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					Journal of Alzheimer’s Disease 2 (2000) 123–131                                                                  123
IOS Press




Vitamin E Prevents Alzheimer’s Amyloid β-Peptide
(1-42)-Induced Neuronal Protein Oxidation and
Reactive Oxygen Species Production

Servet M. Yatina,c, Sridhar Varadarajan1 and                 oxidant vitamin E. To test the hypothesis that vitamin
D. Allan Butterfielda,b,*                                    E’s protective effect may be due to inhibition of fibril
                                                             formation, electron microscopy studies were under-
a
                                                             taken. Vitamin E does not inhibit Aβ(1-42) fibril for-
  Department of Chemistry and Center of                      mation, suggesting that the neuroprotection afforded
Membrane Sciences, University of Kentucky,                   by this molecule stems from other processes, most
Lexington, USA                                               probably through the scavenging of Aβ-associated
b
  Sanders-Brown Center on Aging, Univer-                     free radicals. These results may have implications on
                                                             the treatment of Alzheimer’s disease.
sity of Kentucky, Lexington, USA
c
  Current address: ERPRC/Neurochemistry,
Harvard Medical School, Southborough,                        ABBREVIATIONS: Aβ, amyloid β-peptide; AD,
USA                                                          Alzheimer’s disease; APP, amyloid precursor protein;
                                                             DCF-DA, dicholorofluorescin diacetate; DNPH, 2,4-
                                                             dinitrophenylhydrazine; PBN, phenyl-α-tertbutyl-
Communicated by Mark S. Kindy                                nitrone; ROS, reactive oxygen species; SP, senile
                                                             plaques
ABSTRACT: Amyloid β-peptide (Aβ) is a 42-43
amino acid peptide known to accumulate in Alz-
heimer’s disease (AD) brain. We previously reported
that the neurotoxicity caused by Aβ is a result of its       INTRODUCTION
associated free radicals, which can play an important
role in generating oxidative stress. Aβ(25-35)-                 Alzheimer’s disease (AD) is the most com-
associated oxidative stress-induced neuronal death in        mon form of senile dementia, affecting more
vitro is well established by many laboratories, includ-
                                                             than 4 million people in the US alone. There are
ing ours. However, the oxidative stress-induced by
the full-length [Aβ(1-42)] peptide is not well investi-
                                                             360,000 new cases of AD annually in the United
gated. The protective effect of antioxidant vitamin E        States (22). Unfortunately, there is yet no ef-
in full-length peptide-induced oxidative stress also has     fective therapy available for this deadly disease.
not been reported. Here, we report that the increased        The only two approved drugs available for AD
protein oxidation, reactive oxygen species (ROS) for-        patients, both targeting the improvement of cog-
mation, and neurotoxicity induced by Aβ(1-42) in             nitive function with modest effect, are cholin-
primary rat embryonic hippocampal neuronal culture           esterase inhibitors. However, AD pathogenesis,
are prevented by the free radical scavenger and anti-        although not very well known, involves more
                                                             than a deficiency of neurotransmitters. The
* Corresponding author: D. Allan Butterfield, De-            presence of neurofibrillary tangles (32), extra-
partment of Chemistry, Center of Membrane Sciences           cellular deposits of insoluble amyloid that is the
and Sanders-Brown Center on Aging, 121 Chemistry-            main constituent of the senile plaques (SP) (36),
Physics Bldg., University of Kentucky, Lexington,            and neuronal and synapse loss (11,12) are the
Kentucky 40506-0055, USA, Tel.: +1 606 257 3184,             most pronounced pathological hallmarks of the
Fax: +1 606 257 5876, E-mail: dabcns@pop.uky.edu


1387-2877/00/$8.00 © 2000 – IOS Press. All rights reserved
124                                      S.M. Yatin et al. / Vitamin E

disease. Amyloid β-peptide (Aβ) is a 39-43                 stress. In the present study we investigated the
amino acid peptide derived from the proteolytic            role of the antioxidant and the free radical scav-
processing of β protein precursor (βPP). Evi-              enger vitamin E in protection against Aβ(1-42)-
dence supporting an essential role of Aβ in AD             associated free radical-induced protein oxidation,
includes: mutations in presenilin 1 and presenilin         reactive oxygen species formation (ROS), and
2 or βPP, that lead to early onset AD, are associ-         cell death in primary rat embryonic hippocampal
ated with excess Aβ deposition and oxidative               neuronal culture. In addition, the effect of vita-
stress (33,37); Down’s syndrome patients, who              min E on Aβ (1-42) fibril formation has been in-
carry three copies of chromosome 21, that en-              vestigated.
codes βPP, show AD pathology; transgenic ani-
mals overexpressing mutant βPP show increased
Aβ content in the brain and also exhibit oxidative         MATERIALS AND METHODS
stress (reviewed in (4)). AD brain is under ex-
tensive oxidative stress manifested by lipid per-          Materials and Experimental Treatment of
oxidation, increased protein oxidation in the SP           Cultures
rich region, hippocampus and frontal cortex,
compared to SP poor region, cerebellum, in AD                 Synthetic Aβ(1-42) (AnaSpec, San Jose, CA,
brain (38,19), DNA oxidation, mitochondrial                Lot # 5811) was dissolved in double-distilled
dysfunction and widespread peroxynitrite dam-              water immediately before use at a concentration
age (reviewed in (27,8)).                                  of 1 mg/ml. This stock solution was incubated
   Involvement of oxidative stress in the mecha-           for 24 h for the formation of Aβ aggregates and
nism of Aβ-induced neurotoxicity is supported by           fibrils (confirmed by electron microscopy, see
reports from several laboratories (2-4,7,8,16,18,          below), then added to cultures to produce a final
28,35,40,44-47). An Aβ-associated free radical             concentration of 10 µM. Pretreatment with
oxidative stress model for neuronal death in AD            50 µM vitamin E (pure α-tocopherol, Sigma) and
brain was proposed by our laboratory (7,8). In             treatment with Aβ(1-42) were performed in
this model, Aβ inserts into the plasma membrane            growth medium.
of neuronal or glial cells and oxygen-dependent,
reactive free radicals are formed. Those free              Neuronal Culture
radicals can attack the neuronal plasma mem-
brane, induce Ca2+ influx, disturb cell membrane              Hippocampal neuronal cultures were prepared
functions, increase protein oxidation, and induce          from SD E18 as described previously (44,45).
lipid peroxidation (reviewed in (8)). In agree-            Briefly, rat hippocampi were dissected and incu-
ment with our hypothesis Aβ(1-42) is reported to           bated for 15 min in a solution of 2 mg/mL trypsin
reduce Cu2+ to Cu+, i.e., an electron is derived           in Ca2+- and Mg2+- free Hanks’ balanced salt so-
from the peptide to reduce the metal ion forming           lution (HBSS) buffered with 10 mM HEPES
a peptide radical (20). Aβ neurotoxicity is re-            (Gibco). The tissue was then exposed for 2 min
ported to be attenuated by a number of antioxi-            to soybean trypsin inhibitor (1 mg/mL in HBSS)
dants and free radical scavengers, such as phenyl-         and rinsed 3 times in HBSS. Cells were dissoci-
α-tert-butylnitrone (PBN), EUK-8, estrogen, vi-            ated by trituration and plated at a density of 75-
tamin E and, idebenone (2-4,15,39,42,45,46).               100 cells/mm2. At the time of plating, the culture
The majority of these studies were performed               dishes contained 2 mL of Eagle’s minimum es-
using either Aβ(25-35) or Aβ(1-40), yet, Aβ(1-             sential medium (MEM;GIBCO) that also con-
42) is the major form of Aβ deposited early in             tained (final concentrations) 100 mL/L fetal bo-
AD brain (48). Thus it would be important to               vine serum (Sigma), 1 mM L-glutamine, 20 mM
establish whether Aβ(1-42) induces oxidative               KCl, 1 mM pyruvate, and 40 mM glucose. After
stress. If so, a chain-breaking antioxidant such as        a 5 h period to allow cell attachment, the original
vitamin E would be predicted to ameliorate this            medium was removed and replaced with 1.6 mL
                                       S.M. Yatin et al. / Vitamin E                                   125

of fresh medium of the same composition. After           with the membrane for 1 hour at 37 ºC. Mem-
a 24 h period, 1.2 mL MEM was replaced with              branes were washed after every step in washing
1.0 mL of Neurobasal medium (Gibco) contain-             buffer (PBS with 0.01% sodium azide and 0.2%
ing (final concentrations) 2% v/v B-27 or N-2            Tween 20) for 10 min at room temperature.
(Gibco) depending on the experiment, 2 mM L-             Washed membranes were developed using
glutamine (Gibco), 0.5% w/v D-(+) glucose. On            BCIP-NBT solution (SigmaFast tablets, Sigma).
the fifth day two-thirds of the Neurobasal me-           Western blots were analyzed using computer-
dium was replaced with freshly prepared Neuro-           assisted imaging (MCID/M4 software supplied
basal medium of the same composition. Cultures           by Imaging Research (St. Catharines, Ontario,
were maintained at 37 ºC in a 5% CO2/95% room            Canada)).
air-humidified incubator at all times. Cultures
were aged between 9–11 days before use in the            ROS Measurement
experiments described. In B27/Neurobasal, glial
growth is reported to be less than 0.5% of the              Intracellular reactive oxygen species were
nearly pure neuronal population (5).                     detected by the dicholorofluorescin diacetate
                                                         (DCF-DA) assay as described previously
Protein Carbonyl Measurement                             (44,45). Briefly, cells were loaded with DCFH-
                                                         DA (Molecular Probes, Inc.) by incubating in
   To determine the level of protein oxidation an        the non-CO2 incubator for 50 min, then were
Oxidized Protein Detection Kit (Oxyblot,                 washed three times with warm MSF buffer.
ONCOR Cat # S7150-Kit) was used as de-                   Fluorescence visualization was performed using
scribed previously (44,45). This kit is based on         a confocal laser scanning microscope (Molecu-
immunochemical detection of protein carbonyl             lar Dynamics, Sarastro 2000) coupled to an in-
groups derivatized with 2,4-dinitrophenyl-               verted microscope (Nikon). Fluorescence was
hydrazine (DNPH) (23).                                   excited at 488 nm and emission filtered using a
   Briefly, the samples were treated with 20 mM          510 nm barrier filter. Cells scanned were cho-
2,4-dinitrophenylhydrazine (DNPH) in 10% tri-            sen randomly.
fluoroacetic acid and derivatization-control so-
lution and incubated for 15–30 min. After de-            Cell Toxicity Studies
rivatization and neutralization with 2M tris/30%
glycerol and 19% 2-mercaptoethanol, cell pro-               Cell death was estimated by counting the
teins were separated by SDS-PAGE. Following              number of neurons that internalized Trypan blue
electrophoresis, proteins were transferred on            dye. After 48 h of incubation with or without
nitrocellulose for further immunoblotting analy-         vitamin E (50 µM final concentration) and Aβ
sis. Western blotting was performed according            (1-42) (10 µM final concentration), cells were
to the procedure adapted from Glenney (14).              rinsed three times with 1 mL PBS (pH, 7.4).
The transfer of proteins on nitrocellulose after         Trypan blue (Sigma) (0.4%) was added to cells
SDS-PAGE was completed in two hours. The                 together with 300 µL PBS and incubated for 10
transfer buffer was Tris-Glycine pH 8.5 with             min. Sixteen different microscopic areas were
20% methanol. After the transfer, membranes              counted for Trypan blue uptake, which indexes
were blocked in 3% BSA (in PBS with sodium               cell death. Data are given as percentages of cor-
azide 0.01% and Tween-20 0.2%) for 1 hour at             responding vehicle-treated control values.
room temperature. Rabbit anti-DNP antibody
from ONCOR Oxyblot kit (1:150 working dilu-              Aβ Fibril Formation Analysis
tion) was used as a primary antibody. Secon-
dary antibodies (anti-Rabbit IgG conjugated                 Fibril formation was assayed as previously de-
with alkaline phosphatase, Sigma) were diluted           scribed (8). Briefly, aliquots of 5 µL of the pep-
in the blocking solution 1:15,000 and incubated          tide solution incubated for 24 h were placed on a
126                                      S.M. Yatin et al. / Vitamin E

copper formvar carbon-coated grid. After 1–5               guishable between Aβ(1-42) and Aβ(1-42) in the
min of incubation at room temperature, excess              presence of vitamin E (Fig. 3), suggesting that
liquid was drawn off, and samples were counter-            vitamin E does not inhibit Aβ(1-42) fibril forma-
stained with 2% uranyl acetate. Air-dried sam-             tion.
ples were examined in a Hitachi 7000 transmis-
sion electron microscope at 75 kV.
                                                           DISCUSSION
RESULTS                                                       There are several therapeutic approaches that
                                                           target different alterations seen in AD. These
   A prediction of our model for neurotoxicity in          include acetylcholinesterase inhibition to prevent
AD brain (8) is that Aβ(1-42)-induced neurotoxic-          the loss of the neurotransmitter acetylcholine,
ity is a consequence of oxidative stress. If so,           estrogen therapy, anti-inflammatory drugs, Aβ
Aβ(1-42) is predicted to lead to ROS formation             aggregation inhibitors, and antioxidants. Most of
and to oxidation of neuronal proteins. Figure 1A           these approaches are in development and still
represents a field of untreated neurons showing            need extensive study in in vitro and in vivo sys-
low levels of ROS. Incubation of the neuronal              tems before clinical trials begin. A recent report
culture with 10 µM of Aβ(1-42) for 48 h signifi-           suggests that reduction in chain-breaking antioxi-
cantly increases ROS levels (Fig. 1B). Treatment           dants in patients with dementia may reflect an
of the rat embryonic hippocampal neuronal culture          increased free radical activity (13), supporting the
with 50 µM vitamin E 1 hour prior to 10 µM                 free radical hypothesis, for AD (8,27). We pre-
Aβ(1-42) administration prevented neurons from             viously showed that the antioxidant vitamin E is
increased ROS formation (Fig. 1C). Quantifica-             effective in preventing neuronal cells from
tion of the ROS data is shown Fig. 1D, which in-           Aβ(25-35)-associated free radical-induced oxida-
dicates that Aβ(1-42) increases ROS formation              tive stress in cell culture (45,46). Here we report
four-fold compared to control (*p < 0.001), and            that Aβ(1-42)-associated free radicals increase
that Aβ(1-42)-induced ROS formation is signifi-            neuronal ROS, protein oxidation and cell
cantly reduced by the free radical scavenger vita-         death. Each detrimental effect is inhibited by the
min E [**p < 0.005 vs. Aβ(1-42)] (Fig. 1D).                free radical scavenger vitamin E, supporting the
   Protein carbonyl levels, a measure of protein           free radical oxidative stress hypothesis of Aβ
oxidation (9), in neuronal culture treated with            with this full length peptide that many research-
Aβ(1-42) were found to be 168% those of controls           ers agree may be central to the pathogenesis of
(*p < 0.001 vs. control, Fig. 2). This increased           AD.
protein oxidation was suppressed to control levels            Consistent with our results and hypothesis, a
by pretreatment of cultures with vitamin E.                recent report demonstrated that AD patients with
   Cell survival was assessed by the Trypan blue           moderately severe impairment respond favorably
exclusion assay. Table 1 shows that 10 µM Aβ (1-           to α-tocopherol, as evidenced by slowing of the
42) significantly increased neuronal death                 progression of the disease (34). Another study
(p < 0.05). Consistent with the hypothesis that this       employing 633 persons over 65 years and older
Aβ (1-42)-induced cell death results from peptide-         suggests that use of the high dose vitamin E and
induced oxidative stress, pretreatment of neuronal         vitamin C supplements may lower the risk of AD
cultures with 50 µM vitamin E prevented cell               (30). Recently, a study reported by Brusco et al.
death (Table I).                                           (6) employing monozygotic twins with the diag-
   One possibility for protection by vitamin E             nosis of AD for 8 years showed that one of the
against Aβ (1-42)-induced cell death is that this          twins treated with the antioxidant melatonin had
antioxidant prevents Aβ fibril formation. Elec-            a milder impairment of memory function. These
tron microscopy was used to demonstrate that               reports not only suggest the involvement of oxi-
fibrils are equally obvious and not readily distin-        dative stress in AD indirectly but also point out
                                                  S.M. Yatin et al. / Vitamin E                                                            127


  A                                                                                                     B




  10 µm




                                                                           D
  C
                                                                                                        180



                                                                     DCF Fluo. (Ave. Pixel Intensity)
                                                                                                        160
                                                                                                                           *
                                                                                                        140

                                                                                                        120

                                                                                                        100

                                                                                                         80                          **
                                                                                                         60

                                                                                                         40

                                                                                                         20

                                                                                                          0
                                                                                                              Control Aβ(1-42) Vit E+Aβ(1-42)

Fig. 1. Inhibition of ROS formation by vitamin E, detected by the conversion of 2’,7’- dichlorofluorescin to 2’,7’-
dichlorofluorescein. Color images were taken by using a fluorescence confocal microscope. (A) A field of control
neurons showing low levels of background fluorescence. Color bar shows the fluorescence color code; moving up in
the color code indicates increase in ROS. (B) Neurons treated with 10 µM Aβ(1-42) for 48 h showing increase in
ROS. (C) Neurons treated with 50 µM vitamin E 1 h prior to 10 µM Aβ(1-42) addition. (D) Quantification of the
ROS formation indicates that vitamin E significantly prevents Aβ(1-42)-induced ROS formation. Error bars repre-
sent SEM values. *p < 0.001 vs. control, **p < 0.005 vs. Aβ(1-42) (n=3; each n is the average of 8-11 neurons).



                                                      Table 1
           Percent Survival Relative to Controls Following Aβ(1-42) Addition to Hippocampal Neuronal
                                   Cultures With or Without Added Vitamin E*

                                                            Aβ(1-42)                                          Aβ(1-42) Plus Vit. E
             MEAN +/- SEM                              76.1 +/- 4.56 (n = 6)                                   99 +/- 4.0 (n = 2)
             P-Value                                          < 0.05                                                  N.S.
            *Each n represents four replicates.
128                                        S.M. Yatin et al. / Vitamin E




Fig.2. The relative changes of protein carbonyl content in rat embryonic hippocampal culture treated with 10 µM
Aβ(1-42) and vitamin E + Aβ(1-42) for 48 hours. Error bars represent SEM values. Significance at *p < 0.001
(n = 4).




                Aβ(1-42)                                            Aβ(1-42) + Vit E
Fig. 3. Fibril formation assessed by electron microscopy. Aβ (1-42) at 1 mg/mL was dissolved in 1.7 µL DMSO,
with or without vitamin E, all of which was dispersed in a final volume of 500 µL deionized water. The final vita-
min E concentration was 50 µM. The mixture was incubated for 48 h at 37°C and EM images obtained as de-
scribed in Methods.
                                         S.M. Yatin et al. / Vitamin E                                       129

the potential beneficial effects of free radical           other antioxidants modulate oxidative stress as-
scavengers and antioxidants in the treatment of            sociated with Aβ.
AD.                                                           The results shown in the current study, ob-
   Inhibition of fibril formation has led to abro-         tained by using Aβ(1-42)-treated neuronal cul-
gation of Aβ-induced neurotoxicity (25), al-               tures, one of the in vitro systems with which
though others have challenged the proposed re-             potentially useful therapeutics for AD can be
quirement for fibrillization as a prerequisite for         studied, suggest that oxidative stress plays a
neurotoxicity (10). Recent reports suggest that            major role in Aβ(1-42)-induced cell death and
aggregated, soluble Aβ peptides, so-called proto-          can be prevented by the free radical scavenger
fibrils, are toxic (41), as are mixtures of soluble        vitamin E. The present study in an in vitro sys-
aggregated Aβ in the presence of certain proteins          tem is consistent with the in vivo findings of
but in the absence of fibrils (1,31). In the current       protein oxidation in AD brain (19,33), and in
study, vitamin E, although an inhibitor of Aβ(1-           transgenic C. elegans expressing Aβ(1-42) (47).
42)-induced neurotoxicity, protein oxidation, and          Additionally, this study shows that antioxidant
ROS formation, did not inhibit fibril formation.           treatment ameliorates Aβ(1-42)-induced oxida-
This result suggests that the neuroprotective ac-          tive stress, which may have relevance to AD
tion of vitamin E occurs through a different               treatment.
mechanism, the most obvious of which presuma-
bly is its scavenging of Aβ-associated free radi-
cals.                                                      ACKNOWLEDGEMENTS
   Vitamin E previously had been reported to
block Aβ-induced lipid peroxidation (21,26) and              This work was supported in part by grants
neurotoxicity (17,29,46). Here, it is shown that           NIH (AG-10836; AG-05119; AG-12423). The
vitamin E blocked Aβ(1-42)-induced neuronal                authors gratefully acknowledge Dr. Mark
protein oxidation, ROS formation, and cell death           Mattson and Dr. Jeffrey Keller for the use of the
confirming previous findings with the shorter              confocal laser scanning microscope.
fragment, Aβ(25-35) (39,45). Others showed
that vitamin E protects against Aβ(1-42)-induced
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