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Regular Articles |
From Novartis Pharma AG,*
Nervous System Research, and
the Institute of Pathology,
University of
Basel, Basel, Switzerland, and the Brain Research
Institute,
University of Zürich,
Zürich, Switzerland
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To study the extent of inflammatory processes that accompany amyloid plaque formation, we used a transgenic mouse model, APP23, overexpressing the human ß-amyloid precursor protein (APP) with the Swedish mutation.12,13 Amyloid plaques in these mice are first observed at an age of 6 months and dramatically increase in size and number during aging. The mostly congophilic, dense-core Aß deposits show many characteristics of human AD plaques such as enlarged dystrophic neurites and neuron loss.14 Similar to AD, vascular amyloid is also present in aged APP23 animals.15 Compact amyloid deposits are associated with microglia cells showing a characteristic activated morphology,16 and with reactive astrocytes.12 Studies from Frautschy and colleagues17 have also demonstrated that microglia cells in another transgenic mouse line, Tg 2576, carrying human APP with the Swedish mutation, are activated, when located in close association with amyloid deposits.
In the present study, we immunohistochemically define the activation state of microglia in APP23 mice and, furthermore, identify mechanisms that may contribute to amyloid-associated microglia activation. In addition, we examine the expression of marker proteins for microglia phagocytosis and antigen presentation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The generation of APP23 transgenic mice has previously been described.12,13 These mice express the human APP751 cDNA with the Swedish double mutation under control of the neuron-specific mouse Thy-1 promoter fragment. APP23 mice, established on a B6D2 background, have been continuously back-crossed to C57BL/6J. Eighteen- to 23-month-old heterozygous mice from generations 6 and 7 were analyzed.
Tissue Preparation
Mice were anesthetized, decapitated and brains were removed, shock-frozen with liquid nitrogen, and stored in sealed plastic bags at -80°C. Sagittal sections were cut at 15 to 20 µm on a cryostat and mounted on Superfrost slides (Menzel-Gläser; Braunschweig, Germany). In addition, fresh-frozen sections from a mouse with a mechanical lesion to the frontal cortex were used.18
Immunohistochemistry
Fresh-frozen, cryostat-cut tissue sections were either fixed in 1) acetone for 10 minutes at -20°C (for FA-11, F4/80, and 2.4G2 antibodies), or 2) 3% paraformaldehyde for 10 minutes on ice (for MAC-1, SRA [2F8], and NT11 antibodies), or 3) methanol:acetone (1:1) for 45 seconds at -20°C (IA antibody). Sections were then pretreated with H2O2 for 30 minutes and blocked with 2.5% bovine serum albumin/2% normal serum for 2 hours at room temperature. The tissue sections were incubated with the appropriate primary antibody (3.5 hours at room temperature or overnight at 4°C), followed by incubation with a secondary biotinylated antibody for 2 hours. Bound antibodies were visualized using the avidin-biotin-peroxidase method (Vectastain ABC Elite Kit; Vector Laboratories, Burlingame, CA) with diaminobenzidine (Boehringer Mannheim, Mannheim, Germany) or Vector Vip (Vector Laboratories) as the chromogens. Between all steps, tissue sections were rinsed with phosphate-buffered saline. Some sections were stained with alkaline phosphatase-conjugated secondary antibodies and further processed with naphthol phosphate (Sigma Chemical Co., St. Louis, MO). Finally, sections were counterstained in Mayer’s hemalum (Merck Darmstadt, Germany).
Antibodies
The following primary antibodies were used: rat monoclonal
antibody MAC-1 (anti CR3, CD11b; diluted 1:1,000) (Serotec, Oxford,
England); rabbit antiserum F4/80 against a
macrophage/microglial-specific 160-kd protein (diluted 1:200; Serotec)
as well as rat monoclonal antibodies against T cell markers CD4 and
CD819
(diluted 1:50; kindly supplied by Drs. R. M.
Zinkernagel and B. Odermatt, University of Zürich, Zürich,
Switzerland); rat monoclonal FA-11 antibody against
macrosialin20
(CD68; diluted 1:100); monoclonal antibody
to murine CD45R (B220, diluted 1:75; ImmunoKontact, Frankfurt/Main,
Germany); monoclonal armenian hamster antibody to CD3
(diluted 1:50;
Pharmingen, San Diego, CA); monoclonal rat IA21
(clone
M5/114, dilution 1:50, gift from Dr. I. L. Campbell, The Scripps
Research Institute, La Jolla, CA); monoclonal 2F8 rat antibody to
scavenger receptor A (SRA) (diluted 1:100; gift of Dr. J. El Khoury,
Massachusetts General Hospital, Boston, MA); rabbit anti-receptor for
advanced glycation end products (RAGE) (dilution 1:10; kindly provided
by Dr. Thomas Hughes, Novartis Pharmaceuticals Corp., Summit, NJ);
monoclonal rat 2.4G2 against Fc
II and III receptors (CD16/CD32);
rabbit Aß1-40 antiserum NT1122
(dilution 1:1,000).
The following secondary antibodies were used: Biotinylated rabbit anti-rat IgG (dilution 1:200; Serotec), biotinylated goat anti-rat IgG (dilution 1:70; Southern Biotechnology Associates, Birmingham, AL); biotinylated mouse anti-hamster IgG (dilution 1:70; Pharmingen); biotinylated goat anti-rabbit IgG (dilution 1:200; Vector Laboratories); alkaline phosphatase-conjugated goat anti-rat IgG (dilution 1:75; Tago, Burlingame, CA); and alkaline phosphatase-conjugated donkey anti-goat IgG (dilution 1:75; Jackson ImmunoResearch Laboratories, West Grove, PA).
Immunohistochemical Analyses of Cell Proliferation
The 5'-bromodeoxyuridine (BrdU) incorporation method was used to study cell proliferation. Mice were injected daily by intraperitoneal infusion with the thymidine analogue BrdU (50 µg/g body weight; Sigma) for 5 consecutive days. Two hours after the last injection, mice were transcardially perfused with phosphate-buffered saline, followed by 4% paraformaldehyde. Brains were postfixed in paraformaldehyde, cryoprotected in 30% sucrose, frozen in isopentane at -20°C, and cut with a freezing-sliding microtome. Sections were incubated in 50% formamide/50% 2x standard saline citrate buffer at 65°C for 2 hours. After rinsing in 2x standard saline citrate, sections were incubated in 2 N HCl for 30 minutes at 37°C, and then rinsed in 0.1 mol/L borate buffer (pH 8.5) for 10 minutes as described by others.23 Subsequently, free-floating sections were immunostained with an antibody to BrdU (MAS250c, dilution 1:1,000; Accurate Ltd., Westbury, NY) according to the above described protocol.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To define the activation state of microglia cells in the brains of
APP23 mice, we performed immunohistochemical analyses with antibodies
directed to several microglial proteins known to be up-regulated during
activation. Figure 1A
shows staining with
the MAC-1 antibody detecting the macrophage/microglial-specific
complement receptor 3. Intensively MAC-1-stained microglia were found
in close association with amyloid plaques in all brain regions
containing compact amyloid plaques such as the neocortex and the
hippocampus. Microglia staining was weak or absent in nontransgenic,
age-matched control mouse brain (Figure 1C)
. When fixed under different
conditions, however, fresh-frozen control and transgenic brain tissue
devoid of amyloid plaques revealed positive, although less intense
microglia immunoreactivity, consistent with previous
reports.12,16
High-power light microscopy revealed that
MAC-1-positive microglial processes cover nearly the entire surface of
the amyloid plaque (Figure 1B)
. Moreover, MAC-1-positive microglia cell
bodies occasionally formed darkly labeled clusters. Overall,
immunostainings demonstrated that microglia with high expression levels
of MAC-1 are located in the vicinity of virtually all compact amyloid
plaques, indicating that these cells are not in a resting, but
activated state. The fact that they are activated was verified by
immunohistochemistry using the F4/80 antibody, which detects a
macrophage/microglia-specific 160-kd glycoprotein24
and
clearly showed similar cell staining as MAC-1 (Figure 1, D and E)
.
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. Higher magnification shows the staining of cell bodies around a
plaque (Figure 2C)
. Double immunohistochemistry with antibodies
directed to BrdU and MAC-1 revealed incorporation of this thymidine
analogue into the DNA of microglia, indicating that these
plaque-associated microglia cells are in a proliferative state (Figure 2D)
.
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In vitro studies have shown that SRA is capable of
mediating microglial adhesion to fibrillar Aß resulting in their
activation.10,11,25
Using 2F8, an antibody directed to SRA
that is expressed on mononuclear phagocytes,11
we found
increased immunoreactivity associated with virtually all compact
amyloid plaques (Figure 3A)
. Strongest
labeling was observed at the outer edge of the plaques, at sites where
microglial processes are in contact with the amyloid. In addition, SRA
reactivity was found associated with vascular amyloid deposits (Figure 3B)
. These results indicate that microglia may interact with fibrillar
Aß through SRA, and that this interaction may contribute to their
activation and retention at these sites.
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and at the vascular endothelium (Figure 3D)
.
Moreover, RAGE staining was present only at a small percentage of all
amyloid plaques. Although the staining did not allow us to
unequivocally localize the immunoreactivity to microglia cells, it was
apparent that at best a subpopulation of activated microglia was
RAGE-positive. Therefore, a general contribution of RAGE to microglial
activation in the vicinity of amyloid plaques in the APP23 mice seems
to be unlikely. Components for Phagocytosis Such as Macrosialin and Fc Receptors Are Elevated in Plaque-Associated Microglia
To further assess the functional potential of activated microglial
cells, we used the antibody FA-11, which is directed to the lysosomal
membrane protein macrosialin,20,27
the murine homologue of
CD68. Increased immunoreactivity of this protein is found in cells that
accumulate lysosomal vacuoles, which represent a typical feature of
phagocytic cells.28
As visualized by the strong staining,
plaque-associated microglia in APP23 mice accumulate macrosialin
(Figure 4A)
. Sections from control mice
or from brain regions devoid of amyloid plaques show only weak
labeling, reflecting a low macrosialin expression in all resting
microglia cells (Figure 4C)
. At higher magnification, plaque-associated
microglial cell bodies are visible (Figure 4B)
. Staining of microglia
processes is also evident, possibly because of the appearance of
lysosomal structures in microglial processes or because of an
expression of a small fraction of macrosialin at the cell
surface.27,29
The elevation of macrosialin hints at a
phagocytic capability of microglia cells in the vicinity of plaques.
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RII and FcRIII that bind to
IgG-opsonized particles.30,31
Both Fc receptors have been
reported to be up-regulated on phagocytic cells.32
In
APP23 mice we also found an up-regulation of these receptors on
microglia in the plaque vicinity (Figure 4D)
. However, when performing
immunohistochemical analyses with antibodies directed to mouse IgG, we
did not obtain any evidence of autoantibodies bound to the amyloid
plaques (data not shown). In addition, antibody titers against Aß
were not detectable in the sera of APP23 mice (data not shown). These
results indicate some phagocytic capability of plaque-associated
microglia, but they do not support Fc receptor-mediated phagocytosis of
amyloid by microglia. A Subpopulation of Activated Microglial Cells Is Major Histocompatibility Complex (MHC) Class II-Positive
Phagocytosis and intracellular processing of external proteins are
required for their presentation as antigenic peptides in association
with MHC class II molecules. Given the increase of phagocytic markers
in APP23 mice, we addressed the question whether the antigen-presenting
machinery in microglia is intact. We examined expression levels of MHC
class II molecules using an antibody directed to the murine MHC class
II molecule IA. Strong reactivity was observed in association with the
amyloid plaques, although only a small portion of plaque-associated
microglia appeared to be reactive (Figure 5A)
. To study the spatial relationship of
these MHC class II-positive microglia cells and amyloid plaques in more
detail, we performed double-labeling experiments with antibodies
directed against Aß and IA. As shown in Figure 5B
, MHC class II
protein reactivity was found within as well as very close to the
compact amyloid plaques. Additionally, we observed IA reactivity
associated with blood vessels containing vascular amyloid but not with
diffuse amyloid deposits. To confirm that up-regulated IA was found
exclusively on microglia cells, we used double staining with MAC-1 and
IA (data not shown). These results indicate that the antigen-presenting
machinery in amyloid plaque-associated microglia is intact.
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The increase in MHC class II reactivity at amyloid plaques in the
APP23 transgenic mouse brain led us to examine a potential recruitment
of lymphocytes in the inflammatory processes. We, therefore, searched
for T cells that could be activated by antigenic peptides, which are
associated with MHC class II molecules. Using an antibody against
CD3, a component associated with the T cell receptor, we did not
obtain any evidence for T cells in the cerebral cortex of APP23
transgenic mice (Figure 6A)
including the
plaque regions where MHC class II-positive microglia have been found.
To demonstrate the antibody reactivity, staining of T lymphocytes,
located in the splenic white pulp, was used as a positive control
(Figure 6B)
. Further immunohistochemical staining was performed with an
anti-CD4 antibody, directed against T helper cells to verify the lack
of T cells in aged transgenic mouse brain. Analyses of the cerebral
cortex of APP23 mice containing numerous amyloid deposits repeatedly
did not provide any evidence for the presence of T cells (Figure 6C)
. T
cells in the white pulp of the spleen, however, showed a positive
immunoreactivity when stained with the same antibody (Figure 6D)
. The
same result was obtained with CD8 antibodies, which recognize cytotoxic
T cells that are activated by antigen associated with MHC class I
molecules (data not shown). For direct comparison we also stained post
mortem brain tissue from AD patients with a human T cell-specific
CD3 antibody and detected a few single positive cells in the
capillaries of the cerebral cortex (data not shown). Only one of these
T cells appeared to be located at the outer endothelium of the
capillary. Neither the lack of detectable T lymphocytes in the cerebral
cortex of APP23 transgenic mice nor the incidental detection of single
T lymphocytes in the cerebral cortex of AD patients support a function
of activated microglia as antigen-presenting cells.
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. Analyses of neocortical
tissue from AD patients also did not provide any evidence of B
lymphocytes (data not shown). Sections from several control tissues
demonstrated many B cells in the white pulp of a murine spleen (Figure 6H)
. The detection of single B lymphocytes near a mechanical brain
lesion of the frontal cortex18
(Figure 6G)
as well as in
the medulla of a murine thymus (Figure 6F)
served as additional
positive controls. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To better understand the microglial response, we evaluated their activation state in the brains of APP23 transgenic mice. The observation that both the microglial/macrophage-specific protein MAC-1 and a 160-kd glycoprotein recognized by the F4/80 antibody are increased, demonstrates that microglia cells associated with compact amyloid plaques are in an activated state. Some of the activated cells proliferate, as shown by in vivo labeling of APP23 mice with BrdU. This finding suggests that proliferation of resident or invading microglia/monocytes contributes to the high abundance of microglia cells near amyloid plaques.
Because diffuse amyloid deposits do not show microglia reactivity,16 it is very likely that only fibrillar Aß interacts with the microglia cells to induce their activation. Candidate receptors are SRA and RAGE, which were shown in vitro to mediate adhesion to Aß fibrils and activation of microglia cells.10,11,26 An up-regulation of SRA, at sites where microglial processes interact with Aß, indicates that this receptor may be responsible for activation and accumulation of microglia at the amyloid plaques. A previous study has shown that lack of SRA does not alter the plaque formation itself in APP transgenic mice but the effect on microglia activation as well as other aspects of pathology have not been fully investigated.35 RAGE was also found to be up-regulated on some plaque-associated cells in APP23 mice. Because only a subpopulation of cells showed this up-regulation, RAGE does not seem to be a strong candidate for a general mediator of microglia activation at plaques in the brains of APP23 mice. In addition, cytokines or chemokines may contribute to sustained microglia activation as they were shown to be present in glia cells around amyloid plaques of APP transgenic mice.36
Evidence for a phagocytic capability of microglia cells in APP23 mice
comes from an increase of macrosialin, the mouse homologue of CD68.
Elevated levels of CD68, primarily a lysosomal membrane protein,
indicate that cells are phagocytically active and digest internalized
material because they accumulate lysosomal vacuoles.28
Consistent with these results, we have previously demonstrated
microglia with typical phagocytic morphology in APP23
mice using electron microscopy.16
Interestingly, however,
these microglia were in close contact with the dystrophic terminals
around the amyloid plaques, whereas those in intimate contact with the
amyloid fibrils did not appear phagocytic. Our finding of Fc
receptor up-regulation further suggests that microglia in the APP23
mouse model are generally capable to phagocytose IgG-opsonized
particles.32
However, because we found neither
autoantibodies bound to amyloid plaques, nor antibody producing B
lymphocytes in the brain or Aß antibody titers in the sera, our
results indicate that Fc receptor-mediated phagocytosis does not occur
to a large extent in the brains of APP23 mice. Efficient (likely Fc
receptor-mediated) phagocytosis may be induced under specific
circumstances as recently shown by Schenk and
colleagues,37
who demonstrated clearance of amyloid
deposits in a human APP transgenic mouse line, PDAPP, after
immunization with Aß42 peptide. It is tempting to speculate that
microglial cells may clear the amyloid and that binding of already
up-regulated microglial Fc receptors to the Aß antibody-amyloid
ligands plays an important role in this process.
A subpopulation of plaque-associated, activated microglia cells is characterized by an increase in MHC class II protein and may be capable of presenting plaque-derived antigen, thereby activating T lymphocytes. However, an intensive search did not reveal any T lymphocytes in plaque-containing brain regions of aged APP23 mice, rendering this possibility unlikely. Because we also did not obtain any evidence for B lymphocytes, a contribution of cell-mediated immune responses to the inflammatory processes and to the plaque pathology seems unlikely in APP23 mice.
Taken together, the data presented in this study demonstrate that microglia in the plaque vicinity are in an activated state. Proliferation as well as interaction of the SRA with Aß seem to contribute to microglia accumulation and activation at the periphery of amyloid plaques. Clearance of amyloid deposits seems to be suppressed for reasons that are not related to the phagocytic capability of microglia. Although the antigen-presenting function via MHC class II seems to be intact, the lack of T and B lymphocytes argues against cell-mediated immune responses in the brains of APP23 mice. Because of similar functional characteristics of microglia in APP23 mice compared to Alzheimer patients, these mice serve as a suitable model to further investigate the effect of inflammatory processes on AD pathology.
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Acknowledgements |
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Footnotes |
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Supported by grants 3130-44526.95 and 3130-56753.99 from the Swiss National Foundation.
Accepted for publication September 29, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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R
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