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Neuronal Cyclooxygenase 2 Expression in the Hippocampal Formation as a Function of the Clinical Progression of Alzheimer Disease
Lap Ho, PhD;
Dushyant Purohit, MD;
Vahram Haroutunian, PhD;
James D. Luterman, PhD;
Fitzroy Willis, MS;
Jan Naslund, PhD;
Joseph D. Buxbaum, PhD;
Richard C. Mohs, PhD;
Paul S. Aisen, MD;
Giulio Maria Pasinetti, MD, PhD
Arch Neurol. 2001;58:487-492.
ABSTRACT
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Background Prior studies have shown that cyclooxygenase 2 (COX-2), an enzyme involved
in inflammatory mechanisms and neuronal activities, is up-regulated in the
brain with Alzheimer disease (AD) and may represent a therapeutic target for
anti-inflammatory treatments.
Objective To explore COX-2 expression in the brain as a function of clinical progression
of early AD.
Design and Main Outcome Measures Using semiquantitative immunocytochemistry, we analyzed COX-2 protein
content in the hippocampal formation in 54 postmortem brain specimens from
patients with normal or impaired cognitive status.
Setting and Patients Postmortem study of nursing home residents.
Results The immunointensity of COX-2 signal in the CA3 and CA2 but not CA1 subdivisions
of the pyramidal layers of the hippocampal formation of the AD brain increased
as the disease progressed from questionable to mild clinical dementia as assessed
by Clinical Dementia Rating. COX-2 signal was increased in all 3 regions examined
among cases characterized by severe dementia.
Conclusion Neuronal COX-2 content in subsets of hippocampal pyramidal neurons may
be an indicator of progression of dementia in early AD.
INTRODUCTION
A LARGE NUMBER of epidemiologic studies have indicated that the use
of nonsteroidal anti-inflammatory drugs (NSAIDs) may prevent or delay the
clinical features of Alzheimer disease (AD).1, 2, 3
The pharmacologic activity of NSAIDs is generally attributed to inhibition
of cyclooxygenase (COX), a rate-limiting enzyme in the production of prostaglandins.
Two distinct COX isoforms have been characterized: a constitutive form, COX-1,
and a mitogen-inducible form, COX-2.4 Characterization
of COX expression in the brain may be important to understanding the potential
therapeutic effect of NSAIDs and to devising optimal treatment regimens.
We5, 6 and others7, 8 found that the expression of neuronal
but not glial COX-2 is elevated in the AD brain, where it may be involved
in neuritic plaque (NP)6 and neurofibrillary
tangle (NFT) pathologic conditions.7 The role
of COX-2 in AD neurodegeneration is incompletely understood but may include
potentiation of ß-amyloid (Aß)6 and
glutamate9 neurotoxicity. In the present study,
we further explored COX-2 expression as a function of the clinical progression
of AD dementia.
MATERIALS AND METHODS
POSTMORTEM HUMAN BRAIN
Human postmortem brain specimens from cases with normal or impaired
cognitive status were obtained from the Alzheimer's Disease Brain Bank of
the Mount Sinai School of Medicine (MSSM).10
A multistep approach based on cognitive and functional status during the last
6 months of life was applied to the assignment of Clinical Dementia Rating
(CDR) scores as previously reported.11 Subjects
were divided into groups on the basis of their CDR scores as follows: 0, nondemented;
0.5, questionable dementia; 1, mild dementia; 2, moderate dementia; and 4
to 5, severe or very severe dementia. The extent of NFTs and NP neuropathologic
findings was assessed in accord with the Consortium to Establish a Registry
for Alzheimer's Disease (CERAD) neuropathologic battery.12
Multiple (5 in general) high-power (x200, 0.5-mm2) fields
were examined in each histological slide. The density of NFTs and NPs was
rated on a 4-point CERAD scale: 0, none; 1, sparse; 3, moderate; and 5, frequent
and severe. Visualization of Aß plaques was accomplished by using either
Bielschowsky's silver13 or thioflavin S staining.14 The density of NFTs and amyloid plaques was rated
on a 4-point CERAD scale: 0, none; 1, sparse; 3, moderate; and 5, frequent
and severe. The investigators were blind to the diagnosis of each case until
all quantitative analysis was completed and values were assigned to each specimen.
All assessment were approved by the MSSM Institutional Review Board. Autopsies
were performed after receiving consent from each subject's legal next of kin.
IMMUNOCYTOCHEMISTRY
Paraffin-embedded brain tissue sections encompassing the ventral hippocampal
formation (10 µm) were deparaffinized, hydrated in descending concentrations
of ethanol, and reacted with either an anti–human COX-2 (Cayman Chemical
Co, Ann Arbor, Mich; 1:500 dilution) or an anti–neuron-specific enolase
(NSE) (Dako Corp, Carpinteria, Calif; 1:1000 dilution) antibody overnight
(12 hours) at 4°C as previously described.6
The Vectastain ABC kit (Vector, Burlingame, Calif) was used in subsequent
steps to complete the diaminobenzidine staining as previously described.6 We previously showed that the anti–human COX-2
antiserum used in this study reacts specifically with purified human recombinant
COX-2 but not with human recombinant COX-1 peptide.6
Each immunocytochemistry experiment included 3 to 5 sets of hippocampal tissue
sections from different cases across all CDRs (CDR 0 to CDR 5). All specimens
were subjected to identical primary and secondary biotinylated antibody treatment
(from identical prediluted stocks) and diaminobenzidine staining development
conditions. Control tissue sections incubated in the absence of primary antibody
gave negative staining.6
The immunostaining densities of COX-2 or NSE over pyramidal layers of
the hippocampal formation were digitized with a high-resolution charge-coupled-device
camera (Sony, Tokyo, Japan) and quantified using Bioquant computer-assisted
densitometry (Biometrics, Inc, Nashville, Tenn) as previously described.6 Camera aperture and focus were adjusted to provide
an optimal image. The overall illumination was also adjusted so that the distribution
of relative gray values, ie, number of pixels in the image as a function of
gray value (0-255), fell within the limits of the system, typically within
30 to 220 gray value units, avoiding a floor or ceiling effect. Once established,
the setting remained constant for all the images acquired for all the immunocytochemistry
experiments. Therefore, when all the parameters were fixed, only tissue staining
intensities influenced the measured gray value. Images, acquired as described,
were digitized and stored for later analysis using an IBM-compatible computer.
Average gray value density measurements from individual hippocampal
neurons, which reflected immunostaining intensity, were made on digitized
images by delimiting the cellular area of interest free hand, using predetermined
criteria to define the region of interest. The intensity of the cellular COX-2
and NSE immunostaining per cell was quantified from approximately 6 to 8 frames
per section encompassing the hippocampal pyramidal layers; about 6 to 10 neurons
per frame were randomly quantified. The technician who performed these measurements
had no knowledge of the subject's CDR. To normalize any unevenness in lighting
across the field of view, background gray values were determined over the
white matter area (cortical white matter that gave no cellular staining) of
each individual tissue section and automatically subtracted from the gray
values over hippocampal pyramidal neurons of the corresponding tissue section.
All data were expressed as the percentage of the mean value for CDR 0 cases.
QUANTIFICATION OF Aß1-42 CONTENT
Cortical Aß1-42 was extracted and quantified as previously described.15 Briefly, frozen tissue samples (100 mg) were homogenized
in buffer containing 70% formic acid and 100-mmol/L betaine, and the soluble
Aß1-42 was quantified by enzyme-linked immunosorbent assay (ELISA) using
synthetic Aß1-42 (US Peptides, Fullerton, Calif) as a standard. Microtiter
plates were coated with 2-mg/mL monoclonal antibody 4G8 (Senetek, Maryland
Heights, Mo), which recognizes an epitope between residues 17 and 20 of Aß.
Unoccupied binding sites on the plates were blocked by incubation with casein.
Samples and standards were applied in quadruplicate and incubated for 48 hours
at 4°C. Following the Aß1-42 capture phase, the plates were reacted
with an Aß1-42 C-terminal–specific antibody followed by incubation
with a reporter antibody (alkaline phosphatase–conjugated anti–rabbit
IgG,  -chain–specific; JBL Scientific, San Luis Obispo, Calif).
The assay was developed using an alkaline phosphatase substrate (Attophos;
JBL Scientific), yielding a fluorescent product, and analyzed with a 96-well
fluorescence reader (CytoFluor; Millipore, Bedford, Mass). All samples were
analyzed in the linear range of the ELISA.
STATISTICS
Statistical analysis was performed using the Prism software package
(GraphPad Software, Inc, San Diego, Calif). Analysis of variance (ANOVA) was
used to evaluate differences in mean values among 3 or more groups, and the
Dunnett t test was used to test the significance
of differences in mean immunointensities. One-tailed or 2-tailed tests were
used as indicated. The Welch correction for unequal variance was applied when
appropriate. Correlation analysis between 2 variables was done using the Pearson
parametric method followed by 2-way analysis of P
value.
RESULTS
CASES
Age, postmortem interval, neuropathologic findings, and other information
are shown in Table 1. There was
no significant difference in mean age or mean postmortem interval (ANOVA; P = .40 and P = .82, respectively)
among the CDR groups. Within each CDR group, the average hippocampal neuronal
COX-2 immunostaining intensity did not differ among cases with or without
a previous history of NSAID or steroid use (not shown). Cases of patients
with a history of inflammatory conditions (eg, sepsis) were excluded from
the analysis.
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Characteristics of Study Subjects*
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COX-2 CONTENT IS ELEVATED AS A FUNCTION OF CLINICAL DEMENTIA
The characterization of immunostained hippocampal pyramidal cells as
neurons or glia was based on location within the pyramidal layers of the hippocampal
formation and cell morphologic structure and size. Neuronal COX-2 immunostaining
in pyramidal neurons of the hippocampal formation was compartmentalized to
the perikarya and processes (Figure 1A-B).
There was an overall elevation in COX-2 immunostaining in pyramidal neurons
of the CA3, CA2, and CA1 subdivisions of the hippocampal formation as a function
of the clinical progression of AD dementia by CDR (ANOVA; P<.05, P<.04, and P<.001, respectively) (Figure 2A-C).
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Figure 1. Elevated cyclooxygenase 2 (COX-2)
immunostaining in pyramidal neurons of the hippocampal formation in a cognitive
normal control brain and in a brain with moderate dementia. Representative
micrographs of COX-2 immunostaining among neurons in the CA3 subdivision of
the hippocampal pyramidal layer. A, Cognitive normal control brain with a
Clinical Dementia Rating score of 0. B, Moderate dementia brain with a Clinical
Dementia Rating score of 2. Arrows point to COX-2–immunolabeled cells.
Scale bar equals 20 µm.
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Figure 2. Cyclooxygenase 2 (COX-2) immunostaining
is elevated in the CA2 through CA3 pyramidal neurons of the hippocampal formation
of the brain with Alzheimer disease. Quantification of COX-2 signals in neuronal
cells of the CA3 (A), CA2 (B), and CA1 (C) subdivisions of the hippocampal
pyramidal layer are shown as a function of the Clinical Dementia Rating (CDR)
score. Bar graphs represent mean ± SEM of neuronal COX-2 immunostaining
intensity as a percentage of CDR 0 from approximately 6 to 8 frames encompassing
the hippocampal neuronal layers (about 6 to 10 neurons per frame). One-tailed
Dunnett t test vs CDR 0: asterisk indicates P <.05;
dagger, P <.005; and double dagger, P <.001.
Inset, Anatomical map depicting the 3 subdivisions within the pyramidal layer
of the hippocampal formation.
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Relative to cases with normal cognitive status (CDR 0), definitive elevation
of COX-2 immunostaining in neurons of the CA3 and CA2 layers was found in
cases characterized by mild dementia (CDR 1) (P<.05),
moderate dementia (CDR 2) (P<.05), and severe
dementia (CDR 5) (P<.005 and P<.001 for CA3 and CA2, respectively) (Figure 2 A-B and Figure 1
A-B). COX-2 immunostaining in the CA1 neuronal layer was unaffected in cases
characterized by mild and moderate dementia (Figure 2 C) and increased only in cases characterized by severe
(late) clinical dementia (CDR 5) (P<.005) (Figure 2 C). No detectable COX-2 elevation
was found in cases characterized by questionable AD dementia (CDR 0.5) in
any of the hippocampal regions examined (Figure 2 A-C).
There was no overall elevation in NSE immunostaining in pyramidal neurons
of the CA3, CA2, and CA1 subdivisions of the hippocampal formation as a function
of the progression of AD dementia based on CDR (ANOVA; CA3, P<.75; CA2, P<.55; CA1, P<.52).
Among individual cases, the increased COX-2 immunostaining in the neurons
of the CA3 and CA2 subdivisions positively correlated with cortical Aß1-42
content (CA3, r = 0.55, P<.005;
CA2, r = 0.57, P<.005)
(Figure 3A-B). No correlation between
COX-2 immunostaining in the CA1 subdivision and cortical Aß1-42 content
was found (Figure 3 C).
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Figure 3. Hippocampal cyclooxygenase 2 (COX-2)
immunostaining correlates with cortical ß-amyloid 1-42 (Aß1-42)
content. The COX-2 signal in the CA3 (A) and CA2 (B) subdivisions of the hippocampal
pyramidal layer correlates with cortical Aß1-42 content. Analyses were
conducted using a subset of 25 cases for which there is information on cortical
Aß1-42 content. Solid line represents the best-fit correlation between
COX-2 immunointensity and Aß1-42 content.
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ELEVATION OF COX-2 IMMUNOSTAINING CORRELATES WITH AD NEUROPATHOLOGIC
FINDINGS
There was an overall elevation of COX-2 immunostaining as a function
of NP and NFT pathologic findings in the CA3 subdivision of the hippocampal
formation (ANOVA; NP, P<.05; NFT, P<.005) (Figure 4A-B).
No elevation of COX-2 immunostaining as a function of NP and NFT neuropathologic
findings was found in the CA2 (ANOVA; NP, P = .10;
NFT, P = .06) (Figure
4 C-D) or CA1 (ANOVA; NP, P = .91; NFT, P = .07) (Figure 4
E-F) subdivisions.
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Figure 4. Cyclooxygenase 2 (COX-2) immunostaining
in the CA3 subdivision of the hippocampal formation correlates with the Consortium
to Establish a Registry for Alzheimer's Disease (CERAD) rating for neuritic
plaque (NP) and neurofibrillary tangle (NFT) pathologic findings. The COX-2
immunostaining intensities expressed as a percentage of CDR 0 for the CA3
(A and B), CA2 (C and D), and CA1 (E and F) are shown. Cases were stratified
by NP (A, C, E) or NFT (B, D, F) pathologic findings; 2-tailed Dunnett t test vs CERAD 0 (or 0 to 1): asterisk indicates P <.01
vs CERAD 0; dagger, P <.005. The number of cases evaluated
per group is presented in parentheses.
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Relative to cases characterized by no NP pathologic findings (CERAD
0), definitive elevation of COX-2 immunostaining in the neurons of the CA3
(Figure 4 A) subdivison was found
in cases characterized by moderate NP pathologic findings (CERAD 3) (P<.01). Elevated COX-2 immunostaining in the CA3 subdivison
(Figure 4 B) was also found in cases
characterized by severe NFT pathologic findings (CERAD 5) (P<.005) (Figure 4 B).
COMMENT
The goal of this study was to explore COX-2 expression as a function
of the early stages of clinical AD. We found that COX-2 is elevated in subsets
of neurons of the hippocampal formation during early dementia. In particular,
the intensity of COX-2 immunostaining in the neurons of the CA2 and CA3 but
not CA1 subdivisions of the pyramidal neuron layer of the hippocampal formation
rose as the disease progressed from questionable (CDR 0) to mild (CDR 1) clinical
stages. The changes in COX-2 immunostaining in the CA2 and CA3 subdivisions
of the hippocampal formation of cases characterized by mild dementia were
rather specific, since no detectable increase of NSE immunostaining was found.
Among individual cases, COX-2 signal in these neuronal layers correlated with
total cortical Aß1-42 content. When the cases examined were stratified
by neuropathology ratings, we found that the neuronal COX-2 immunostaining
was selectively elevated in the CA3 subdivison of the pyramidal neuron layer
of cases characterized by moderate and severe NP and NFT neuropathologic findings,
respectively, relative to cases characterized by CERAD 0. No overall elevation
of COX-2 immunostaining was found in the CA2 and CA1 subdivisions of the pyramidal
layer as a function of NP and NFT neuropathologic findings. COX-2 was elevated
(>50%) in the CA2 subdivision of cases characterized by moderate NP neuropathologic
findings; however, we point out that this finding must be viewed with some
caution in light of multiple comparisons. The data provide a rational basis
for targeting COX-2 activity in therapeutic trials aimed at the prevention
and treatment of early AD.
Several pharmaceutical company– and government-sponsored trials
are currently investigating the therapeutic potential of NSAIDs with regard
to AD.16 The results of 2 small pilot studies
of NSAIDs have been published; one suggested a neuroprotective effect with
indomethacin treatment,1 whereas the other
reported equivocal results with diclofenac.17
Current randomized, placebo-controlled trials testing the efficacy of NSAIDs
and other agents select subjects based on clinical criteria such as CDR score
and cognitive test results. The optimal design of such studies should consider
the expression of the presumed molecular target of the therapeutic intervention
at different clinical stages of disease. The presumed mechanism of the possible
beneficial effect of NSAIDs in AD involves COX inhibition. Thus, elucidation
of the role of COX-2 in mechanisms of neural degeneration in various clinical
stages of dementia will certainly aid the rational design of such trials.
We found that COX-2 immunostaining was preferentially increased in the
CA3 and, to a lesser extent, in the CA2 subdivision of the hippocampal pyramidal
layer of cases characterized by moderate and severe NP and NFT pathologic
findings. However, there was no increase in COX-2 immunostaining with neuropathologic
progression in the CA1 subdivision, which is also highly vulnerable to NFT
neuropathologic findings.18 This result suggests
that COX-2 regulation may involve qualitatively different mechanisms in specific
subsets of neurons of the hippocampal formation, consistent with previous
findings.7
In conclusion, the present study provides evidence for involvement of
COX-2 in hippocampal neuronal pathologic conditions during mild AD dementia.
Elevated expression of COX-2 in subdivisions of the hippocampal formation
is correlated with progression of clinical disease stage. Although controlled
trials of therapeutic interventions directed at COX-2 inhibition may thus
be appropriate at any stage of disease, these data suggest that trials that
include subjects at early stages may be particularly promising.
AUTHOR INFORMATION
Accepted for publication September 11, 2000.
This work was supported by grants AG13799, AG14239, and AG 16743 and
the Zenith Award and Temple Discovery Program from the Alzheimer's Association
(Dr Pasinetti), and by grants AG05138 (Alzheimer's Disease Research Center
of Mount Sinai School of Medicine) and AG02219 (Dr Mohs).
From the Neuroinflammation Research Laboratories (Drs Ho, Luterman,
and Pasinetti and Mr Willis) and Departments of Pathology (Dr Purohit) and
Psychiatry (Drs Haroutunian, Buxbaum, and Mohs), The Mount Sinai School of
Medicine, New York, NY; Department of Clinical Neuroscience, Karolinska Institutet,
Huddinge, Sweden (Dr Naslund); and Department of Neurology, Georgetown University
Medical Center, Washington, DC (Dr Aisen).
Corresponding author and reprints: Giulio Maria Pasinetti, MD, PhD,
Neuroinflammation Research Laboratories, Department of Psychiatry, Box 1229,
Mount Sinai Medical Center, One Gustave L. Levy Place, New York, NY 10029
(e-mail: gp2{at}doc.mssm.edu).
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