Western blotting. After cell lysis,
insoluble material was removed by centrifugation at 10,000 × g at 4°C for 10 min. Protein concentrations were
determined by the method of Bradford (1976) using bovine serum albumin
as a standard. Lysates were added to 30 µl of protein A-agarose with
the primary antibody (2 µg of primary antibody/mg of lysate) and
incubated with rocking for 2 hr at 4°C. Immune complexes were washed
three times in Triton X-100 buffer. Lysates and immune complexes were resolved by 7.5 or 12% SDS-PAGE and Western blotted with primary antibody (4G10, 1:1500), anti-phospho-ERK (1:1000), anti-ERK2 (1:2000),
anti-Fyn (1:1000), or anti-IL-1 (1:1000) overnight at 4°C.
Antibody binding was detected by enhanced chemiluminescence (Pierce, Rockford, IL). IL-1 , 4G10, and phospho-ERK
blots were stripped by incubation in stripping buffer (62.5 mM Tris, pH 6.8, 100 mM
-mercaptoethanol, and 2% SDS) for 30 min at 50°C and then reprobed with anti-Fyn or anti-ERK2 antibodies. Quantitation of the
A -stimulated Tyr phosphorylation was obtained by imaging the ECL
signal using a Bio-Rad (Hercules, CA) VersaDoc, and the integrated optical density of the individual lanes was obtained using
Quantity One software.
Respiratory burst. Intracellular superoxide radical
generation was assayed by measuring nitroblue tetrazolium (NBT)
reduction (Pick, 1986 ; McDonald et al., 1997 ). THP-1 cells (2 × 106) were resuspended at 37°C for 30 min
in the presence or absence of fucoidan, anti-CD36 antibody,
anti- 1 antibody, or an isotype-specific mouse
IgG and with 1 mg/ml NBT. Cells were collected by centrifugation and
sonicated in 4°C RIPA buffer. NBT reduction was measured by the
change in absorbance at 550 nm. The assays were performed in triplicate.
Cell adhesion assay. THP-1 monocytes were preincubated with
antibody or peptide antagonist for 30 min in 4°C serum-free RPMI 1640 medium. The fibrillar A peptides (2 µg) were applied directly to a
glass slide and allowed to dry. The adherent A fibrils could be
visualized by eye. Although the percentage of peptide that bound was
not determined, it was constant between individual spots in each
experiment. Approximately 50,000 cells were applied to either the glass
slide or the A fibrils and allowed to adhere for 5 min. Cells were
washed at 37°C, and the number of adherent cells were counted
microscopically. The data are reported as cell number bound per square
millimeter. The assays were performed in triplicate.
Immunochemistry. Microglia were fixed in ice-cold acetone
for 15 min, washed, blocked with PBS containing 20% goat serum, incubated with 20 µg/ml mouse anti-murine CD36 IgA or control IgA for
60 min, washed, incubated with 1 µg/ml biotinylated goat anti-mouse
IgA for 30 min at room temperature, washed, and incubated with 2 mg/ml
avidin-conjugated Alexa 488 (Molecular Probes, Eugene, OR)
in PBS at room temperature. All antibodies were diluted in PBS
containing 3% goat serum.
Statistical analysis. Experiments were done in triplicate.
Mean values ± SEM for each experiment were determined, and values statistically different from controls were calculated using one-way ANOVA. The Tukey-Kramer multiple-comparisons post test was used to
determine P values.
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Results |
Stimulation of protein-Tyr phosphorylation in THP-1 monocytes by
fibrillar A peptides
We have previously demonstrated that fibrillar A peptides,
A 1-40, A 1-42, and A 25-35, stimulated protein-Tyr
phosphorylation in THP-1 monocytes and microglia (McDonald et al.,
1997 , 1998 ; Combs et al., 1999 ). Quantitative analysis of the response
revealed that the three peptides elicited similar increases in
protein-Tyr phosphorylation in THP-1 cells, with the A 25-35 peptide
exhibiting a modestly greater response than the longer peptides (Fig.
1). These data indicate that fibrillar
A peptides containing the terminal 10 amino acids that form a
-pleated sheet are sufficient to stimulate intracellular signaling
cascades (Terzi et al., 1994 ). The response to the various fibrillar
A peptides was qualitatively similar, indicating that they act
through common mechanisms to initiate intracellular signaling
events.

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Figure 1.
Fibrillar A 25-35, 1-40, and 1-42 peptides
stimulate comparable increases in protein-Tyr phosphorylation in THP-1
monocytes. THP-1 monocytes were stimulated with fibrillar A 25-35,
1-40, and 1-42 peptides for 3 min. Cell lysates were analyzed by
Western blot analysis using the anti-phospho-Tyr antibody 4G10. The
integrated optical density (IOD) ratio of the
protein-Tyr phosphorylation signal stimulated by the different A
ligands was quantitated.
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Scavenger receptors mediate interactions of A fibrils with THP-1
monocytes and microglia
Senile plaque-associated microglia are activated after the
interaction of A fibrils with microglia (Akiyama et al., 2000 ). Previous reports have provided evidence for a role for both SR-A and
SR-B1 in the binding of fibrillar A peptides to neonatal microglia,
resulting in the subsequent generation of ROS (El Khoury et al., 1996 ;
Paresce et al., 1996 ; Husemann et al., 2001 ). Scavenger receptors
constitute a structurally diverse family of cell surface receptors that
exhibit broad substrate specificity and participate in both cellular
adhesion and uptake of ligands (Krieger and Herz, 1994 ). Sulfated
polysaccharides such as fucoidan act to inhibit SR-ligand interactions
in an SR class-independent manner. We have verified that incubation of
THP-1 monocytes with fucoidan inhibited the ability of these cells to
bind to surfaces coated with fibrillar A peptides (Fig.
2A). Because THP-1
monocytes do not normally express high levels of SR-A or SR-B1 unless
differentiated into macrophages (Hsu et al., 1996 ), fucoidan-mediated
inhibition of cell binding to A fibrils provoked us to examine the
involvement of additional SR class members.

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Figure 2.
Scavenger receptors are expressed on microglia and
are involved in cellular adhesion to fibrillar A . THP-1 monocytes
were preincubated in serum-free RPMI 1640 medium with 300 µg/ml
fucoidan (A) or 100 nM
GST-CD36-(93-120) (B), and the cell suspension
was applied to the fibrillar A (2 µg) bound to a glass slide.
Dose-dependent inhibition of adhesion of THP-1 monocytes to A 25-35
fibrils in the presence of 20-100 nM GST-CD36-(93-120)
(C) and 50 nM GST or GST-CD36
(D) was evaluated. Cells were treated as
described in (A, B). The number of adherent cells per
square millimeter was recorded. The data shown represent the mean ± SEM of triplicate determinations. (*p < 0.001)
E, Primary murine microglia were stained with an
anti-CD36 antibody (left panel) or control Ig
(middle panel) as described in Materials and
Methods or visualized by phase microscopy (right
panel).
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We examined whether the B class scavenger receptor CD36 participated in
monocyte adhesion to fibrillar A and found that the binding of THP-1
monocytes to A 25-35 and A 1-40 fibrils was inhibited by a
peptide derived from the extracellular domain of CD36 (residues 93-120
fused to GST; Fig. 2B) with a
Ki of ~50nm (Fig. 2C).
The inhibition of cell adhesion was specific to GST-CD36-(93-120) fusion peptide, because GST alone did not have any effect on cell binding to A fibrils (Fig. 2D). Amino acids
93-120 of CD36 represent the minimal region of the CD36 receptor
required for the binding of the fibrillar angiogenesis peptide
thrombospondin-1 (TSP-1; Pearce et al., 1995 ). Anti-CD36 antibodies
directed to other epitopes on CD36 did not inhibit cell adhesion (data
not shown; Coraci et al., 2002 ), indicating that the interaction of
A fibrils was restricted to the same domain as that required for
TSP-1 binding. We wished to verify that CD36 was expressed on
microglia. We demonstrated the expression of CD36 on neonatal murine
microglia by fluorescent immunohistochemistry (Fig.
2E). Microglia stained with control Ig showed no
staining (Fig. 2E).
A primary goal of these studies was to establish the identity of cell
surface receptors linked to activation of intracellular signaling
pathways. CD36 is physically associated with members of the Src family
of Tyr kinases (Huang et al., 1991 ; Bull et al., 1994 ), which transduce
signals from this receptor (Jimenez et al., 2000 ). We have previously
demonstrated that exposure of murine microglia and THP-1 monocytes to
A 25-35, A 1-40, or A 1-42 fibrils resulted in the activation
of Tyr kinase-based signaling pathways, including activation of the Src
family kinase Lyn and Syk, leading to the activation of the ERK and p38
MAP kinase cascades (McDonald et al., 1997 , 1998 ; Combs et al., 1999 ).
We found that exposure of cells to CD36 antagonists, either fucoidan or
the GST-CD36-(93-120) peptide, inhibited the A -stimulated
activation of intracellular protein-Tyr phosphorylation and subsequent
ERK phosphorylation in THP-1 monocytes (Fig.
3A,B) and microglia (Fig. 3C). A control GST peptide did not have any effect on
A -stimulated intracellular signaling (data not shown). We were
unable to demonstrate ligand-dependent changes in the association of
Src family kinases with CD36 (data not shown).

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Figure 3.
Scavenger receptors mediate A stimulation of
intracellular Tyr signaling cascades in THP-1 monocytes and microglia.
THP-1 monocytes were preincubated with 300 µg/ml fucoidan
(A) or 100 nM GST-CD36-(93-120)
(B) for 30 min before stimulation with fibrillar
or nonfibrillar A . C, Primary murine microglia were
treated with 100 nM GST-CD36-(93-120) before A
stimulation. Cell lysates were analyzed by Western blot using the
anti-phospho-Tyr antibody 4G10 (PY) or an
anti-phospho-ERK antibody (P-ERK). P-ERK blots
were stripped and reprobed with an anti-ERK antibody
(ERK) as a protein-loading control.
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The 6 1-integrin and the
integrin-associated protein CD47 mediate A -stimulated phospho-Tyr
signaling and adhesion in THP-1 monocytes and microglia
The integrins represent a family of molecules that activate
intracellular signaling cascades and promote adhesion to other cells as
well as matrix proteins. The identification of the signaling molecules
transducing A -stimulated responses suggested the participation of
this superfamily of receptors in the binding of other fibrillar proteins (McDonald et al., 1997 , 1998 ). Evidence for the involvement of
the 1-integrin as an element of the A
receptor complex was obtained using a peptide containing the consensus
1-integrin-binding epitope RHD. This peptide
comprises residues 1-11 of A (DAEFRHDSGYE) and contains
a sequence closely related to the canonical integrin recognition site
peptide RGD. However, although RGD binds to most integrins,
heterodimers containing the 1 subunit display
an RHD binding preference (Ghiso et al., 1992 ). The RHD-containing
peptide inhibited A -mediated intracellular Tyr and ERK
phosphorylation in THP-1 monocytes (Fig.
4A) and microglia (Fig.
4B). It is evident that the epitope present in the
fibrillar A species that interacts with the
1-integrin is distinct from the RHD sequence,
because fibrils derived from A 25-35 are also antagonized by the
anti- 1 antibody. To confirm that the
1-integrin subunit was specifically involved
in mediating A stimulation of protein-Tyr phosphorylation, THP-1
monocytes were incubated with an anti- 1
antibody. Western blot analysis confirmed inhibition of A -mediated
intracellular phospho-Tyr signaling by the 1
antibody (Fig. 4C). To identify the corresponding
-integrin subunit, we used a panel of antibodies and found that an
antibody to 6 (Fig. 4D), but
not other -integrin subunits (Fig. 4E;
3-integrin data not shown), inhibited both intracellular phospho-Tyr signaling and ERK phosphorylation.

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Figure 4.
The 6 1-integrin is
required for A binding and stimulation of THP-1 monocytes.
A, THP-1 monocytes were preincubated with 100 µg/ml
RHD peptide for 30 min before fibrillar or nonfibrillar A 1-40
stimulation. Cell lysates were analyzed by Western blot using the
anti-phospho-Tyr antibody 4G10 (PY) or an
anti-phospho-ERK antibody (P-ERK).
B, Primary murine microglia were pretreated with RHD
peptide as described in A but stimulated with fibrillar
A 25-35 and analyzed by P-ERK Western blot analysis of cell lysates.
Blots were stripped and reprobed with anti-ERK antibody
(ERK) as a protein-loading control.
C-E, THP-1 monocytes were preincubated with antibodies
(40 µg/ml) to the 1 (C),
6 (D), and
1,2,4,5,v (E) integrins as
described in A and stimulated with fibrillar A 25-35.
Cell lysates were evaluated by Western blot analysis, using the 4G10,
P-ERK, and ERK antibodies. F, G, Adhesion of THP-1 cells
to fibrillar A evaluated by preincubation in serum-free RPMI 1640 medium with antibodies to the 1-6, v- and
1-integrin subunits (40 µg/ml;
F) or anti- 2-integrin subunit (40 µg/ml; G) and added to 2 µg of fibrillar A bound
to a glass slide. The number of adherent cells per square millimeter
was recorded. The data shown represent the mean ± SEM of
triplicate determinations (*p < 0.05;
F).
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One of the primary functions of integrins is to mediate cellular
adhesion, and we next evaluated which integrins were responsible for
cellular binding to A fibrils using a panel of antibodies to
1-integrin partners. We found that antibodies
to the 6- and 1-integrin subunits decreased cell adhesion of
THP-1 monocytes to A 1-42 fibrils. We were unable to implicate other
subunits ( 1-5 and
v; Fig. 4F) or the
2 (Fig. 4G) and
3 (data not shown) integrin subunits in
cellular adhesion. These data demonstrate that the
6 1-integrin is the
principal integrin species responsible for the interaction of A
fibrils with the cells.
The integrin-associated protein CD47 is a transmembrane receptor
expressed on many cell types and acts primarily to modulate integrin-dependent signaling through its physical and functional association with integrins (Porter and Hogg, 1998 ) as well as intracellular signaling molecules, including the Tyr kinases Lyn and
Syk (Chung et al., 1997 ). We tested whether CD47 was involved in
A -stimulated intracellular signaling cascades and adhesion events. A
peptide antagonist of CD47, 4N1K, is derived from the cell-binding
domain of TSP-1 and specifically blocks the interaction of CD47 with
TSP-1 (Chung et al., 1997 ). Incubation of THP-1 monocytes with 4N1K
inhibited the ability of THP-1 monocytes to adhere to A 1-42 fibrils
(Fig. 5A). In addition,
blocking the association of CD47 with A fibrils inhibited A
fibril stimulation of intracellular protein-Tyr and ERK phosphorylation
in THP-1 monocytes (Fig. 5B).

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Figure 5.
Inhibition of CD47 interactions with A fibrils
blocks A -mediated THP-1 monocyte activation. A, THP-1
monocytes were preincubated in serum-free RPMI 1640 medium with 100 µM CD47 antagonist peptide 4N1K and added to 2 µg of
fibrillar A bound to a glass slide. The number of adherent cells per
square millimeter was recorded. The data shown represent the mean ± SEM of triplicate determinations (*p < 0.01).
B, THP-1 monocytes were preincubated with 100 µM 4N1K for 30 min before fibrillar A 25-35 or
A 1-42 stimulation. Cell lysates were analyzed by Western blot using
the anti-phospho-Tyr antibody 4G10 (PY) or an
anti-phospho-ERK antibody (P-ERK). The P-ERK blot
was stripped and reprobed with an anti-ERK antibody
(ERK) as a protein-loading control.
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A -stimulated signaling requires elements of the A -binding
receptor complex
It has been well documented that exposure of microglia and
monocytes to fibrillar forms of A stimulates NADPH oxidase
activation and a respiratory burst, resulting in the generation and
secretion of ROS (Meda et al., 1995 ; El Khoury et al., 1996 ; McDonald
et al., 1997 ; Bianca et al., 1999 ; Van Muiswinkel et al., 1999 ). Preincubation of THP-1 monocytes with fucoidan, an anti-CD36 antibody, and an anti- 1-integrin subunit antibody
inhibited the A -stimulated respiratory burst (Fig.
6A-C). Thus, these
data support an essential role for scavenger receptors, specifically
CD36, as well as the 1-integrin in mediating
the A -stimulated respiratory burst in microglia cells and
monocytes.

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Figure 6.
The A receptor complex mediates the
stimulation of ROS and IL-1 production. A-C, THP-1
monocytes were incubated with fucoidan (300 µg/ml; A),
anti- 1 (40 µg/ml; B), isotype-specific
IgG (C) phorbol 12-myristate 13-acetate
(PMA, C) or anti-CD36 (OKM5,
40 µg/ml; C) in serum-free RPMI containing NBT
and stimulated with fibrillar A 25-35 for 25 min at 37°C.
Superoxide anion generation was measured by the change in
absorbance at 550 nm. The data shown represent the mean ± SEM of
triplicate determinations (*p < 0.001;
A-C). D, Mature IL-1 production in
A -stimulated THP-1 monocytes was evaluated in the presence of 300 µg/ml fucoidan, 100 µM 4N1K, and 100 µg/ml RHD
peptide. Cell lysates were resolved by 12% SDS-PAGE, transferred to
polyvinylidene difluoride, and probed with the anti-IL-1 antibody.
The blot was stripped and reprobed with an anti-ERK antibody
(ERK) as a protein-loading
control.
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The proinflammatory cytokine IL-1 is elevated in AD and augments the
inflammatory response of the disease through its autocrine and
paracrine actions (Akiyama et al., 2000 ). It has previously been
demonstrated that microglia secrete IL-1 as well as other cytokines
on exposure to fibrillar A and other immune stimuli (Araujo and
Cotman, 1992 ; Meda et al., 1995 , 1996 , 1999 ; Lorton et al., 1996 ; Fiala
et al., 1998 ; Murphy et al., 1998 ; Combs et al., 2000 , 2001 ). We
therefore assessed the role of the putative A receptors in
A -stimulated IL-1 production. The 4 hr time course required to
measure IL-1 levels in response to extracellular stimuli technically
excluded our ability to assess the effects of the occupancy of the
individual receptors on this response. However, blocking the
association of A fibrils with the A receptor complex using
antagonists of CD47, the 1-integrin, and
scavenger receptors inhibited A -mediated stimulation of IL-1
production (Fig. 6D). Therefore, the engagement of
the A -binding receptor complex is required for the ability of A
fibrils to mediate intracellular changes and subsequent production of
neurotoxic and proinflammatory factors.
To formally test whether the concerted actions of the receptor elements
were required for the activation of intracellular signaling cascades,
we evaluated the effects of antagonists of the individual receptor
elements on the activation of Src kinases. We report that Fyn, like its
family member Lyn, is activated in response to A stimulation.
Importantly, Fyn phosphorylation is dependent on the interaction of
each receptor with fibrillar A (Fig.
7). The activation of Fyn and its
association with downstream signaling elements are inhibited after
blockade of scavenger receptors, specifically CD36, CD47, and the
1-integrin (Fig. 7).

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Figure 7.
Members of the A receptor complex are required
for A stimulation of Fyn phosphorylation. THP-1 monocytes were
preincubated in serum free RPMI 1640 medium with 300 µg/ml fucoidan,
100 nM GST-CD36-(93-120), 100 µM 4N1K, or
100 µg/ml RHD for 30 min before stimulation with fibrillar A . Cell
lysates were immunoprecipitated with the anti-Fyn JD3 antibody. Cell
lysates and immunoprecipitates were resolved by 7.5% SDS-PAGE and
analyzed by Western blot using the anti-phospho-Tyr antibody 4G10
(PY). Blots were stripped and reprobed with an
anti-Fyn JD3 antibody (FYN) as a protein-loading
control.
|
|
A Gi-linked receptor is not involved in A
stimulation of Tyr kinase-based signaling pathways in THP-1
monocytes
The heterotrimeric small G-protein Gi is an
effector of some CD47-linked receptors and the chemotactic FPR (Gao et
al., 1996 ; Chung et al., 1997 ; Lorton, 1997 ; Frazier et al., 1999 ; Wang
et al., 1999 ; Le et al., 2001 ). We tested the involvement of
Gi-proteins in A -mediated stimulation of
intracellular signaling cascades. Inhibition of
Gi action by pertussis toxin treatment of THP-1 monocytes did not affect A stimulation of protein-Tyr
phosphorylation or ERK phosphorylation (Fig.
8). The specificity of pertussis toxin
activity was monitored using the chemotactic peptide fMLP, which
stimulates ERK phosphorylation after binding of FPR receptors in a
pertussis toxin-sensitive manner. We conclude that a
Gi-linked receptor is not involved in A
stimulation of intracellular signaling in THP-1 monocytes, and the
participation of CD47 in this event is independent of its ability to
functionally associate with Gi-proteins.

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Figure 8.
A Gi-linked receptor is not involved
in A -stimulated intracellular signaling. THP-1 monocytes were
preincubated with 200 ng/ml pertussis toxin (PTX)
for 30 min at 37°C and stimulated with A 25-35 or 1 µM fMLP for 3 min. Western blots of cellular lysates were
probed with the anti-phospho-Tyr antibody 4G10
(PY) or with the anti-phospho-ERK antibody
(P-ERK). Blots were stripped and reprobed with
the anti-ERK antibody (ERK).
|
|
RAGE does not mediate A stimulation of Tyr kinase-based
signaling pathways in THP-1 monocytes
RAGE was previously reported to be an A -binding protein,
capable of interacting with both fibrillar and nonfibrillar forms of
A and provoking microglia activation (Yan et al., 1996 ; Lue et al.,
2001 ). However, it is unclear whether there is a preference of RAGE for
aggregated forms of A (Yan et al., 1996 ). We (McDonald et al., 1997 ,
1998 ; Combs et al., 1999 ) and others (Bianca et al., 1999 ) have failed
to demonstrate that engagement of RAGE on microglia or THP-1 monocytes
stimulates cellular effects similar to those induced by fibrillar A .
In the present study, we extended our analysis of RAGE as a candidate
A -binding receptor mediating stimulation of intracellular signaling.
The addition of sRAGE at 2× (120 µM) or 20× (1.2 mM) the concentration of fibrillar A did not alter
A -mediated stimulation of protein-Tyr phosphorylation, as
demonstrated by Western blot analysis (Fig.
9). We verified that sRAGE alone did not
affect the ability of A fibrils to stimulate intracellular
signaling, nor did sRAGE alone stimulate any changes in intracellular
Tyr phosphorylation. Although we cannot rule out that RAGE may
participate in the adhesion of cells to A and act in common with
other cell surface proteins such as SR-A, we do not find evidence for
the involvement of RAGE in A -mediated stimulation of intracellular
signaling cascades.

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Figure 9.
RAGE is not involved in A -mediated
intracellular signaling. THP-1 monocytes were incubated for 30 min at
37°C and stimulated with A 25-35, 2 or 20× sRAGE, or both
for 3 min. Western blots of cellular lysates were probed with
the anti-phospho-Tyr antibody 4G10
(PY).
|
|
 |
Discussion |
There has been substantial interest in the identity of cell
surface molecules that bind A , because this represents the first potential point of intervention in the events leading to the
pathophysiology of AD. Our approach to the identification of microglial
A receptors derived from consideration of the mechanisms through
which macrophages interact with foreign elements, including protein
fibrils. These cells use ensembles of receptors whose individual
receptor elements exhibit relatively broad substrate specificity. The
resulting receptor complex can mediate adhesion, migration, a
respiratory burst, or proinflammatory responses. For example, the
fibrillar proteins Bordetella pertussis filamentous
hemagglutinin (FHA) and TSP-1 provoke cellular activation, a response
similar to that observed in A -stimulated microglia. TSP-1 interacts
with CD36, CD47, and 1- and
3-integrins and several other cell surface proteins (Bornstein, 1995 ), whereas FHA binds to monocytes via CD87
(urokinase receptor),
m 2- and
v 3-integrins, and
CD47 (Ishibashi et al., 1994 ; Wong et al., 1996 ). Thus, we reasoned that A fibrils, which consist of repetitive units linked through C-terminal -pleated sheet domains, may use some of the same
receptors to interact with microglia and monocytes. Importantly, we
evaluated the participation of candidate receptor elements by
monitoring the ability of these molecules to stimulate A -activated
intracellular signaling pathways whose activation is functionally
linked to the production and secretion of proinflammatory and
neurotoxic factors (McDonald et al., 1997 ; Bianca et al., 1999 ; Combs
et al., 1999 ; Meda et al., 1999 ).
We report the identification of a multicomponent A receptor complex
consisting of CD36,
6 1-integrin, and
CD47. This complex mediates the adhesion of A fibrils to microglia
and subsequent activation of intracellular Tyr kinase-based signal
transduction cascades, leading to the stimulation of a respiratory
burst and IL-1 cytokine production (Fig.
10). It is significant that this receptor does not interact with nonfibrillar forms of A , whereas association with all fibrillar forms of A was shown to elicit cellular responses (Pike et al., 1993 ; Lorton et al., 1996 ; McDonald et
al., 1997 , 1998 ; Combs et al., 1999 ).

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Figure 10.
Model of A fibril interaction with a
microglial cell surface receptor complex resulting in activation of
intracellular signal transduction cascades.
|
|
Scavenger receptors are expressed on cells of monocytic lineage and
interact with a structurally diverse range of ligands. The A class of
SRs has been shown to participate in binding of A by microglia and
has been implicated in chemotaxis, ROS generation, and A peptide
uptake (Hartung et al., 1986 ; Klegeris et al., 1994 ; Meda et al., 1995 ;
El Khoury et al., 1996 ; Paresce et al., 1996 ). An exclusive role for
SR-A in these events appears unlikely in view of recent reports that
microglia from SR-A null animals are only modestly impaired in their
ability to bind A peptides (Husemann et al., 2001 ). Moreover,
transgenic animals overexpressing the amyloid precursor protein but
lacking SR-A expression exhibited levels of amyloid deposition similar
to those of SR-A-expressing control animals (Huang et al., 1999 ). The
compensatory action of B-class SRs may explain these findings.
We have provided evidence that the B-class SR CD36 plays an essential
role in both the binding of A fibrils to the cells and the
initiation of intracellular signaling events. This view is supported by
the report that macrophage binding to oxidized low-density lipoprotein
is mediated by SR-A, whereas subsequent intracellular production of
H2O2 is dependent on CD36
(Maxeiner et al., 1998 ). Moreover, despite considerable work, it has
not been possible to conclusively show that SR-A acts independently to
elicit activation of intracellular signaling cascades. CD36 is
physically associated with Src family protein kinases, and it has
recently been demonstrated that TSP-1 binding results in the activation
of these Tyr kinases (Jimenez et al., 2000 ). Importantly, TSP-1 and
A peptides interact with a common domain on CD36, and we have
demonstrated that binding of A fibrils to microglia and monocytes
elicits the activation of the Src family kinases Lyn and Fyn (McDonald
et al., 1997 ; Combs et al., 1999 ). These data support our hypothesis
that CD36 (and possibly SR-BI) is a critical component of the A
receptor complex linking fibril binding to stimulation of signal
transduction pathways and that SR-A acts primarily to tether A
fibrils to the cell surface of microglia and is not critical for A
stimulation of intracellular signaling events (Maxeiner et al., 1998 ;
McDonald et al., 1998 ; Husemann et al., 2001 ).
While this manuscript was under review, Coraci et al. (2002) and Moore
et al. (2002) published compelling evidence that CD36 acts as a
receptor for A fibrils and participates in both cellular adhesion
and initiation of intracellular signaling events. Their observations
are consistent with those reported here and provide further support for
critical involvement of this scavenger receptor in A -stimulated
activation of microglia.
Integrins are likely candidate receptors for A on microglia cells,
because they promote adhesion to other cells and matrix proteins. We
have shown that the
6 1-integrin is a
central element of the receptor complex and is essential for eliciting
a cellular response to A and adhesion of A fibrils. Ligation of
the 1-integrin subunit has been shown to
increase the protein-Tyr phosphorylation of paxillin, focal adhesion
kinase, Syk, and Fyn, leading to the production of proinflammatory
cytokines such as IL-1 (Lin et al., 1995 ; Chen et al., 2000 ). Many
of the Tyr kinases that are stimulated by A interaction with
microglia and monocytic lineage cells are also components of integrin
signaling pathways, including those linked to ERK phosphorylation
(McDonald et al., 1997 , 1998 ; Combs et al., 1999 ). It was previously
reported that the
5 1-integrin recognizes nonfibrillar A (Matter et al., 1998 ). However, we did not
detect any effect of a blocking antibody directed against 5. Thus,
5 1 is unlikely to be
involved in microglial activation by fibrillar A in AD.
We have also implicated CD47 in mediating A stimulation of THP-1
monocytes and microglia. CD47 is an integral membrane protein that
functionally interacts with both 1- and
3-integrins, where it serves to modulate
integrin signaling functions and cellular adhesion. Importantly, CD47
physically interacts with both integrins and intracellular signaling
elements and may act to assemble signaling complexes and functionally
integrate signals generated through ligand binding at the cell surface
(Porter and Hogg, 1998 ). In addition, CD47 can act independently to
promote cell-cell adhesion through its interactions with fibrillar
proteins such as TSP-1 and cell surface proteins on adjacent cells
(Jiang et al., 1999 ; Babic et al., 2000 ) and has been demonstrated to
have a role in integrin-independent signaling events (Brown and
Frazier, 2001 ). We have demonstrated a critical requirement for CD47 in
cellular binding of fibrillar A and the subsequent activation of
intracellular protein-Tyr kinase cascades.
We provide evidence for a receptor complex that acts both to mediate
the adhesion of cells to A fibrils and to activate intracellular signaling cascades. There is now extensive literature documenting the
influence of cellular contacts with the extracellular matrix and other
cells on the organization and coupling to intracellular signaling
systems (Woods and Shimizu, 2001 ). These data have clearly demonstrated
that the process of adhesion itself activates specific signaling
pathways and also influences the efficiency of other receptors in
stimulating their downstream effectors. We cannot distinguish the
relative contribution of the individual receptor elements to activation
of intracellular signaling pathways as distinct from those responsible
for adhesion, but it seems probable that these events are intimately linked.
Microglial recognition of A fibrils uses a cell surface receptor
complex that capitalizes on the broad substrate specificity of the
individual receptor elements. We postulate that the engagement of A
fibrils with the core CD36,
6 1, and CD47
receptors serves to bind the fibril to the cell surface, leading to
immobilization and the focal aggregation of the receptors into a
complex. The cooperative action of the receptor core elements confers a
unique binding capability to the receptor complex that is a composite of the actions of the individual receptors. It is important to note
that CD36, CD47, and
6 1 are physically
associated with Tyr kinases as well as other intracellular signaling
molecules. Moreover, it has been reported that the
6 1-integrin exists in a complex with CD36 (Thorne et al., 2000 ; Miao et al., 2001 ), and
1-containing integrins have been shown to
physically interact with CD47 (Wang and Frazier, 1998 ; Chung et al.,
1999 ). We demonstrate a direct role of these receptors in transducing
signals generated from microglial interactions with A fibrils,
resulting in the stimulation of proinflammatory pathways. The assembly
of the receptor complex results in activation of Tyr kinases and
downstream signaling pathways in a manner directly analogous to that of
other immune receptor complexes. Importantly, disrupting the
interaction of A fibrils with any component of the receptor complex
inhibits A stimulation of intracellular signaling cascades. The
peptides interacting with the binding sites of the individual receptors do not exhibit agonist activity, suggesting that the fibrillar peptide
serves to focally assemble a signaling complex. It is possible that
additional cell surface receptors are involved in A stimulation of
microglial activation, either in the binding of A fibrils to the
cell surface or the activation of intracellular signaling cascades. It
is noteworthy that both CD36 and
6 1 expression is
induced on activation of myeloid-derived cells (Tontonoz et al., 1998 ;
Kloss et al., 2001 ). Thus, the identification of an A -binding
receptor complex provides a therapeutic intervention point, targeting
the specific cell surface event resulting in the proinflammatory
activation of microglia associated with A deposits in the AD brain.
 |
FOOTNOTES |
Received Aug. 8, 2002; revised Jan. 14, 2003; accepted Jan 14, 2003.
This work was supported by National Institutes of Health Grants AG
16740 and AG 08012 and Training Grant GM 08056-18 (M.E.B.). J.H. was
was supported by Columbia University Alzheimer's Disease Research
Center Pilot Grant Award AG 08702 and the Alzheimer's Association. We
thank the Blanchett Hooker Rockefeller Foundation and the Coins for
Alzheimer's Research Trust Fund of Rotary International for
generous support of our work. We thank Dr. Colin Combs for assistance
and helpful comments on this manuscript and Dr. Frieda Pearce and Dr.
Mark Kindy for providing us with reagents.
Correspondence should be addressed to Dr. Gary Landreth, Alzheimer
Research Laboratory, E504, Case Western Reserve University School of
Medicine, 10900 Euclid Avenue, Cleveland, OH 44106. E-mail:
gel2{at}po.cwru.edu.
 |
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