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The Journal of Neuroscience, June 15, 2001, 21(12):4183-4187
Increased Lipid Peroxidation Precedes Amyloid Plaque Formation in
an Animal Model of Alzheimer Amyloidosis
Domenico
Praticò,
Kunihiro
Uryu,
Susan
Leight,
John Q.
Trojanoswki, and
Virginia M.-Y.
Lee
Center for Experimental Therapeutics and Department of
Pharmacology, Center for Neurodegenerative Disease Research, University
of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
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ABSTRACT |
Oxidative stress is a key feature in the Alzheimer's disease (AD)
brain and manifests as lipid peroxidation (LPO). Isoprostanes (iPs) are
specific and sensitive markers of in vivo LPO. To
determine whether amyloid  (A) deposition in vivo
is associated with increased LPO, we examined iP levels in a transgenic
mouse model (Tg2576) of AD amyloidosis. Urine, plasma, and brain
tissues were collected from Tg2576 and littermate wild-type (WT)
animals at different time points starting at 4 months of age and
continuing until 18 months of age. Levels of urinary
8,12-iso-iPF2 -VI were
higher in Tg2576 than in WT animals as early as 8 months of age and
remained this high for the rest of the study. A similar pattern was
observed for plasma levels of
8,12-iso-iPF2-VI. Homogenates from
the cerebral cortex and hippocampus of Tg2576 mice had higher levels of
8,12-iso-iPF2-VI than those from WT mice
starting at 8 months of age. In contrast, a surge of A 1-40 and
1-42 levels as well as A deposits in Tg2576 mouse brains occurred
later, at 12 months of age. A direct correlation was observed between brain 8,12-iso-iPF2-VI and A 1-40 and
1-42. Because LPO precedes amyloid plaque formation in Tg2576 mice,
this suggests that brain oxidative damage contributes to AD
pathogenesis before A accumulation in the AD brain.
Key words:
Alzheimer's disease; Tg2576 transgenic animal model; lipid peroxidation; isoprostanes; amyloid protein; plasma; urine
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INTRODUCTION |
Increasing evidence suggests that
oxidative stress plays an important role in the pathogenesis of
Alzheimer's disease (AD) (Markesbery and Carney, 1999 ; Praticò
and Delanty, 2000). The CNS is particularly vulnerable to
oxidative damage because it has a high energy requirement, a high
oxygen consumption rate, and a relative deficit of antioxidant defense
systems compared with other organs (Floyd, 1999). Oxidative damage to
the CNS predominantly manifests as lipid peroxidation (LPO) because of
the high content of polyunsaturated fatty acids that are particularly
susceptible to oxidation. Isoprostanes (iPs) are specific and sensitive
markers of in vivo LPO (Praticò, 1999). We have shown
recently that levels of a major iP,
8,12-iso-iPF2-VI, are
increased not only in specific AD brain regions (Praticò et al.,
1998) but also in the urine, plasma, and CSF of patients with a
clinical diagnosis of AD (Praticò et al., 2000). The specific
increase of 8,12-iso-iPF2-VI in
urine and plasma raised the possibility that it may be a useful peripheral biomarker for progression of AD. However, the mechanisms underlying the specific increase in
8,12-iso-iPF2-VI in AD brain and
bodily fluids are unknown, and it is unclear whether oxidative damage
is a cause or a consequence of amyloid (A) peptide (A)
accumulation or whether they are two independent processes.
To address this, we examined iP levels in a transgenic (Tg) mouse model
(Tg2576 mice) of AD amyloidosis, which develops characteristic AD-like
A brain deposits because of overexpression of a human amyloid
precursor protein (APP) transgene with a double mutation found in a
Swedish (APP swe) family with early onset AD (Hsiao et al., 1996).
Urine, plasma, and brain tissues were collected from these animals and
from wild-type (WT) littermate controls at different time points,
starting at 4 months of age and continuing until 18 months of age.
Biochemical analyses revealed that urine, plasma, and CNS levels of
8,12-iso-iPF2-VI are increased as
early as 8 months of age in Tg2576 mice compared with WT mice; this
preceded the onset of A deposition and a surge in CNS levels (A
1-40 and 1-42 levels) in the Tg2576 mice. These results suggest that
LPO may play an earlier role than previously anticipated in the
pathogenesis of AD.
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MATERIALS AND METHODS |
Animals. The genotype and phenotypic features of the
heterozygote APP swe (K670N, M671L) transgenic mice (Tg2576) and WT
littermates studied here have been described previously (Hsiao et al.,
1995, 1996). A total of 20 Tg2576 and 20 WT animals were studied. Mice were weaned at 4 weeks of age and kept on a chow diet; males were always separated from females for the entire study. Starting at 4 months of age, a 24 hr urine collection was performed every month in
metabolic cages (Nalgene, Rochester, NY), and blood was collected
retro-orbitally. Brain tissue was obtained from cohorts of these
animals at 4, 8, 12, and 15 months of age (three Tg mice and three WT
mice for each time point). Finally, brain collection for similar
studies was performed at 18 months of age (five Tg mice and five WT mice).
Isoprostane analysis. Urine was collected in plastic tubes
containing 0.01% of the antioxidant butylated hydroxytoluene (BHT). Samples were spiked with a fixed amount of internal standard
(d4-8,12-iso-iPF2-VI) extracted on a C18 cartridge column. The eluate was purified by thin-layer chromatography and finally assayed by negative ion chemical
ionization gas chromatography-mass spectrometry as described previously (Praticò et al., 1998, 1999, 2000). A urine aliquot (0.1 ml) was used for measurement of creatinine levels by a
commercially available, standardized, automated colorimetric assay
(Sigma, St. Louis, MO). Urine levels were expressed as nanograms per
milligram of creatinine. Blood was anticoagulated with trisodium
citrate (3.8%) and centrifuged at 3000 rpm for 15 min at 4°C to
obtain plasma. Plasma was spiked and treated as described above for
urine. Levels were expressed as picograms per milliliter. All of the assays were performed without knowledge of the genotype or age.
Tissue preparation. Animals were anesthetized and
killed according to the recommendation of the Panel on
Euthanasia of the American Veterinary Medical Association. They
were perfused intracardially for 30 min with ice-cold 0.9% PBS
containing 2 mm/l EDTA and 20 mM/l BHT, pH 7.4. Brains were removed, and one hemisphere was fixed by immersion in 4%
paraformaldehyde in 0.1 M PBS, pH 7.4, at 4°C
overnight, blocked in the coronal plane, and embedded in paraffin as
described previously for immunohistochemistry (Murai et al., 1998;
Nakagawa et al., 2000). The other hemisphere was gently rinsed in cold
0.9% PBS and then immediately dissected in three anatomical regions
(cerebral cortex, cerebellum, and hippocampus) for isoprostane and A measurements.
For isoprostane analysis, tissue was homogenized, and total lipids were
extracted using Folch solution (chloroform/methanol 2:1 vol)
(Praticò et al., 1999). Next, base hydrolysis was performed using
15% KOH at 45°C for 1 hr, and the total
8,12-iso-iPF2-VI levels were
measured as described above. Brain tissues were always analyzed in a
coded manner.
A sandwich ELISA. Brain tissues were
homogenized in 1 ml of 70% formic acid and centrifuged at 100,000 × g for 1 hr. The supernatant was recovered and neutralized
by a 20-fold dilution in 1 M Tris base buffer.
Samples were mixed with buffer EC [0.02 M sodium
phosphate, 0.2 mM EDTA, 0.4 M NaCl, 0.2% BSA, 0.05%
3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate, 0.4% Block-ace (Dainippon Suita, Osaka, Japan), and 0.05% sodium azide, pH 7.0] and analyzed directly using the Ban50-BA27 (for A
1-40) or Ban50-BC-05 (for A 1-42/43) sandwich ELISA systems as
described previously (Gravina et al., 1995). The values were calculated
by comparison with a standard curve of synthetic A 1-40 and A
1-42 (Bachem, King of Prussia, PA) as described previously (Turner et
al., 1996). Absorbance values were calculated for dilution and initial
weight. Results were expressed as picomoles per gram of tissue.
Analyses were always performed in duplicate and in a coded manner.
Immunohistochemistry. Serial 6-µm-thick paraffin sections
were cut throughout each brain and mounted on
3-aminopropyltriethoxysilane-coated slides. Sections were
deparaffinized, hydrated, rinsed with PBS, and pretreated with formic
acid (88%) for 10 min for antigen retrieval; with 3%
H2O2 in methanol for 30 min
to eliminate endogenous peroxidase activity in the tissue; and with the
blocking solution (5% normal horse serum in Tris buffer, pH 7.6).
Subsequently, sections were incubated with a biotinylated antibody
against A (4G8) (1:10,000 dilution) at 4°C overnight (Nakagawa et
al., 2000). Sections were then incubated with secondary antibody for 1 hr (dilution 1:1000) and reacted with horseradish
peroxidase-avidin-biotin complex (Vector Laboratories, Burlingame,
CA); immunocomplexes were visualized by using
3,3'-diaminobenzidine as the chromogen. Finally, the sections were
dehydrated with ethanol, cleared with xylene, and coverslipped with
Cytoseal. As a control, sections from the same group of animals were
treated in the same manner, except for the primary antibody. Analyses
were always performed in a coded manner.
Statistical analysis. Data for
8,12-iso-iPF2-VI and A 1-40 and
A 1-42 were expressed as the mean ± SEM. Isoprostane and A levels were assessed by ANOVA and subsequently by a
Student's unpaired two-tailed t test. Significance was set
at p < 0.05. Correlations between parameters were
tested by linear regression analysis.
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RESULTS |
Starting at 4 months of age, 24 hr urine collections were
performed monthly until the mice were 18 months old. Urinary
8,12-iso-iPF2-VI levels in Tg2576
mice were not different from the levels observed in WT mice until 6 months of age (Fig. 1); thereafter, these
levels increased in Tg mice compared with WT mice, and this increase became statistically significant (p < 0.01) by
8 months (Fig. 1). Urinary
8,12-iso-iPF2-VI levels continued
to increase, reaching a plateau by ~12 months of age (Fig. 1). A
similar pattern was observed for plasma
8,12-iso-iPF2-VI levels in Tg mice, with significantly higher levels at 8 months that reached a maximum by
9-10 months of age compared with WT mice (Fig.
2). Indeed, there were no significant
changes in urine or plasma
8,12-iso-iPF2-VI levels with
advancing age in the WT mice. Because previous studies documented the
onset of A deposition in Tg2576 mice at ~10-12 months (Hsiao et
al., 1995, 1996), these data and ours suggest that elevated
8,12-iso-iPF2-VI levels beginning
at ~7-8 months of age precede A deposition in Tg2576 mice. In
addition, the direct correlation between urine and plasma
8,12-iso-iPF2-VI levels
(r2 = 0.81; p < 0.01) suggests a common mechanism for LPO in Tg2576 mice.
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Figure 1.
Increased urinary levels of
8,12-iso-iPF2-VI in Tg2576 mice. Urinary
levels of 8,12-iso-iPF2-VI in
Tg2576 mice (closed circles) and wild-type littermates
(closed squares) from 4 until 18 months of age are shown
(*p < 0.01; **p < 0.001).
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Figure 2.
Increased plasma levels of
8,12-iso-iPF2-VI in Tg2576 mice. Plasma
levels of 8,12-iso-iPF2-VI in Tg2576 mice
(closed circles) and wild-type littermates
(closed squares) from 4 until 18 months of age are shown
(*p < 0.01; **p < 0.001).
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To determine whether urine and plasma reflect brain iP levels, Tg and
WT mice at 4, 8, 12, and 15 months of age (n = 3 Tg and
3 WT mice for each time point) as well as at 18 months of age
(n = 5 Tg and 5 WT mice) were killed, and the cerebral
cortex, hippocampus, and cerebellum were immediately dissected and
homogenized to measure total
8,12-iso-iPF2-VI levels. No
difference was observed between Tg and WT animals at 4 months of age in
all regions examined, but by 8 months of age, the cerebral cortex of Tg
mice had significantly higher
8,12-iso-iPF2-VI levels than that of WT mice, and this difference became increasingly significant at  12
months of age (Fig. 3A). These
values also directly correlated with plasma and urinary levels of
8,12-iso-iPF2-VI in the Tg mice
(r2 = 0.70, p < 0.01; r2 = 0.68, p < 0.001, respectively). A similar pattern was
observed for the hippocampus (Fig. 3B), but cortical
8,12-iso-iPF2-VI levels were higher
than those in the hippocampus (Fig. 3, compare A with
B) of the Tg mice, whereas
8,12-iso-iPF2-VI levels in the
cerebellum of Tg mice did not differ from those in WT mice (Fig.
3C).
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Figure 3.
Tg2567 mice have elevated
8,12-iso-iPF2-VI levels in brain
homogenates. Total brain cortex (A), hippocampus
(B), and cerebellum (C)
levels of 8,12-iso-iPF2-VI in Tg2576 mice
(filled bars) and wild-type littermates
(open bars) at different ages (*p < 0.01; **p < 0.003).
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To compare these data with brain levels of A 1-40 and 1-42, we
measured both species of A using a sensitive sandwich ELISA at the
same time points and in the same brain regions as for
8,12-iso-iPF2-VI. Although WT mice
showed undetectable (at 4, 8, and 12 months) or negligible (at 15 and
18 months) levels of A 1-40 and 1-42 (Table
1), the Tg2576 mice showed low cortical
levels of both peptides at 4 and 8 months but dramatically increased
cortical levels of A 1-40 and 1-42 by 12 months of age, which
continued to increase at 15 and 18 months of age (Table 1). A similar
pattern was observed for the hippocampus, although lower levels of A 1-40 and 1-42 were detected in the hippocampus compared with the cortex, and the cerebellum showed no significant increase in A 1-40
and 1-42 with aging in these Tg mice (Table 1). Interestingly, increased levels of
8,12-iso-iPF2-VI were found only in
Tg mouse brain regions with high levels of A 1-40 and 1-42 (i.e., the cortex and hippocampus, but not the cerebellum), whereas
cortical levels of A 1-40 and 1-42 were highly correlated with
cortical levels of 8,12-iso-iPF2-VI
(r2 = 0.77, p < 0.001; r2 = 0.64, p < 0.001, respectively) in the Tg mice (Fig.
4A,B).
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Table 1.
A 1-40 and A 1-42 levels in the cerebral cortex,
hippocampus, and cerebellum of Tg and WT littermates at different ages
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Figure 4.
Cortex A 1-40 and 1-42 highly correlate with
cortex 8,12-iso-iPF2-VI levels in Tg2576
mice. A correlation between the total cerebral cortex levels of
8,12-iso-iPF2-VI and A 1-40
(A) and A 1-42 (B) in
Tg2576 mice is apparent.
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Because a surge in brain A 1-40 and 1-42 levels correlates with
onset of A deposition (Hsiao et al., 1995, 1996), we monitored the
brains of the Tg mice for A plaques using immunohistochemistry, which revealed no A deposits at 8 months of age (Fig.
5A) but scattered A
deposits in the cerebral cortex and the hippocampus at 12 months of age
(Fig. 5B) and more abundant A deposits throughout the
neocortex and hippocampus by 18 months of age (Fig. 5C). No detectable immunoreactive A deposits were observed in any WT brains
(data not shown).
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Figure 5.
Tg2576 mice have an age-dependent increase in A
immunostaining. Immunohistochemical staining of a Tg2576 mouse brain at
8, 12, and 18 months of age is shown; the 4G8 antibody was used for
staining. Immunostaining was conducted on the same Tg2576 mice
as for brain A 1-40, A 1-42, and
8,12-iso-iPF2-VI measurements. All of the
panels are at the same magnification. Scale bar, 0.5 mm.
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DISCUSSION |
Our study provides compelling evidence that Tg2576, a mouse model
of AD amyloidosis, shows evidence of brain oxidative damage reflected
by an age-dependent brain and a systemic increase in LPO compared with
WT littermates. Significantly, we also observed that increased LPO, as
indicated by elevated levels of
8,12-iso-iPF2-VI, preceded onset of
significant A deposition in the Tg2576 mice. Thus, these data
provide important and novel insights into the pathogenesis of AD.
First, our observation that the Tg2576 mice showed an age-dependent
increase in LPO that correlated with subsequent elevations in brain
A levels suggests an early mechanistic role for brain oxidative
stress in AD pathogenesis. Although oxidative stress has been primarily
implicated in mechanisms of AD brain degeneration (Markesbery and
Carney, 1999; Praticò and Delanty, 2000), it has been difficult
to fully evaluate the contribution of oxidative processes to the
neuropathology of AD for several reasons. For example, only the recent
development of Tg mouse models of AD amyloidosis has enabled testing of
the oxidative stress and A hypotheses of AD pathogenesis (Guenette
and Tanzi, 1999; Janus et al., 2000; Takeuchi et al., 2000). The Tg2576
mice are well characterized models of AD amyloidosis (Hsiao et al.,
1996) because these mice develop extensive extracellular A deposits
and some associated AD-like neuropathology (Irizarry et al., 1997).
Indeed, previous immunohistochemical studies of brains from
20-month-old Tg2576 mice demonstrated evidence of oxidative stress
(Pappolla et al., 1998; Smith et al., 1998). However, it is difficult
to determine from these studies of older Tg mice whether oxidant stress
is important in the early evolution of AD amyloidosis, or a consequence
thereof. Thus, our study is novel and highly significant because it
provides the first quantitative analysis of oxidant stress and LPO in
an animal model of AD amyloidosis from onset to terminal stages of this
neuropathology. In addition, assessment of LPO in vivo has
been hampered by the use of assays with unsatisfactory specificity
and/or sensitivity (Gutteridge and Halliwell, 1990). iPs, a recently
described new family of lipids, are chemically stable isomers of
prostaglandins formed by a free radical peroxidation of polyunsaturated
fatty acids and are sensitive and specific markers of LPO in
vivo (Praticò, 1999). Thus, using this highly sensitive
marker enabled us to demonstrate increased biosynthesis of
8,12-iso-iPF2-VI in the urine,
plasma, and brain of Tg2576 mice as a function of advancing age.
Second, although signatures of oxidant damage have been detected in AD
brains, it remained unclear whether they reflected causes or
consequences of AD neuropathology. However, the early and continued
increase of cortical and hippocampal
8,12-iso-iPF2-VI levels in the
Tg2576 mice, and their correlation with subsequent elevations of A
and amyloid plaque formation in the same brain regions, would support
the hypothesis that LPO is not a consequence of AD amyloidosis.
However, our observation that there is increased production of
8,12-iso-iPF2-VI in the absence of
significant A deposition in Tg2576 mice does not completely
eliminate the possibility that immunohistochemically undetectable
microaggregates of extracellular or intracytoplasmic A could
initiate LPO in these mice. Indeed, the recent demonstration of rare
A plaques as well as scant amounts of formic acid-extractable A
in 8-month-old Tg2576 mouse brains prompts cautious interpretation of
our data with respect to whether LPO precedes or is linked to the
initial stages of AD-like amyloidosis in Tg2576 mice (Kawarabayashi et al., 2001). For example, the shift in A from SDS to formic
acid-soluble pools may reflect early evidence of A
fibrillation, including -pleated sheet formation
(Kawarabayashi et al., 2001), and it is possible that these subtle
changes augment LPO as reflected in the urine and plasma of the Tg2576 mice.
Third, the results presented here support emerging data from studies of
AD patients that indicate that increased levels of 8,12-iso-iPF2-VI in blood or urine
appear to herald the onset of AD (Praticò et al., 2000) and that
oxidative damage is integral to mechanisms of AD progression (Yan et
al., 1995; Zhang et al., 1997; Iadecola et al., 1999; Markesbery and
Carney, 1999; Praticò and Delanty, 2000). Indeed, our ability to
demonstrate a significant increase in LPO, as indicated by a rise in
8,12-iso-iPF2-VI levels without
similar increases A 1-40 and 1-42 as well as without appreciable
A deposition in 7- to 8-month-old Tg2576 mice, suggests that
monitoring this peripheral biomarker may be useful for confirming the
onset and following the progression of AD. Indeed, before the recent
demonstration of elevated
8,12-iso-iPF2-VI levels in the
urine and plasma of AD patients, there were no convenient peripheral
biomarkers for AD (Praticò et al., 2000). Thus, the early
detection of this iP in the Tg2576 mice provides additional evidence
for its utility as an AD biomarker and suggests that 8,12-iso-iPF2-VI levels may be
informative for assessing the response of AD patients to novel
therapies for this disorder. Nonetheless, additional studies are needed
to clarify the utility of measuring iPs for early diagnosis for AD, as
well as to assess the potential of antioxidant therapy to treat living
AD patients.
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FOOTNOTES |
Received Feb. 9, 2001; revised March 23, 2001; accepted March 28, 2001.
This work was supported in part by grants from the American Heart
Association, the National Institutes of Health (AG11542), and the
Oxford Foundation. V.M.-Y.L. is the John M. Ware Professor of
Alzheimer's disease. We thank Dr. Karen Hsiao for the Tg2576 mice.
Correspondence should be addressed to Domenico Praticò, Center
for Experimental Therapeutics, University of Pennsylvania, BRB II/III,
Room 812, 421 Curie Boulevard, Philadelphia, PA 19104. E-mail:
domenico{at}spirit.gcrc.upenn.edu.
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TOP
ABSTRACT
INTRODUCTION
Compound via MeSH
