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The Journal of Neuroscience, August 1, 2000, 20(15):5709-5714
Ibuprofen Suppresses Plaque Pathology and Inflammation in a Mouse
Model for Alzheimer's Disease
G. P.
Lim1, 3,
F.
Yang1, 3,
T.
Chu1, 3,
P.
Chen1, 3,
W.
Beech1, 3,
B.
Teter1, 3,
T.
Tran1, 3,
O.
Ubeda1, 3,
K. Hsiao
Ashe5,
S. A.
Frautschy1, 2, 3, 4, and
G. M.
Cole1, 2, 3, 4
University of California Los Angeles, Departments of
1 Medicine and 2 Neurology, Los Angeles,
California 90095, 3 The Greater Los Angeles Veterans
Affairs Healthcare System, and 4 Veterans Administration
Medical Center Geriatric Research, Education, and Clinic Center,
Sepulveda, California 91343, and 5 Center for Clinical and
Molecular Neurobiology, Departments of Neurology and Neuroscience,
University of Minnesota, Minneapolis, Minnesota 55455
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ABSTRACT |
The brain in Alzheimer's disease (AD) shows a chronic inflammatory
response characterized by activated glial cells and increased expression of cytokines and complement factors surrounding amyloid deposits. Several epidemiological studies have demonstrated a reduced
risk for AD in patients using nonsteroidal anti-inflammatory drugs
(NSAIDs), prompting further inquiries about how NSAIDs might influence
the development of AD pathology and inflammation in the CNS. We tested
the impact of chronic orally administered ibuprofen, the most commonly
used NSAID, in a transgenic model of AD displaying widespread
microglial activation, age-related amyloid deposits, and dystrophic
neurites. These mice were created by overexpressing a variant of the
amyloid precursor protein found in familial AD. Transgene-positive (Tg+) and negative (Tg ) mice began receiving chow
containing 375 ppm ibuprofen at 10 months of age, when amyloid plaques first appear, and were fed continuously for 6 months. This
treatment produced significant reductions in final interleukin-1 and
glial fibrillary acidic protein levels, as well as a significant diminution in the ultimate number and total area of -amyloid deposits. Reductions in amyloid deposition were supported by ELISA measurements showing significantly decreased SDS-insoluble A. Ibuprofen also decreased the numbers of ubiquitin-labeled dystrophic neurites and the percentage area per plaque of
anti-phosphotyrosine-labeled microglia. Thus, the anti-inflammatory
drug ibuprofen, which has been associated with reduced AD risk in human
epidemiological studies, can significantly delay some forms of AD
pathology, including amyloid deposition, when administered early in the
disease course of a transgenic mouse model of AD.
Key words:
inflammation; cytokines; microglia; amyloid; Alzheimer; NSAID
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INTRODUCTION |
A chronic inflammatory response
characterized by activated microglia, reactive astrocytes, complement
factors, and increased inflammatory cytokine expression associated with
-amyloid deposits has been described in the brains of Alzheimer's
patients (Rogers et al., 1996 ). Evidence that this inflammation
contributes to the pathogenesis of Alzheimer's disease (AD) has
stemmed from 20 retrospective epidemiological studies and one
prospective, longitudinal study showing up to a 50% reduction in the
risk of AD associated with nonsteroidal anti-inflammatory drug (NSAID) consumption (Stewart et al., 1997; McGeer and McGeer, 1998). Ibuprofen was the most frequently used anti-inflammatory drug in these studies, taken by 39-50% of the subjects (Breitner et al., 1995; Stewart et
al., 1997). These studies raise the question of how NSAIDs, particularly the nonprescription medication ibuprofen, might influence CNS inflammation and AD pathology.
To address this problem, we used a previously described transgenic
mouse, Tg(HuAPP695.K670N-M671L)2576 (Tg2576), with amyloid pathology
and activated microglia (Hsiao et al., 1996; Frautschy et al., 1998).
These mice, which overexpress the 695 amino acid form of human amyloid
precursor protein (APP) containing a double mutation found in a Swedish
kindred with familial AD, display age-related hippocampal and
neocortical amyloid deposits first appearing at ~10 months of age, as
well as microglial activation, reactive astrocytes with increased glial
fibrillary acidic protein (GFAP), and dystrophic neurites.
Plaque-associated reactive microglia in these mice also show enhanced
staining for tumor necrosis factor- (TNF-) and interleukin-1
(IL-1) (Benzing et al., 2000), two pro-inflammatory cytokines
elevated in microglia of brains from AD patients (Dickson et al., 1993;
Griffin et al., 1998). To determine whether the development of
AD-related pathology is sensitive to ibuprofen treatment, we analyzed
brain tissue of ibuprofen-fed Tg2576 mice for changes in levels of
IL-1, GFAP, activated microglia, dystrophic neurites, amyloid
plaques, and detergent-insoluble and water-soluble amyloid -protein
(A). Ten-month-old Tg2576 mice were fed chow containing no drug or
ibuprofen (375 ppm) for 6 months. We found that a chronic dose of oral
ibuprofen reduced changes in levels of all these parameters, indicating
that ibuprofen can significantly interfere with the development of some
forms of AD pathology in this transgenic mouse model of AD.
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MATERIALS AND METHODS |
Animals. Ten-month-old male and female Tg2576 Tg+ and
Tg mice from 12 litters were randomly split between treatment groups. Tg+ mice were fed either chow (Research Diets, New Brunswick, NJ)
containing ibuprofen (Sigma, St. Louis, MO; 375 ppm; n = 9) or no drug (n = 8) for 6 months before being
sacrificed. Tg littermates were fed the same chow containing no drug
(n = 5) or ibuprofen (n = 9). One
animal was removed from the study for failure to gain weight. At the
time of sacrifice, neither the weights nor the ages of the mice were
significantly different. Animals were perfused before brain dissection
with 0.9% normal saline followed by HEPES buffer, pH 7.2, containing
protease inhibitors. Brain regions were dissected from one hemisphere
using mouse brain atlas coordinates (Franklin and Paxinos, 1997). One
brain hemisphere was lined up with the interaural line at 0 mm. From
the interaural line, vertical cuts were made at +3 and +0.72 mm, just
posterior to the mammillary bodies. Thalamic, cortical, and hippocampal regions, as well as entorhinal cortex and piriform cortex/amygdala sections, were dissected out and snap-frozen in liquid nitrogen. Biochemical measurements were performed in the hippocampus, entorhinal cortex, piriform cortex/amygdala, and residual cortex (cortex region
without frontal, entorhinal, or piriform areas). The other brain
hemisphere was fixed in 4% paraformaldehyde, processed in 10-20%
sucrose, frozen in liquid nitrogen, and sectioned (10 µm) for immunohistochemistry.
Tissue preparation. Tissue samples were homogenized in 10 wet weight volumes of TBS, pH 8.0, containing a cocktail of protease inhibitors (20 µg/ml each of pepstatin A, aprotinin, phosphoramidon, and leupeptin, 0.5 mM PMSF, and 1 mM EGTA).
Samples were sonicated briefly (10 W, 2 × 5 sec) and centrifuged
at 100,000 × g for 20 min at 4°C. The soluble
fraction (supernatant) was used for IL-1 or A ELISAs. To analyze
insoluble A, the SDS-insoluble pellet was solubilized and sonicated
in 70% formic acid. The extract was neutralized with 0.25 M Tris, pH 8.0, containing 30% acetonitrile and
5 M NaOH before loading onto the ELISA plate.
Sandwich ELISA for A. Monoclonal 4G8 against A17-24
(Senentek, Napa, CA) was used as the capture antibody at 3 µg/ml in 0.1 M carbonate buffer, pH 9.6, in a Dynex 96 well plate.
Blocking was completed with 2% bovine serum albumin in TBS. Processed
and neutralized samples were diluted with EC buffer (TBS containing 0.1 mM EDTA, 1% BSA, and 0.05%
3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid
(CHAPS), pH 7.4, containing protease inhibitors (20 µg/ml each of
pepstatin, aprotinin, phosphoramidon, and leupeptin, 0.5 mM
PMSF, 1 mM EGTA, and 2 mM EDTA). Equal volumes
of sample and detector antibody (biotinylated 10G4, against amino acids
5-13; 1:500) were loaded onto the wells overnight at 4°C. The
reporter system was streptavidin-alkaline phosphatase using AttoPhos
(JBL Scientific, San Luis Obispo, CA) as the substrate. Fluorescence of
the product was monitored at an excitation wavelength of 450 nm and an
emission wavelength of 580 nm.
Sandwich ELISA for IL-1. A polyclonal antibody against
mouse IL-1 (Endogen, Woburn, MA) was used as the capture antibody at
2 µg/ml in PBS in a Dynex 96 well plate. Blocking was completed with
2% bovine serum albumin in TBS. Equal amounts of sample (80 µg of
brain protein extract) were loaded onto the wells overnight at 4°C. A
monoclonal antibody against mouse IL1- (Endogen; 0.5 µg/ml) was
used as the detecting antibody. The development of the ELISA was
performed as described above for A. The minimum detectable quantity
of IL- was 0.5 pg under most conditions.
Immunoblot of GFAP. Brain homogenates (50 µg) were
electrophoresed on a 10% acrylamide gel under reducing conditions.
Proteins were transferred to a polyvinylidene difluoride
membrane (400 mA for 2 hr) before blocking in 10% nonfat dry
milk and 0.1% gelatin in PBS for 1.5 hr. Blots were incubated with
monoclonal antibodies against GFAP (Sigma) overnight at 4°C. After
three rinses, blots were incubated in HRP-conjugated goat anti-mouse
(1:10,000) for 45 min before development with SuperSignal (Pierce,
Rockford, IL). Bands were analyzed using densitometric software
(Molecular Analyst II).
Immunostaining and image analysis. Ten micrometer hemibrain
cryostat sections were cut from the posterior pole to the anterior margin of the hippocampus. Anti-phosphotyrosine (anti-PT) staining was
performed on cryostat sections from middle hippocampus as previously
described (Frautschy et al., 1998). To identify neuritic plaques,
sections were incubated overnight at 4°C (1:100) in "DAE" polyclonal antibody (anti-A1-13) made against synthetic peptides A1-13 and named after the first three amino acids of the A
peptide, Asp-Ala-Glu. Vascular amyloid was labeled overnight at 4°C
with a polyclonal antibody anti-A34-40 (Mak et al., 1994).
Dystrophic neurites were labeled overnight at 4°C with a polyclonal
antibody against ubiquitin (1:500; Dako, Carpinteria, CA). Slides were incubated in biotinylated goat anti-rabbit antibodies (1:1000) followed
by ABC reagent, each for 30 min at 37°C. Sections were developed
using peroxidase/DAB (Pierce). If sections were double-labeled for DAE,
immunostaining was developed with alkaline phosphatase substrate kit
III (Vector Laboratories, Burlingame, CA).
For image analysis of DAE and ubiquitin staining, we examined
immunolabeling from three coronal sections taken from anterior (bregma,
1.22 mm), middle (bregma, 1.70 mm), and posterior hippocampus (bregma, 2.80 mm) of Tg+ animals treated or untreated with ibuprofen. Specifically, residual cortex areas were defined as the cortical region
dorsal to the rhinal fissure, whereas entorhinal and piriform/amygdala regions were defined as areas ventral to the rhinal fissure on coronal
sections. All images were acquired from an Olympus Vanox-T (AHBT)
microscope with an Optronix Engineering LX-450A CCD video system. The
video signal was routed into a Macintosh computer via a Scion
Corporation AG-5 averaging frame grabber, and these digitized images
were analyzed with NIH Image public domain software. Custom Pascal
macro subroutines were written to calculate various parameters of DAE
and ubiquitin immunostaining. DAE parameters included number of
plaques, mean diameter, mean area, mean percentage area, and total area
of plaques. Ubiquitin parameters consisted of the number of small
particles (ranging from 3 to 25 µm), mean area and total area of
small ubiquitin particles, and percentage area of positively stained
particles per subregion. Analysis of anti-PT immunostaining was
performed using a quantitative ring analysis as previously described
(Frautschy et al., 1998).
Statistical analyses. A two-factor ANOVA (diet × region or transgene × region) was performed to analyze
differences in IL-1 and GFAP levels, A levels, and image analysis
data. Post hoc comparisons between regions were performed
using Fisher's protected least significant difference.
Bartlett's test for homogeneity of variances was also performed to
determine whether variances were equal. Some analyses required
logarithmic or square root transformations to establish homogeneity.
P values < 0.05 were considered significant.
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RESULTS |
Ibuprofen decreases IL-1 and GFAP levels in brains of
transgenic animals
IL-1 levels were quantified in brain supernatant extracted from
dissected brain regions in three groups of mice: Tg+ mice fed control
diet, Tg mice fed control diet, and Tg+ mice fed ibuprofen diet.
Dissected brain regions included hippocampus, entorhinal cortex,
piriform cortex/amygdala, and residual cortex. Results analyzed by
ANOVA revealed a significant transgene-dependent increase in IL-1 in
hippocampal and residual cortical regions (F(1,21) = 19.934; p = 0.0002) (Fig. 1A), but
not in entorhinal and piriform/amygdala areas
(F(1,20) = 2.696; p = 0.11). Hippocampus and residual cortex data were grouped together
because their variances were more similar to each other than entorhinal
and piriform cortex regions. Levels of IL-1 were elevated 2.4-fold
in hippocampus and 6.7-fold in residual cortex. ANOVA analyses showed
an overall treatment effect in all regions
(F(1,50) = 13.689; p = 0.0005) (Fig. 1B). There was also a significant
treatment-region interaction, indicating that reductions in IL-1
levels were dependent on region. Levels were decreased 75% in
hippocampus and 68% in residual cortex.
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Figure 1.
Effect of ibuprofen on IL-1 levels
and GFAP levels in Tg2576 brains. A, B, IL-1
measurements. ANOVA analyses were performed on measurements in Tg
mice fed control diet (n = 5), Tg+ mice fed control
diet (n = 8), and Tg+ mice fed ibuprofen
(n = 9). A, Measurement of IL-1
levels in hippocampus and residual cortex in 16-month-old Tg+ and Tg
mice. IL-1 protein levels were measured in TBS-extracted supernatant
fractions from Tg mice fed control diet (open bar) and
Tg+ mice fed control diet (hatched bar). Levels were
significantly increased in both regions in Tg+ compared to Tg
animals. B, Effect of ibuprofen on IL-1 levels in Tg+
mice. IL-1 was decreased by 64.7% across all regions in
ibuprofen-treated animals. Equality of variance was established with a
logarithmic transformation. C, D, GFAP
levels. C, Effect of transgene on GFAP levels.
Semiquantitative measurements of GFAP were performed on immunoblots of
Tg and Tg+ animals fed control diet. A highly significant 51.7%
elevation in Tg+ animals was found. D, Effect of
ibuprofen on GFAP levels in Tg+ mice. Treatment with ibuprofen
significantly decreased GFAP levels 20% across all regions in Tg+
animals. *p < 0.05. ***p < 0.001. Error bars indicate SE.
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Western analysis was used to determine the effect of ibuprofen
treatment on GFAP levels in Tg2576 mice. GFAP is a marker of astrocytosis that is elevated with age in mammals and is increased in
amyloid-forming APP transgenic mice (Laping et al., 1994; Irizarry et
al., 1997). ANOVA analyses demonstrated an overall transgene-dependent increase in GFAP levels (F(1,38) = 37.997; p = 0.001) (Fig. 1C), that was
region-dependent (F(3,38) = 7.693;
p = 0.004). GFAP levels were significantly lower in the
ibuprofen-treated group (F(1,48) = 4.891; p = 0.03), with no significant treatment-region
interaction (Fig. 1D). Regionally, the largest
transgene-associated increase in GFAP was observed in entorhinal cortex
(7.1-fold), whereas GFAP levels were reduced 76% with ibuprofen
treatment. Smaller (1.25- to 2-fold) transgene-dependent elevations in
GFAP were observed in other regions, whereas relatively lesser 15-25%
reductions were observed with ibuprofen treatment.
Microglial activation is significantly decreased in
ibuprofen-treated mice
Quantitative morphometric image analysis of anti-PT-labeled
microglia was previously used to demonstrate evidence of activated microglia clustered within and around plaques in aging Tg2576 mice
(Frautschy et al., 1998). This ring analysis, which quantifies PT-labeled microglia within four plaque-centered rings one to four
plaque radii from the center of A-labeled deposits, was performed on
cryostat sections stained for A (DAE, blue) and microglia
(PT, brown). Results of double-blind ring analysis of plaques in parietal and temporal cortex and hippocampus showed that the
percentage of area occupied by PT-labeled microglia was significantly
decreased in the ibuprofen group (Fig.
2A). Within four plaque
radii from plaque center, there was a 29% reduction (F(1,1472) = 56.208; p < 0.0001) in the area covered by activated microglia in the ibuprofen
group. Two-factor ANOVA analysis showed a significant treatment-ring
interaction, indicating that the ibuprofen-associated reductions of
microglial activation were dependent on distance from the A
deposits. Microglial activation decreased significantly within and
immediately adjacent to A-labeled plaques (rings 1 and 2;
p < 0.0001), but not significantly in outlying rings 3 and 4 (Fig. 2B).
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Figure 2.
Image analysis of
phosphotyrosine-labeled microglia. Histograms illustrate the percentage
of anti-PT-stained microglial area plus or minus 95% confidence
interval in and around A-stained plaque deposits in Tg+ mice on
either a control diet (n = 6 mice) or ibuprofen
diet (n = 5 mice) in the midhippocampal region
(bregma, 1.70 mm). An average of 37 ± 6.0 and 27.35 ± 7.6 plaques were counted per mouse in the control and ibuprofen diets,
respectively. A illustrates that ibuprofen induced a
29.3% reduction in the percentage of PT-stained area within
four plaque radii from A-stained plaque center, compared to the
control diet (p < 0.0001). Logarithmic
transformation was needed to establish homogeneity of variance.
B, Two-way ANOVA (treatment × ring) showed
significant treatment and ring effects as well as a significant
treatment-ring interaction (*p < 0.0001). This
histogram shows the greater reduction in PT-stained
microglia in radii outside the plaque compared to within the plaque
(each ring corresponds to one plaque radii). NS, Not
statistically significant.
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The effect of ibuprofen on microglial staining was more dramatic
outside the plaques (ring 2) than within the plaques (ring 1). This
effect is illustrated in Figure 3, in
which sections of piriform cortex/amygdala regions from Tg+ mice fed
control diet (D) and Tg+ fed ibuprofen
(E) were double-labeled for A (Vector,
blue) and phosphotyrosine (diaminobenzidine,
brown). In brains of Tg+ mice fed control diet in which PT
labeling was upregulated, A deposits (purple) are
surrounded by activated microglia (brown), which are more
numerous when close to (arrowheads) than when distal to
deposits (arrows). Compared to microglia surrounding plaques
in Tg+ mice fed control diet (F), fewer microglia
cluster around plaques in the Tg+ mice fed ibuprofen
(E).
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Figure 3.
Representative examples of immunostaining of
piriform cortex/amygdala regions from Tg+ mice fed control diet.
A and B show staining with
anti-A34-40 (A) and DAE
(B). Magnification for both is 25×. These
antibodies are rabbit polyclonal antisera made to synthetic peptides
representing A 34-40 (Mak et al. 1994) and A 1-13,
respectively. C shows staining with a rabbit polyclonal
antibody made to ubiquitin conjugates (Dako; magnification 25×). Tg+
mice fed control diet (D, magnification 100×) and Tg+
mice fed ibuprofen diet (E, magnification 132×) show
double labeling with a monoclonal anti-phosphotyrosine
(brown) followed by a light development of DAE
(blue). Arrowheads depict microglia
(within A-labeled plaque), whereas arrows show microglia
surrounding the plaque.
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Amyloid pathology is reduced by ibuprofen
To evaluate the effect of ibuprofen on amyloid and plaque
pathology, cryostat sections from anterior to posterior hippocampus were immunostained for A using a rabbit polyclonal antibody made to
synthetic A1-13 peptide ("DAE"). This antibody labeled plaques similarly to the commercially available mouse monoclonal antibody, 4G8
(Senentek) (data not shown), and more robustly than anti-A34-40 (Fig. 3A), but exhibited lower levels of endogenous IgG
artifacts associated with using mouse antibodies on mouse tissue. An
example of anti-A DAE immunostaining of piriform cortex/amygdala of
Tg+ mice fed control diet is shown in Figure 3B. Using NIH
Image public domain software, sections were analyzed for total plaque
counts, plaque size, and total area of plaques. The ibuprofen diet
group had significantly fewer (53%) overall plaque numbers compared to
the control diet group analyzed across all regions
(F(1,28) = 5.78; p = 0.02) (Table 1). The treatment group also
showed a reduction in the overall percentage and total area staining for A by 53% (F(1,28) = 3.603;
p = 0.07) and 56%
(F(1,28) = 5.515; p = 0.01), respectively, compared with the control diet group. A 57%
reduction in percentage area stained was observed in residual cortex of
ibuprofen-treated animals. Ibuprofen treatment did not affect plaque
size (mean area) (F(1,28) = 0.032;
p = 0.85). None of the treatment effects on amyloid
deposits showed a significant dependence on region.
In addition to analysis of A immunohistochemically, the effect of
ibuprofen on A levels in the opposite hemisphere was also analyzed
biochemically in dissected brain regions by an ELISA that detects total
A. "Soluble" A was first extracted with TBS and then in 2%
SDS, and the remaining SDS "insoluble" A was pelleted at
100,000 × g and extracted with 70% formic acid.
Insoluble A levels were significantly decreased overall by 39% in
the ibuprofen-treated mice (F(1,50) = 4.709; p = 0.03) (Fig.
4A). There was no
significant treatment-region interaction, indicating that the
reduction of insoluble A was fairly uniform across regions. Analysis
of individual regions showed the greatest reduction of 40% in the
residual cortex (54.7 ng of control diet vs 32.7 ng of ibuprofen diet),
with a consistent trend for reductions of 20-35% in every other
region. Two-factor ANOVA for soluble A similarly demonstrated that
levels were decreased overall by 34% in the ibuprofen-treated group
(Fig. 4B) (F(1,41) = 3.683; p = 0.06), with no significant treatment-region interaction. Regionally, strong trends toward ibuprofen-associated reductions in soluble A were found in all regions varying from 21 to
62%.
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Figure 4.
ELISA measurement of water-soluble and
SDS-insoluble A. These histograms illustrate A levels plus or
minus 95% confidence interval of formic acid-extracted (SDS-insoluble)
A (nanograms per total pellet) or soluble A (picograms per
microgram of protein) as measured by sandwich ELISA for dissected brain
regions of the Tg2576 brain. A two-way ANOVA (treatment × region)
showed significant treatment effects in insoluble A levels
(*p < 0.05) and regional effects
(p < 0.0001) with no treatment-region
interaction. Decreases in soluble A levels were consistent in all
regions but did not quite reach statistical significance
(p = 0.06).
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Ubiquitin-positive structures are significantly decreased in number
with ibuprofen
The effect of ibuprofen on the numbers and size of small
ubiquitin-positive profiles (neurites) was measured using image
analysis of cryostat sections immunolabeled with anti-ubiquitin from
mice fed either ibuprofen or control diet. A representative example of
this labeling is seen in Figure 3C. Anti-ubiquitin labeled no neurites in Tg- mice. Double labeling in Tg+ mice with anti-A or
synaptic markers revealed most ubiquitin staining in plaque-associated dystrophic neurites (data not shown). Image analysis (NIH Image) revealed that the numbers of small ubiquitin-labeled dystrophic neurites (ranging from 3 to 20 µm in diameter) were decreased by 48%
in the ibuprofen group (F(1,30) = 4.903; p = 0.03) (Table 2). Whereas the average size of small
particles was increased by 31%, the mean percentage of area occupied
by ubiquitin-positive small particles was significantly smaller with
ibuprofen (67%) than in the control group
(F(1,30) = 9.299; p = 0.005). Furthermore, the total area of ubiquitin-positive staining was
decreased by 51% in ibuprofen-treated animals
(F(1,30) = 7.058; p = 0.01), indicating that ibuprofen affected dystrophic neurite pathology. None of these treatment effects were region-dependent.
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DISCUSSION |
In this study we found that ibuprofen, a commonly used
nonprescription NSAID associated with reduced AD risk in
epidemiological studies, decreased inflammation, dystrophic neurite
formation, and amyloid deposition in aging transgenic mice expressing a
familial AD gene. This is the first report to demonstrate significant
effects of NSAID treatment on AD pathology in a transgenic Alzheimer's model.
The mechanism by which NSAIDs reduce the risk of Alzheimer's disease
is unknown. Two possibilities are: (1) NSAIDs decrease the inflammatory
reaction engendered by amyloid deposits, leading to diminished
neurotoxicity; and (2) NSAIDs attenuate the production of inflammatory
cytokines, such as IL-1 and transforming growth factor-
(TGF-), and products of reactive glia, such as apolipoprotein E
(ApoE), which have been implicated in amyloid deposition (Mrak et al.,
1995; Wyss-Coray et al., 1997; Harris-White et al., 1998). The results
of our study strongly support the latter hypothesis, because amyloid
deposition was dramatically suppressed with ibuprofen treatment.
Support for the former hypothesis was less obvious and more difficult
to assess, because traditional measures of neurotoxicity such as neuron
loss and a reduction in synaptic markers are not evident in
16-month-old Tg 2576 mice (Irizarry et al., 1997). However, the
percentage of plaque area occupied by microglia was smaller in treated
animals, suggesting a decreased inflammatory reaction per plaque. One
measure of neurotoxicity, the area occupied by ubiquitin-labeled
dystrophic neurites, was diminished 48% in ibuprofen-treated mice, but
this reduction in dystrophic neurites could be directly related to the
reduction in amyloid deposition because final plaque number and total
plaque area decreased 52-56% with ibuprofen treatment.
Ibuprofen also reduced both water-soluble and SDS-insoluble A by 34 and 40%, respectively, effects that were less pronounced that the
>50% decrease in amyloid plaque deposition. The inclusion of vascular
A in the ELISA, but not in the image analyses of amyloid deposits,
may have limited the size of the ibuprofen effect in the biochemical
measurements of A relative to the immunohistochemical measurements.
Because A40 comprises >50% of the total A in Tg2576 mice (Hsiao
et al., 1996) and is the major component of vascular amyloid, we
stained vascular amyloid with anti-A34-40 in Tg+ mice and found
ibuprofen had no significant effect on the amount of vascular A40
immunoreactivity in meningeal and plexus vessels (data not shown).
The observed reduction in soluble A by ibuprofen treatment at an
early stage might contribute to a decrease in amyloid seeds and
subsequent plaque numbers. This could occur through its influence on
microglia, which have been proposed to affect the formation or
clearance of small, diffusible A oligomers or multimers (Ard et al.,
1996), or through an effect on ApoE, TGFs, or other cytokine circuits with diffusible effectors (Griffin et al., 1998). In AD brain,
soluble A is sixfold higher than in control brains and contains both
monomers and oligomers (10 to >100 kDa), hypothesized to be seeds or
precursors to insoluble, filamentous amyloid (Kuo et al., 1996).
Soluble A levels in residual cortex of 16-month-old untreated Tg2576
mice averaged 174.6 pmol/gm tissue but were less than 60 pmol/gm tissue
in 3- to 4-month-old Tg2576 mice (data not shown). The attenuation of
this rise by ibuprofen in Tg2576 mice supports the possibility that
small A aggregates or oligomers were reduced by this treatment. In
humans a greater impact of NSAID treatment at an earlier stage of AD
has been suggested by two epidemiological studies, which found a
greater risk reduction when NSAID use was begun more than 2 years
before diagnosis (Stewart et al., 1997; In't Veld et al., 1998).
Conversely, the lack of effect of NSAIDs on plaque numbers in the
mesial temporal cortex of clinically normal elderly control and
arthritic patients (Mackenzie and Munoz, 1998) might be explained by
the fact that plaques stop accumulating rapidly with age in this brain
area (Mackenzie et al., 1995), obscuring any potential effect on plaque
initiation that NSAID consumption could produce.
Griffin et al. (1998) and Sheng et al. (1996, 1998) argue that
plaque-associated IL-1 elevations in Down's syndrome and AD brains
play an important role in cytokine circuits promoting GFAP and S100
overexpression, APP synthesis, astrocyte activation, dystrophic neurite
formation, and neuritic plaque pathogenesis. In particular, dystrophic
neurites, the hallmark of neuritic plaques, appear closely correlated
with activated microglia and are hypothesized to be induced by
cytokines from activated microglia. Increased expression of IL-1 has
also been implicated in memory deficits and reduced long-term
potentiation in aging rat hippocampus (Lynch, 1998). Our results show
that chronic administration of ibuprofen prevents transgene- and
age-related increases in brain levels of the inflammatory cytokine
IL-1 in Tg2576 mice. This treatment also diminished the
proliferation of activated microglia associated with amyloid plaques
and decreased the number of ubiquitin-positive dystrophic neurites in
plaque-forming regions of these mice. A significant reduction in
overall dystrophic neurite formation may have resulted from a decrease
in amyloid plaque number and a weakened microglial response surrounding
plaques. Neuritic plaques are an important endpoint because increased
density of neocortical neuritic plaques is associated with even very
mild dementia (Haroutunian et al., 1998) and correlates with cognitive
deficits (Nagy et al., 1995).
Interestingly, ring analyses of the microglial response to ibuprofen
within and around plaques showed a more marked attenuation in ring 2 just outside plaques than in ring 1 located within plaques of 40 and
25%, respectively. This positional effect is consistent with a report
showing NSAIDs markedly reducing microglia numbers outside and
surrounding plaques in elderly, nondemented controls and arthritic
patients, but producing a smaller effect on microglia in "close
physical association with the plaque" (Mackenzie and Munoz,
1998).
The ibuprofen dose our mice received was estimated to be ~56 mg/kg of
ibuprofen per day, a dose considered high enough to both inhibit
cyclooxygenase (COX) and stimulate peroxisome proliferator-activated receptors- (PPAR-s), the two main pharmacological targets of ibuprofen and other NSAIDs (Lehmann et al., 1997; Combs et al., 2000).
Because both COX and PPAR expression are increased in Alzheimer
brains (Kitamura et al., 1999), it is likely that at least some effects
of ibuprofen on AD pathology are mediated through changes in the
activities of these enzymes. COX inhibitors decrease production of
prostaglandins, a major extracellular signal that can induce neuronal
degeneration (Prasad et al., 1998). PPAR- agonists inhibit
inflammatory cytokine synthesis by monocytic lineage cells, including
IL-1, and block A-stimulated expression of IL-1 and TNF- by
microglia, and thus may be important in controlling A-mediated
microglial inflammatory responses (Combs et al., 2000). Whether lower,
safer doses of ibuprofen, such as 5-20 mg/kg (400-1000 mg/d in
humans), are effective in delaying AD pathogenesis remains to be
tested. If COX inhibition is the critical step, doses in this range,
which are known to diminish centrally mediated nociceptive activity (Ferrari et al., 1990; Lotsch et al., 1997) and decrease prostaglandin levels in the mouse brain (Fitzpatrick and Wynalda, 1976), but are less effective in ameliorating peripheral inflammation in arthritis (Garcia Rodriguez, 1997), may nevertheless be beneficial in AD.
Our results show that a widely used NSAID, ibuprofen, can significantly
delay both CNS inflammation and Alzheimer plaque deposition in the
Tg2576 mouse model for AD. An effect at an early stage of plaque
formation is proposed and is consistent with the reduced AD risk
associated with chronic NSAID consumption in epidemiological studies.
Studies in this and other mouse models will better define the choice of
NSAIDs, appropriate target stages of disease, and doses for AD
prevention or treatment in humans.
| |
FOOTNOTES |
Received April 1, 2000; accepted May 5, 2000.
This work was supported by National Institute on Aging Grants AG13471
(G.M.C.) and AG15453 (K.H.A.), Veterans Affairs Merit, the Alzheimer
Association, the Elizabeth and Thomas Plott Family Foundation, and the
Katherine and Benjamin Kagan Alzheimer's Treatment Program. We thank
Boris Oks, Robert McBean, and Ulises Garcia for their excellent work
genotyping the transgenic mice. We also thank Mychica Simmons for
assistance with the amyloid and ubiquitin image analysis. We are
grateful to Dr. Judith Harker for her help with the statistical analyses.
Correspondence should be addressed to Dr. Greg M. Cole, Sepulveda VAMC
GRECC 11E, University of California Los Angeles, Department of
Medicine and Neurology (SFVP), 16111 Plummer Street, Sepulveda, CA 91343. E-mail: gmcole{at}ucla.edu.
| |
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TOP
ABSTRACT
INTRODUCTION
