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From the Neuropathology Laboratory,*
Institute of
Pathology, University of Basel, and Novartis Pharma,
Inc.,
Nervous System Research,
Basel, 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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Recently, transgenic mice have been produced that overexpress mutant human ßPP (APP23 line, Swedish double mutation) under the control of a neuron-specific Thy-1 promoter element.15 These mice develop amyloid plaques, predominantly in neocortex and hippocampus, progressively with age. The plaques have most characteristics of human AD plaques, including fibrillar Aß cores, and are surrounded by dystrophic neurites and activated glial cells. Region-specific amyloid-associated neurodegeneration including neuron loss, synapse deficits, and cholinergic alterations have been reported16,45 in these mice. To study the involvement of microglia in amyloid plaque formation and neurodegeneration, we have analyzed the microglial response in both young and adult APP23 transgenic mice at light microscopic and ultrastructural levels.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The APP23 transgenic mice used in this study have been described previously.15 The mice express mutated human ßPP (Swedish double mutation) under a brain and neuron-specific murine Thy-1 promoter element. We used a total of 12 hemizygous and homozygous male APP23 mice between 14 and 18 months of age and 10 control mice from the F3-F5 generation (most of these animals have been used to assess neurodegeneration.16,45 In addition, a group of young male 4- to 9-month-old hemizygous APP23 mice and littermate controls from the F6-F8 generation were used. APP23 mice were initially on a B6D2 background and subsequently have been backcrossed with B6 mice.
Tissue Preparation for Light Microscopy
Animals were injected with an overdose of pentobarbital and transcardially perfused with phosphate buffered saline (PBS) (pH 7.4) followed by 4% paraformaldehyde in PBS at room temperature. Brains were removed and postfixed in the same fixative overnight and placed in 30% sucrose in PBS for 2 days, all at 4°C. Brains were then frozen in 2-methylbutane at -25°C and serially sectioned on a freezing-sliding microtome at 10–40 µm.
Immunohistochemistry and Congo Red Staining
Immunohistochemical staining was performed according to a previously published protocol.17 In brief, sections were preincubated for 30 minutes in 1% H2O2 followed by 0.3% Triton X-100 in Tris-buffered saline for 10 minutes and 5% blocking serum for 30 minutes. Sections were reacted overnight at 4°C with primary antibodies in 0.3% Triton and 2% serum. The avidin-biotin-peroxidase method (ABC Elite Kit, Vector Laboratories, Burlingame, CA) with diaminobenzidine (DAB) as the chromogen was used to visualize the antibodies (brown reaction product). In some experiments NiCl2 was added to the DAB leading to a black reaction product. Some sections were counterstained with cresyl-violet according to standard protocols.
The following antibodies were used: rat monoclonal anti-mouse CR3 (CD11b; Mac-1; diluted 1:2000; Serotec, Oxford, UK), mouse monoclonal antibody to phosphotyrosine (PT-66; diluted 1:500; Sigma, St. Louis, MO), and polyclonal antibody NT-11 to human Aß (1:2000).15
For double labeling, a sequential protocol was used. The first primary antibody (NT-11) was visualized with DAB alone and the second primary antibody (Mac-1) was visualized with Vector SP (Vector Laboratories). Congo Red staining was performed on Mac-1 immunostained sections according to standard protocols and viewed under cross-polarized light.
Semithin Sections and Ultrastructural Analysis
For electron microscopy, mice were transcardially perfused with PBS followed by 4% paraformaldehyde plus 1–2.5% glutaraldehyde in PBS. Mice used for immunoelectron microscopy were perfused with PBS followed by 4% paraformaldehyde containing 0.1% glutaraldehyde in PBS. Brains were removed and postfixed overnight in 4% paraformaldehyde. Sections were cut with a vibratome (60 µm). Sections used for immunoelectron microscopy were stained free-floating with the Mac-1 antibody under the same conditions as described above but without H2O2 and Triton X-100. Sections prepared for both electron and immunoelectron microscopy were postfixed with 0.5% OsO4 in PBS containing 6.86% sucrose for 30 minutes, dehydrated in ascending series of ethanol and acetone, and flat-embedded between glass slides and coverslips in EMbed-812 (Electron Microscopy Sciences, Fort Washington, PA). Using an ultramicrotome, semithin (2 µm) and ultrathin sections were cut from the tissue surface. Ultrathin sections were mounted on copper grids and some sections were contrasted with uranyl acetate and lead citrate and finally analyzed with a Zeiss EM 900 electron microscope.
Semiquantitative Analyses
To study early plaque formation serial 15-µm sections were cut from the brain of young 4- to 9-month-old APP23 mice. A sequence of sections was alternately immunostained for Mac-1 (microglia) and NT-11 (amyloid plaques). Early Aß-immunoreactive deposits were identified and the corresponding microglia activation in adjacent sections was quantified. In reverse, activated microglia were identified and evidence for corresponding Aß deposits was determined in adjacent sections. Microglia were considered activated when clustering of at least 2 microglia was observed and both cell body and processes were intensely immunoreactive and hypertrophic. The quantification (number of amyloid plaques with a corresponding microglial reaction, number of clusters of activated microglia with corresponding amyloid deposition) was carried out by two different raters and results were within 10% of each other.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Consistent with previous reports in mice and
humans,18,19
immunostaining using an antibody to CD11b
(Mac-1) revealed specific labeling of microglia in all white and gray
matter regions of the APP23 mouse brain. In 14- to 18-month-old APP23
transgenic mice clusters of microglia intensely stained with Mac-1 were
observed in all regions with plaque formation, primarily neocortex and
hippocampus (Figure 1A)
. The microglia
clusters appeared as focal aggregations when the periphery of a plaque
was sectioned and as clusters around an unstained
center when the core of an amyloid plaque was sectioned. No such
aggregations of Mac-1-positive microglia were observed in nontransgenic
littermates (Figure 1B)
. Similarly, using an antibody to
phosphotyrosine, which is a specific marker for microglia in the
central nervous system,20,21
clusters of intensely stained
microglia were observed in transgenic mice but not in littermate
controls (Figure 1, C and D)
. In contrast to anti-Mac-1 staining,
antibodies to phosphotyrosine revealed only weak staining of microglia
in nontransgenic control mice (Figure 1D)
. Overall, the activation of
microglia as characterized by swollen processes and cell bodies was
restricted to the plaque areas. Based on morphological and
immunohistochemical observations, no global activation of microglia in
transgenic compared to nontransgenic brains was observed.
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. Depending on the size of the plaques,
between 3 and ~20 microglial cell bodies were observed at the
periphery of amyloid plaques. Mac-1-positive microglial cells, with
their processes penetrating deeply into the amyloid, appeared to cover
nearly the entire surface of a plaque (Figure 1, E and F)
. These
amyloid-associated microglial cells revealed a polar morphology with
thin processes away from the plaque and hypertrophic processes directed
toward the plaque (Figure 1, E and F)
. Mac-1-positive cell bodies were
not observed within the center of amyloid plaques. Occasionally, a
microglial cell body had the appearance of being trapped between a main
plaque and satellite plaques, giving the impression that the microglia
resides in the center of a large plaque.
Although the amyloid core in the center of such microglial clusters
could easily be recognized in unstained sections using Nomarski optics,
double labeling with Congo Red and Aß antibodies was performed.
Results revealed that virtually all congophilic amyloid plaques in 14-
to 18-month-old APP23 mice were associated with clusters of activated
microglia (Figure 2A)
. When adjacent
serial sections were immunolabeled alternately for Aß and Mac-1 it
was noted again that the vast majority (>90%) of compact amyloid
deposits were surrounded by hypertrophic microglia (Figure 2, B and C)
.
Diffuse amyloid was observed in the striatum, the dentate gyrus
molecular layer, and the cingulate and entorhinal cortices but overall
accounted for less than 10% of the total amyloid burden in 14- to
18-month-old APP23 mice.16
Comparison of adjacent sections
that immunoreacted either with Aß or Mac-1 revealed that diffuse
amyloid was not associated with a detectable microglia activation (Figure 2, D–G)
.
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To study more closely the interaction between microglia and
amyloid fibrils, semithin and ultrathin sections were cut from
unstained and Mac-1-immunostained plastic embedded sections. In both
semithin and ultrathin sections, specificity of Mac-1 staining to the
surface of microglial cell bodies and processes was confirmed (Figures 3 and 4)
.
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. Microglia
cell bodies were typically located at the periphery of the plaques,
where the amyloid fibrils had the appearance of "streaming out" and
forming amyloid stars. At least one Mac-1-positive hypertrophic process
was always in direct contact with an amyloid finger. At the interfaces
between amyloid and microglia, the Mac-1-positive microglial surface
membrane appeared to be discontinuous (Figure 3)
.
Electron and immunoelectron micrographs confirmed the observations
obtained from semithin Mac-1-immunostained sections (Figures 4, 5, and 6)
.
Microglia were observed at the periphery of amyloid plaques, often
among a group of dystrophic neurites and often in contact with
amyloid fibrils. Similar to the observations at light microscopic
levels, Mac-1-positive cell surface membranes appeared discontinuous in
the region of communicating fibrils between microglial cells and
amyloid deposits and parallel arrays of amyloid bundles were observed
close to both microglial organelles and nucleus (Figure 4A)
.
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. Sometimes, a membrane surrounding these bundles
was detectable. The microglia cytoplasm had a characteristic dense
granular appearance with prominent endoplasmic reticulum and numerous
free polyribosomes (Figures 5 and 6)
.
At the amyloid-microglia interface lysosomes, vacuoles, lipofuscin, and
other inclusion bodies indicative of microglial phagocytosis were
absent22
(Figures 5 and 6)
. Microglia cells with the
typical characteristics of phagocytosis were observed but these
microglia were not usually the ones in contact with the amyloid fibrils
(Figures 4A, 5, and 6)
. Rather, microglia with the typical features of
phagocytosis were the ones preferentially associated with dystrophic
boutons at the plaque periphery (Figure 4, B and C)
. Dystrophic boutons
contained the typical membranous dense bodies but no paired helical
filaments were observed.
Because tissue prepared for immunoelectron microscopy revealed a
suboptimal preservation of the ultrastructure, it was difficult to
determine unequivocally whether membranes surrounding amyloid fibrils
in the microglia cytoplasm were part of the Mac-1-positive cell surface
membrane or part of the subcellular membrane system. Therefore, it is
possible that these membrane-bound bundles of amyloid within the
microglia cytoplasm may be transversely sectioned deep infoldings of
the microglia cell surface that are filled with amyloid (Figures 5 and 6)
.
Early Amyloid Deposits in Young Mice Associated with Activated Microglia
To investigate the role of microglia in early amyloid
deposition we studied the distribution and appearance of microglia in
young hemizygous 4- to 9-month-old APP23 mice. The earliest plaques in
hemizygous APP23 mice appear at about 6 months of age.15
A
series of serial 15-µm sagittal sections was cut through the brains
and alternately immunostained for Mac-1 (microglia) and NT11 (amyloid)
(Figure 7)
. Additional sections were
stained for Congo red. Results revealed that the early plaques were
preferentially deposited in the frontal cortex and subiculum and ranged
from tiny focal amyloid aggregates (<5 µm) to medium-sized plaques
(15–30 µm). Interestingly, the tiniest and earliest plaques already
appeared to have a dense core, were Congo red-positive, and were
surrounded by hypertrophic microglial processes stained intensely with
Mac-1 (Figure 7)
. This microglial activation around small plaques was
confined to only 2 or 3 microglial cells. Our semiquantitative results
revealed that in 85% of the amyloid deposits, a corresponding
microglial response was found in adjacent sections. In a reverse
analysis, in 78% of the observed microglia aggregations an amyloid
plaque was detected on adjacent sections. It should also be noted that
microglia clusters consisting of 2 to 4 microglia (always without
hypertrophic cell bodies and processes) have been observed in
nontransgenic littermates.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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These findings in APP23 mice are very similar to immunohistochemical and ultrastructural observations previously described in AD brain.4,8,23,24 In AD, activation of microglia has been reported in association with neuritic plaques but not with diffuse amyloid.5,25 In the present study, we have found diffuse amyloid deposits in noticeable amounts only in aged mice with a high overall plaque load. Diffuse amyloid was always accompanied by significant amounts of congophilic plaques. An exception was the striatum, where we found exclusively diffuse amyloid, paralleling observations in AD brain.26 These results suggest that, at least in APP23 mice, diffuse amyloid deposits are not a necessary precursor of dense-core congophilic amyloid plaques. Moreover, even the earliest amyloid deposits in young APP23 mice were congophilic, compact, and surrounded by activated microglia.
The tight association of amyloid fibrils and microglia in AD brain has led to the suggestion that microglia are involved in either the phagocytosis or deposition of amyloid.3-5,7 In culture, there is clear evidence that microglia are capable of taking up Aß and amyloid fibrils via the receptor for advanced glycation end products (RAGE) and scavenger receptors.27-29 However, our ultrastructural observations may be interpreted as having found microglia engaged in the formation of amyloid rather than in its phagocytosis. The absence of phagocytotic characteristics of the microglia at the amyloid-microglia interface is different from the subcellular alterations previously identified in amyloid phagocytosing microglia in culture and after stroke.9,30 Moreover, in AD brain membrane-bound amyloid fibrils have been observed in direct contact with the endoplasmic reticulum of the microglia, thus implicating microglia as amyloid-producing cells.4,7,8,24
In AD, microglia express ßPP31-33 and thus it is feasible that microglia in AD brain are both ßPP-processing cells and amyloid-producing cells.8 ßPP or Aß might also be taken up by microglia from the environment and subsequently processed into amyloid fibrils.6,10 APP23 transgenic mice express ßPP under the control of a brain- and neuron-specific Thy-1 promoter element and we have confirmed the exclusive neuronal expression of the human ßPP protein15 (Calhoun M, Wiederhold K, Staufenbiel M, Jucker M, unpublished manuscript). If microglia in APP23 mice are involved in amyloid deposition, our results then suggest that microglia take up neuron-derived human ßPP or Aß, which may then be processed into amyloid fibrils. Along this line, the possibility must be considered that in APP23 mice neuron-derived human ßPP and/or Aß activates microglia and may then stimulate the production of endogenous mouse Aß.33,34 Therefore, we cannot exclude that some of the amyloid in our transgenic mice is in fact mouse Aß. However, our recent analysis of amyloid plaque formation in crosses of APP23 mice with APP-null mice (Sturchler-Pierrat C, Duke M, Wiederhold K, Sommer B, unpublished work) suggests that the vast majority of the deposited amyloid is human amyloid. Moreover, the ultrastructure of microglia in APP23 x APP-null mice is identical to the present observations (results not shown).
In APP23 mice, a discontinuous cell surface membrane was observed at the amyloid-facing pole of microglia and the same observation has been reported in AD brain. Such a consolidated microglia-amyloid space may give rise to leakage of cytotoxic and inflammatory microglial proteins into the surrounding neuropil.10 However, an open microglia membrane clearly suggests amyloid-associated microglia cell death. In APP23 mice we have not observed convincing evidence for microglia cell death around amyloid plaques, although recent observations in AD brain suggest that amyloid-associated microglial cell death may indeed occur.35
We have reported a significant correlation between neuron loss and amyloid plaque load in the CA1 region of hippocampus16 in the exact same APP23 mice used in the present study. More than 90% of the amyloid deposits were congophilic in nature and here we report that these plaques are surrounded by activated microglia. Because plaque load, neuron loss, and activated microglia all seem to be related, these observations suggest that amyloid-associated microglia activation may play a role in CA1 neuron loss. Activated microglia release various cytokines and neurotoxins including reactive oxygen species25,36-38 and persistent activation of microglia may give rise to chronic inflammation and neurodegeneration.11,12
In PrP-APP transgenic mice, another mouse model with amyloid plaque formation,39 a microglia activation very similar to the one observed in APP23 mice has been described at the light microscopic level.40 With a plaque load significantly less than the one in APP23 mice, a nonsignificant neuron loss was reported in PrP-APP mice.41 In contrast, in a third mouse model with amyloid plaque formation, PD-APP mice,42 significant amounts of diffuse amyloid, no neuronal loss, and only occasional microglial clustering around amyloid plaques were reported.43,44 The observations from the APP23, PrP-APP, and PD-APP transgenic mouse models suggest that amyloid-associated activated microglia may be important for the neurodegeneration in these mice and perhaps in AD.
In summary, the present results together with previous observations demonstrate that overexpression of human mutated ßPP in neurons is sufficient to induce amyloid plaque formation, region-specific neurodegeneration,15,16,45 and amyloid-associated microglia activation. Although the present observations cannot unequivocally determine whether microglia are causal, contributory, or consequential to cerebral amyloidosis, our results are most consistent with the idea that microglia are intimately involved in cerebral amyloidosis, by processing uptaken ßPP or Aß into amyloid fibrils and/or by ingesting neuron-derived ßPP or amyloid fibrils by an uncommon phagocytotic mechanism. In any case, activation of microglia in APP23 mice seems to be important for the pathogenesis of AD-like pathology.
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Acknowledgements |
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Footnotes |
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Supported by grants 3130–44526.95 and 3100–46612.96 from the Swiss National Foundation.
Accepted for publication March 3, 1999.
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References |
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. Nature 1995, 374:647–650
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 Y.-M. Kuo, T. A. Kokjohn, T. G. Beach, L. I. Sue, D. Brune, J. C. Lopez, W. M. Kalback, D. Abramowski, C. Sturchler-Pierrat, M. Staufenbiel, et al. Comparative Analysis of Amyloid-beta Chemical Structure and Amyloid Plaque Morphology of Transgenic Mouse and Alzheimer's Disease Brains J. Biol. Chem., April 13, 2001; 276(16): 12991 - 12998. [Abstract] [Full Text] [PDF]
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H. L. Tiffany, M. C. Lavigne, Y.-H. Cui, J.-M. Wang, T. L. Leto, J.-L. Gao, and P. M. Murphy Amyloid-beta Induces Chemotaxis and Oxidant Stress by Acting at Formylpeptide Receptor 2, a G Protein-coupled Receptor Expressed in Phagocytes and Brain J. Biol. Chem., June 22, 2001; 276(26): 23645 - 23652. [Abstract] [Full Text] [PDF]
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Y. Le, W. Gong, H. L. Tiffany, A. Tumanov, S. Nedospasov, W. Shen, N. M. Dunlop, J.-L. Gao, P. M. Murphy, J. J. Oppenheim, et al. Amyloid {beta}42 Activates a G-Protein-Coupled Chemoattractant Receptor, FPR-Like-1 J. Neurosci., January 15, 2001; 21(2): RC123 - RC123. [Abstract] [Full Text] [PDF]
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