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From the Dementia Research Group,*
Nathan Kline
Institute/New York University Medical Center, Orangeburg, New York; the
Mayo Clinic,
Jacksonville, Florida; the
Department of Neurobiology and Anatomy,
University of Rochester Medical Center, Rochester, New York; the
Department of Molecular Biology and
Biochemistry,§
University of California,
Irvine, California; and the Center for Neurologic
Diseases,¶
Brigham and Women’s Hospital, Harvard
Institutes of Medicine, Boston, Massachusetts
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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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It has now been well demonstrated that immune and inflammatory responses can take place in the central nervous system (CNS) as well as the periphery,7 and that microglia can be considered to be a brain macrophage. Resting microglia exist in a resident (ramified) form characterized by long, thin processes, but on activation, the morphology changes to an ameboid form, with short, thick processes.8 Astrocytes also undergo activation in the CNS, and both glial types produce inflammatory-response proteins such as interleukins (ILs), tumor necrosis factor, nitric oxide synthase, cyclooxygenase, and complement proteins. Such immune and inflammatory responses in the CNS are observed in several chronic and acute neurodegenerative diseases including AD, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, and stroke.9,10
To examine how glial cells in the CNS of the PS/APP mouse respond to Aß accumulation, we correlated Aß deposition with the activation of glial cells (microglia and astrocytes) and the up-regulation of cyclooxygenase-2 (COX-2) and complement component 1q (C1q).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mice expressing mutant APPK670N,M671L
(mutant APP, Tg2576)4
and mutant
PS1M146L (mutant PS1, line 6.2)5
were crossed to generate the PS/APP line. The mice used in this study
were 3, 7, 12, 18, and 30 months old (n 
3 at
each age). For the COX-2 study we used 7- and 12-month-old mice
(n = 3). For the C1q study, we used 7-, 12-,
14-, and 18-month-old mice (total n = 4), and two of
the mice were subjected to the double labeling study with the microglia
marker.
The following antibodies were used in this study. Rat anti-mouse CD11b,
also known as Mac-1 
chain (clone M1/70.15) (Caltag Laboratories,
San Francisco, CA); rat anti-F4/80 (Serotec, Raleigh, NC); mouse
anti-glial fibrillary acidic protein (GFAP; clone G-A-5) (Roche
Diagnostics, Indianapolis, IN); mouse anti-human Aß residues 17–24
(clone 4G8) (Senetek, Maryland Heights, MO); rabbit anti-murine COX-2
(Cayman Chemical, Ann Arbor, MI); rabbit anti-GFAP (for human
immunohistochemistry; Dako, Carpenteria, CA).
Polyclonal antibodies against human Aß, C40 and C42, were kind gifts from Dr. Saido (RIKEN Brain Institute, Saitama, Japan). C40 and C42 were developed using synthetic Aß peptide residue 36–40 and 38–42, respectively, as an antigen, and are specific for Aß ending at residue 40 and 42, respectively.11 Goat anti-mouse C1q antibody was a kind gift from Dr. F. Petry (Institute of Medical Microbiology and Hygiene, Johannes-Gutenberg University, Mainz, Germany).12
Immunohistochemistry
The animals were perfused through the left cardiac ventricle with 10 ml of cold 10 mmol/L phosphate-buffered saline (PBS), pH 7.4, under deep anesthesia, followed by 40 ml of a cold fixative consisting of 4% paraformaldehyde in 100 mmol/L phosphate buffer, pH 7.4. After perfusion, the brain was quickly removed and postfixed for 18 hours with the same fixative at 4°C, and 30-µm-thick frozen sections were prepared using a freezing microtome (Physitemp, Clifton, NJ, and Leica, Heidelberg, Germany). Free-floating sections were treated with 0.3% hydrogen peroxide in 100 mmol/L PBS containing 0.3% Triton-X 100 (PBST) for 30 minutes, and nonspecific protein binding was blocked by incubation with 10% normal goat serum in PBST for 1 hour. Sections were incubated with primary antibodies against Aß (333 ng IgG/ml), CD11b (1 µg IgG/ml), and GFAP (20 ng IgG/ml) overnight at room temperature. Primary antibodies were detected by biotinylated secondary antibodies (1.5 µg IgG/ml each, Vector Laboratories, Burlingame, CA) and visualized by the ABC method (ABC Elite kit, Vector Laboratories). After each incubation, sections were rinsed in PBST 3 times for 10 minutes each.
For COX-2 immunohistochemistry, unfixed frozen brain tissue was cut at 18 µm using a sledge microtome, mounted onto slides, and fixed in 4% paraformaldehyde for 10 minutes. Slides were washed in 150 mmol/L phosphate buffer, and antigen retrieval was performed in 100% cold methanol for 10 minutes13 After rehydration, sections were blocked with normal goat serum, then incubated with anti-COX-2 antibody (1:500). COX-2 antibody was detected as described above. For double labeling, sections were incubated with primary antibodies against COX-2 and GFAP, then visualized with Alexa Fluor 488- or 588-labeled secondary antibodies (Molecular Probes, Eugene, OR). Fluorescent images were captured using a Zeiss Axioplan microscope equipped with a Spot II digital camera and software (Diagnostic Instruments Inc., Sterling Heights, MI).
For C1q immunostaining, sections were incubated for 1 hour with 2% bovine serum albumin and 1% normal rabbit serum in Tris-HCl buffer (pH 7.4) containing 0.1% Triton X-100, and then incubated with anti-C1q antibody (7 µg/ml) overnight at 4°C. Antibody was detected by the ABC method. For double immunolabeling of C1q and a marker for microglia, C1q was first detected by FITC-labeled anti-goat Ig (1:500, Jackson Immunoresearch, West Grove, PA) and photographed. Sections were washed and then stained with F4/80 (1:50). Label was detected with biotinylated secondary and ABC method as above.
Immunohistochemistry on human brain was performed as described previously.14 Primary antibodies were used at dilutions of 1:500 (C40 and C42) or 1:1000 (GFAP).
To clarify the association between fibrillar Aß and a specific antigen, immunostained sections were mounted on glass slides and incubated with 1% thioflavin-S (Sigma, St. Louis, MO) in 70% ethanol for 20 minutes, then rinsed with 70, 95, and 100% ethanol. Thioflavin-S was visualized using a specific filter set (excitation, 405–445 nm; emission, 515–565 nm).
Amyloid burden was assessed according to the method of Takeuchi et al.15 In brief, the percentage of the frontal cortex covered by 4G8-immunoreactivity or thioflavin-S, was assessed on consecutive sections from 3 separate mice using MCID image analysis software (Imaging Research, St. Catharines, ON).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mice younger than 3 months of age initially deposit Aß in the
frontal cortex (Figure 1A)
as visualized
with anti-Aß antibody (4G8). Visible deposits were not seen in more
caudal regions at this age (Figure 1B)
. As the animals aged, Aß
deposition spreads throughout the cortex, and to the hippocampus,
thalamus, and amygdala (Figure 1C)
. By 1 year of age, Aß deposits
were widely observed, but there was not a marked change in the total
amount of amyloid deposited beyond that age (Figure 1, D–F)
. A second
monoclonal antibody that recognizes Aß residues 1–17 (6E10) showed
essentially the same distribution pattern (data not shown). For our
purposes, 4G8 was considered to recognize total Aß as it recognizes
both diffuse and fibrillar Aß.
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, but
they were absent from more caudal regions (Figure 2B)
. The number of
fibrillar Aß deposits increased synchronously with an increase in
total Aß up to 1 year of age, although fibrillar Aß deposits were
fewer and smaller than 4G8 immunoreactive total Aß deposits in the
brains of younger animals (Figure 1, A–D
, vs. Figure 2, A–D
). Fibrillar Aß increased markedly after 1 year of age (Figure 2, D–F)
, although total Aß levels remained relatively consistent. The
relative amount of total and fibrillar Aß was quantified (Figure 3)
. The area covered by total Aß
increased markedly up to 1 year of age, but the levels did not show a
marked change at older ages (Figure 3
, open column and continuous
line). In contrast, the area covered by fibrillar Aß increased
consistently up to 2 years of age (Figure 3
, closed column and dotted
line). At 1 year of age, the percentage of brain covered by fibrillar
Aß (15 ± 2%) was approximately half that covered by total Aß
(29 ± 5%), but by 2.5 years of age, fibrillar Aß (32 ±
4%) accounts for almost all of the 4G8-immunoreactive Aß present
(33 ± 2%) in the brain.
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Activated microglia accumulated around Aß deposits (Figure 4F)
from the earliest age at which they
were visible (approximately 3 months), and the number increased
synchronously with age and increased amyloid burden (Figure 4, B–E)
.
Very few activated CD11b-immunoreactive microglia were observed in
regions of the brain (Figure 4A)
where visible amyloid deposits had not
yet developed (Figure 2A)
. Neither amyloid deposits nor activated
microglia were observed in nontransgenic littermate animals using these
staining protocols (data not shown).
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) and anti-CD11b antibody
(Figure 5B)
. After immunostaining, sections were counterstained with
thioflavin-S (Figure 5C)
. CD11b-immunoreactive activated microglia
associated with both diffuse and fibrillar Aß deposits (Figure 5)
.
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, but
they were very rarely seen in regions of the brain devoid of
accumulated amyloid (Figure 6B)
. By 7 months of age,
GFAP-immunoreactive astrocytes were abundant and closely associated
with Aß deposits throughout the brain (Figure 6, C and G)
. As the
animals aged, astrocytosis and amyloidosis increased in parallel except
in some regions of the cortex of older animals, where the astrocytes
appeared dystrophic and no longer closely associated with the plaque
(Figure 6, E, F, and H)
. This has also been seen occasionally around
very compacted plaques in late stage human AD brain, as shown in Figure 7
. This figure shows sections from the
temporal cortex of an early onset familial AD (FAD) patient carrying
the E280A PS-1 mutation who has very advanced AD
pathology.14
The figure shows a plaque that is devoid of
GFAP-reactive astrocytes (Figure 7, D–F)
, lying close to plaques that
are still associated with reactive astrocytes (Figure 7, A–C)
. This
type of pathology around burned-out plaques has been observed in
several FAD and non-FAD brains, although it is rare (approximately 2 to
5% of very compact, cortical plaques in FAD brains lack an association
with GFAP-immunopositive astrocytes; CA Lemere, unpublished data). We
have now observed this type of astrocyte pathology in the cerebral
cortex of more than five PS/APP mice aged 12 to 18 months that have had
extensive and protracted amyloid accumulation.
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COX-2 expression was observed in neurons in the brains of both
transgenic (Figure 8B)
and nontransgenic
mice (data not shown). In the brains of PS/APP mice, COX-2 expression
was also identified in glial cells associated with Aß deposits
(Figure 8A)
, however, many deposits (including thioflavin-S-positive
fibrillar Aß deposits) were not associated with COX-2 immunoreactive
cells. Double immunostaining with COX-2 and GFAP confirmed the
astrocytic phenotype of the plaque-associated COX-2 immunoreactive
cells (Figure 8A
, inset).
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In the four PS/APP mice studied, C1q-immunoreactivity colocalized
with thioflavin-S positive fibrillar Aß (Figure 9A and D, B and E)
and was also
identified in cells associated with plaques. Double immunostaining with
a microglial marker (F4/80) and C1q shows that in the PS/APP mouse
brain, C1q colocalizes with activated microglia (Figure 9, C and F)
. We
did not observe neuronal staining of C1q in the PS/APP mice examined,
nor was immunoreactivity observed in nontransgenic littermates (data
not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the PS/APP mice, nonfibrillar amyloid accumulates to a greater
extent in the initial deposition period, but at later stages (after 1
year of age) fibrillar forms are increasingly represented. CD11b, a
170-kd integrin M chain protein (also referred
to as a Mac-1 chain), and GFAP are specific markers for activated
microglia and astrocytes, respectively. Activated microglia
(CD11b-immunoreactive) and astrocytes (GFAP-immunoreactive) were
colocalized with amyloid deposits, as has also been shown in other
transgenic models of amyloidosis.16
Both diffuse and
fibrillar deposits were associated with activated astrocytes and
microglia. In human AD brain, approximately half of the diffuse
(nonfibrillar) deposits had no activated microglia associated with
them, and a large percentage of the remainder had single microglia
colocalized with the diffuse plaques. In contrast, nearly all compact
deposits had single or multiple activated microglia embedded in their
core.17,18
The transgenic mouse models have plaque
morphologies more closely representing compact, dense cores, which may
explain why more plaques are associated with glial reactivity. In aged
PS/APP mice, the association of reactive astrocytes with deposits in
some regions of the cortex is diminished. Whether this population of
plaques represent the type of burned-out plaques that lack associated
reactive astrocytes seen occasionally in some late stage human AD
cases19
remains to be clarified, and the significance of
this type of plaque can only be speculated on.20-23
The accumulation of Aß leads to the activation of several pathways in
cells closely associated with the deposits. In the PS/APP mouse, as in
human AD brain, C1q is found associated with fibrillar Aß itself
(Figure 9)
.20
In PS/APP mice, C1q has also been identified
in microglia surrounding some of the deposits. C1q is the first
component of the classic complement pathway, and it is possible that
induction is evoked for the other members of the pathway (C2-C9) and
formation of the membrane-attack complex (MAC), although there are
currently few mouse complement-specific antibodies to test this
possibility. MAC has been cited as playing a role in
neurodegeneration,21,22
and one possible explanation for
why the mice show so little neurodegeneration is that some of the mouse
strains that comprise the PS/APP background are
complement-insufficient.23
The presence of C1q suggests
that the mice are able to mount an inflammatory response to Aß that
would result in the formation of MAC, although this has not been shown
in the mouse as of yet. In addition, the sequence of mouse and human
C1q are sufficiently divergent that it has been postulated that mouse
C1 will be activated less effectively by fibrillar Aß than human
C1.24
Although a direct comparison between mouse and human
C1 activation has not been performed in vivo, it is clear
that there is an abundance of mouse C1q in the PS/APP mouse plaques.
The cyclooxygenases catalyze the first step in the conversion of arachidonic acid into prostaglandins (PG), and the resulting PGs have a wide variety of physiological functions.25-27 Our observation of neuronal COX-2 immunoreactivity in normal and transgenic mouse brain is consistent with observations in other species.28 Although COX-2 is readily induced in cultured astrocytes and microglia treated with proinflammatory agents and growth factors,29-32 there are relatively few examples of glial COX-2 expression in vivo. Hirst et al33 showed increased COX-2 immunoreactivity in rat astrocytes following injection of kainic acid, and Tonai et al34 reported COX-2 immunoreactive astrocytes in rat spinal cord after IL-1 injection. COX-2 immunoreactive microglia have been reported in chronic inflammation associated with a murine prion disease model.35 To our knowledge, our findings represent the first report of COX-2 immunoreactive glial cells in a murine model of AD. It should be noted, however, that in the human AD brain, up-regulation of COX-2 has been noted in neurons but not in plaque-associated astrocytes. Initial studies suggest there is no gross up-regulation of neuronal COX-2 in plaque-dense areas of the PS/APP mouse brain, but quantitative studies have not yet been performed.
In conclusion, we have studied the inflammatory responses in doubly transgenic mice with abundant amyloid. Our longitudinal studies show that the accumulation of fibrillar Aß starts at 10 to 12 weeks and continues to increase up to at least 2.5 years of age. Microglia and astrocytes become activated in the presence of aggregated amyloid, leading to profound gliosis in older age. This progression correlates with activation of the classical complement pathway as shown by the presence of C1q both in plaques, and in activated microglia, and with the activation of the PG pathway as shown by the up-regulation of COX-2 in plaque-associated astrocytes.
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Acknowledgements |
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Footnotes |
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Supported by National Institutes of Health grants NIH AG-16573 (to A. J. T.), NIH AG-172116 (to K. D.), and NS 33553 (to M. K. O.).
Accepted for publication January 12, 2001.
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