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Next Article 
Volume 17, Number 8,
Issue of April 15, 1997
pp. 2653-2657
Copyright ©1997 Society for Neuroscience
Widespread Peroxynitrite-Mediated Damage in Alzheimer's
Disease
Mark A. Smith1,
Peggy
L. Richey Harris1,
Lawrence M. Sayre2,
Joseph S. Beckman3, and
George Perry1
1 Institute of Pathology and 2 Department
of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106, and 3 Department of Anesthesiology, School of Medicine,
University of Alabama, Birmingham, Alabama 35233
 ABSTRACT
- INTRODUCTION
- MATERIALS AND METHODS
- RESULTS
- DISCUSSION
- FOOTNOTES
- REFERENCES
ABSTRACT 
Increasing evidence suggests that oxidative damage to proteins and
other macromolecules is a salient feature of the pathology of
Alzheimer's disease. Establishing the source of oxidants is key to
understanding what role they play in the pathogenesis of Alzheimer's
disease, and one way to examine this issue is to determine which
oxidants are involved in damage.
In this study, we examine whether peroxynitrite, a powerful oxidant
produced from the reaction of superoxide with nitric oxide, is involved
in Alzheimer's disease. Peroxynitrite is a source of hydroxyl
radical-like reactivity, and it directly oxidizes proteins and other
macromolecules with resultant carbonyl formation from side-chain and
peptide-bond cleavage. Although carbonyl formation is a major oxidative
modification induced by peroxynitrite, nitration of tyrosine residues
is an indicator of peroxynitrite involvement. In brain tissue from
cases of Alzheimer's disease, we found increased protein nitration in
neurons, including but certainly not restricted to those containing
neurofibrillary tangles (NFTs). Conversely, nitrotyrosine was
undetectable in the cerebral cortex of age-matched control brains. This
distribution is essentially identical to that of free carbonyls.
These findings provide strong evidence that peroxynitrite is involved
in oxidative damage of Alzheimer's disease. Moreover, the widespread
occurrence of nitrotyrosine in neurons suggests that oxidative damage
is not restricted to long-lived polymers such as NFTs, but instead
reflects a generalized oxidative stress that is important in disease
pathogenesis.
Key words:
Alzheimer's disease;
carbonyls;
glycation;
nitrotyrosine;
oxidative stress;
protein modification
INTRODUCTION
During the past 2 years, a number of oxidative
modifications have been found in association with the pathological
lesions of Alzheimer's disease. For example, advanced glycation end
products (AGE), lipid peroxidation adducts, and free carbonyls are
detected in both neurofibrillary tangles (NFTs) and senile plaques
(Ledesma et al., 1994 ; Smith et al., 1994, 1996a; Vitek et al., 1994;
Yan et al., 1994; Sayre et al., 1997). Such oxidative modifications of
proteins may define many of the unique properties of the lesions, in
particular their sparing solubility (Smith et al., 1996b) and association with degenerating neurons (Yan et al., 1994, 1995; Praprotnik et al., 1996). Nonetheless, despite this evidence, the
source of the oxygen radicals in vivo is not completely
understood. In this study, we examine this issue by determining whether
peroxynitrite, a powerful oxidant produced as a result of the
diffusion-limited reaction of superoxide with nitric oxide, is involved
in oxidation of proteins, lipids, and nucleic acids in Alzheimer's
disease. Peroxynitrite is a source of hydroxyl radical-like reactivity that directly oxidizes proteins and other macromolecules, with resultant carbonyl formation from side-chain and peptide-bond cleavage.
Peroxynitrite also causes the nitration of tyrosine residues, and this
can be used as an index of peroxynitrite involvement. Here we show that
nitrotyrosine immunoreactivity in Alzheimer's disease is increased in
the neuronal cytoplasm of the cerebral cortex within regions of
neurodegeneration, whereas it is undetectable in the same brain regions
of controls.
MATERIALS AND METHODS
Tissue. Hippocampal tissue, including the adjacent
entorhinal and neocortex from 16 cases of Alzheimer's disease (ages
60-91 years; average 79) and five control cases with no clinical or pathological history of neurological disease (ages 32-82 years; average 55), and cerebellar tissue from three Alzheimer's disease (ages 69-84) and two control (ages 64 and 74) cases with similar postmortem interval were fixed in methacarn (chloroform/methanol/acetic acid, 60:30:10) at 4°C overnight. The apolipoprotein E genotype of
the cases of Alzheimer's disease was  4/4 (n = 2); 3/4 (n = 3); 3/3 (n = 4); 2/3 (n = 1); unknown (n = 5).
After fixation, tissue was dehydrated through ascending ethanol and
embedded in paraffin, and 6-µm-thick sections were placed on
silane-coated slides (Sigma, St. Louis, MO).
Antibodies and immunocytochemistry. Affinity-purified rabbit
antiserum 4708 and mouse monoclonal antibodies 7A2 and 1A6, raised to
nitrated keyhole limpet hemocyanin, were used at a 1:100 dilution in
1% normal goat serum, 150 mM NaCl, 50 mM
Tris-HCl, pH 7.6 (Beckman et al., 1994). After incubation at 4°C for
16 hr, sections were immunostained with the peroxidase-antiperoxidase
method, with 3,3 -diaminobenzidine as cosubstrate (Sternberger, 1986).
Adjacent sections were immunostained with antiserum to ubiquitin
(Manetto et al., 1988) to confirm the identity and location of
pathological structures.
Controls consisted of (1) omission of the primary antibody; (2)
adsorption of the antibody with 50 µM nitrated BSA or 15 µM nitrated glycine-tyrosine-alanine (Gly-Tyr-Ala)
peptide at 4°C overnight before application to the section; and (3)
chemical reduction of nitrotyrosine by treating sections with 15 mM sodium hydrosulfite in 50 mM carbonate
buffer, pH 8.0, for 15 min at room temperature (Cuatrecasas et al.,
1968) before immunostaining. These procedures were performed in
parallel with the antisera to ubiquitin as controls against artifactual
inactivation of either primary or secondary antibodies from use of
sodium hydrosulfite-reduced sections and against nonspecific adsorption
with nitrated BSA or nitrated Gly-Tyr-Ala. After they were
immunostained, in some cases the sections were stained with Congo red
and viewed under cross-polarized light to show NFTs and amyloid-
deposits of senile plaques.
RESULTS
In all 16 cases of Alzheimer's disease, all three
antibodies to nitrotyrosine recognized neuronal cytoplasm and nuclei in hippocampal sections (Fig. 1A,C),
whereas, conversely, in the five control cases no specific structures
were stained (Fig. 1B,D). In sections taken from
cases of Alzheimer's disease that were counterstained with Congo red,
although the most intensely nitrotyrosine-positive neurons often
contained NFTs, many neurons lacking NFTs were also intensely stained
(Fig. 1C). Nuclei of glia were also stained in the cases of
Alzheimer's disease. No reaction was noted to extracellular NFTs,
amyloid deposits, or dystrophic neurites of senile plaques (Fig.
1C). This distribution is essentially identical to our
findings of increased free carbonyls in Alzheimer's disease that were
also localized to neuronal cell bodies and nuclei of both neurons and
glia but, as here, was restricted to regions of Alzheimer's disease
pathology (Smith et al., 1996a). Although differences were noted in the
intensity of immunoreactivity between cases of Alzheimer's disease, we
found no correlations to apolipoprotein E genotype, age, or postmortem
interval for those cases where this information was available.
Statistically, for the 21 cases analyzed, neuronal nitrotyrosine
immunoreactivity showed complete sensitivity for detecting Alzheimer's
disease and complete specificity in not detecting any of the control
cases. Additional studies will be required to evaluate whether the
specificity is unique to Alzheimer's disease or whether neuronal
nitrotyrosine immunoreactivity is also increased in other neurological
diseases.
Fig. 1.
Nitrotyrosine immunoreactivity is prominent in the
cytoplasm and nuclei of hippocampal neurons in cases of Alzheimer's
disease (A, C), whereas it is absent from control cases
(B, D). Immunoreactivity was often but not always more
intense in neurons containing NFTs (arrows) than in
those lacking NFTs, which were also intensely stained
(arrowheads). In contrast, amyloid- deposits ( )
and surrounding dystrophic neurites of senile plaques as well as
extracellular-NFTs (unmarked) were unstained. The location of NFTs and
amyloid- deposits was determined by Congo red counterstaining. In
contrast, in the cerebellum, nitrotyrosine immunoreactivity was present at the same level in cases of Alzheimer's disease (E)
as it was in controls (F). Scale bars: A,
B, 500 µm; C, D, 100 µm; E,
F, 50 µm.
[View Larger Version of this Image (195K GIF file)]
To understand whether increased nitrotyrosine represents a global
alteration of the oxidative stress in Alzheimer's disease, we studied
the cerebellum. In Alzheimer's disease, the cerebellum is spared from
neuronal degeneration. Pathology in the cerebellum is restricted to
diffuse amyloid- deposits. Cerebellum from controls and Alzheimer's
disease (Fig. 1E,F) showed nitrotyrosine
immunoreactivity in Purkinje cells, with no apparent difference between
controls and the cases of Alzheimer's disease. This finding supports
the idea that peroxynitrite-dependent damage is restricted to regions of Alzheimer's disease pathology, although the basal level of protein
nitration is dependent on the physiology of the neurons involved.
Nitrotyrosine immunoreactivity is specific, because (1) all three
antibodies recognized similar structures, with 7A2 showing the
strongest immunoreactivity; (2) no immunostaining was noted with
omission of the primary antibody; (3) preabsorption of the antibodies
with nitrated BSA or nitrated Gly-Tyr-Ala blocked recognition (Fig.
2); and (4) chemical reduction of nitrotyrosine with
sodium hydrosulfite abolished immunoreactivity (Fig. 3).
Importantly, there was no diminution of labeling with ubiquitin
antisera after hydrosulfite reduction of the section, indicating that
chemical reduction did not interfere with the
peroxidase-antiperoxidase reaction or antibody recognition of other
antigens (results not shown) (Kooy et al., 1995). Moreover, absorption
of ubiquitin antisera with nitrated BSA or nitrated Gly-Tyr-Ala had no
effect on consequent immunoreactivity (results not shown).
Fig. 2.
Nitrotyrosine immunoreactivity (A)
is completely blocked by adsorption with nitrated Gly-Tyr-Ala
(B). Adjacent serial section with a blood vessel is
indicated by in each section. Scale bar, 100 µm.
[View Larger Version of this Image (80K GIF file)]
Fig. 3.
Nitrotyrosine immunoreactivity (A)
is completely abolished by chemical reduction of nitrotyrosine with
sodium hydrosulfite (B). Adjacent serial section with a
blood vessel is indicated by in each section. Scale bar, 100 µm.
[View Larger Version of this Image (88K GIF file)]
DISCUSSION
This study demonstrates that tyrosine nitration is increased in
the neuronal cytoplasm as well as in the nuclei of both neurons and
glia in regions of Alzheimer's disease pathology. In stark contrast,
nitrotyrosine immunoreactivity is undetectable in the cerebral cortex
of controls. These findings implicate oxidants derived from nitric
oxide, most likely peroxynitrite, in the pathogenesis of Alzheimer's
disease. Although one of the major oxidative modifications of proteins
resulting from peroxynitrite is carbonyl formation from side-chain and
peptide-bond cleavage, electrophilic nitration of tyrosine phenols is a
signature of peroxynitrite involvement. Significantly, peroxynitrite
formation is dependent on nitric oxide as well as superoxide,
suggesting that nitric oxide synthase (NOS)-containing neurons or
microglia may play a role in oxidative damage. NOS production increases
after excitotoxicity, and it is suggested that neurodegeneration in
Alzheimer's disease is brought about by excitotoxicity resulting from
overstimulation (Gibson, 1989). NOS-containing neurons are relatively
spared in Alzheimer's disease (Hyman et al., 1992), perhaps suggesting
that NOS-containing neurons are better able to deal with oxidative stress than other neurons or, alternatively, that nitric oxide, from
NOS-positive neurons, diffuses to other cells and reacts with
superoxide to form peroxynitrite distal to the NOS-positive neurons.
Activated microglia, present in most senile plaques in Alzheimer's
disease (Cras et al., 1991), can also produce nitric oxide (Goodwin et
al., 1995; Nakashima et al., 1995; Paakkari and Lindsberg, 1995), and
it is of note that the involvement of nitric oxide produced by
microglia may provide an additional link to the lower incidence of
Alzheimer's disease with use of anti-inflammatory agents (Marx,
1996).
The strong association of peroxynitrite-related damage to regions of
pathology indicates that the source for superoxide must lie in close
proximity, because superoxide either reacts with tissue components
(Hausladen and Fridovich, 1994) or is readily dismutated by superoxide
dismutase, known to be associated with NFTs (Pappolla et al., 1992).
The pathological lesions are a likely source, because glycated proteins
(Yim et al., 1995), and particularly glycated  in NFTs, produce
superoxide (Yan et al., 1995). Therefore, this offers the possibility
that NFT-containing neurons play a role in the oxidative damage of
adjacent neurons. This hypothesis is consistent with the coordinate
neuronal degeneration seen in sites of Alzheimer's disease pathology
and its dependence on NFT formation.
Although all of the Alzheimer's disease cases examined show
nitrotyrosine immunoreactivity, there was some case-to-case variation in intensity of staining, suggesting that nitrotyrosine may represent a
specific pathological stage, that the epitope is often "masked," or
that the extent of involvement of nitrotyrosine is case-dependent. In
this latter regard, we found no relationship between the extent of
immunostaining and apolipoprotein E genotype. Significantly, our
results differ from a recent report using a different antibody and
formalin-fixed sections in which nitrotyrosine is described as being
limited to NFTs (Good et al., 1996). By marked contrast, using
methacarn-fixed material, which is not carbonyl cross-linked, we found
evidence of widespread neuronal oxidative damage in Alzheimer's disease. We were unable to obtain consistent nitrotyrosine
immunostaining using formalin-fixed material, a peculiarity that may be
restricted to brain, because nitrotyrosine has been localized in other
tissues with these same antibodies after formalin fixation (Beckman et al., 1994). In preliminary immunoblotting studies, we were unable to
establish whether there is a preferential nitration of specific neuronal proteins (our unpublished data). Nonetheless, by extending beyond the lesions, our findings suggest that oxidative damage in
Alzheimer's disease may result from a chronic abnormality of oxidative
balance that affects neurons regardless of whether they themselves
contain an NFT.
The distribution of nitrotyrosine presented here is essentially
identical to the distribution of free carbonyls (Smith et al., 1996a),
although additional studies will be necessary to establish the relative
contribution of peroxynitrite or other oxidants to protein oxidation.
The distinction between neurons, which show damage throughout the
cytoplasm and nucleus, and glia, whose damage is limited to the
nucleus, suggests cell type-dependent differences with respect to
oxidative damage. An understanding of these distinctions may provide an
insight into the neuronal specificity of cell degeneration in
Alzheimer's disease.
FOOTNOTES
Received Aug. 26, 1996; accepted Jan. 22, 1997.
This work was supported by National Institutes of Health (AG09287 and
NS22688), the American Health Assistance Foundation, the American
Federation for Aging Research, and a Daland Fellowship from the
American Philosophical Society.
Correspondence should be addressed to Dr. Mark A. Smith, Institute of
Pathology, 2085 Adelbert Road, Case Western Reserve University,
Cleveland, OH 44106.
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