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Lipid peroxidation in neurodegeneration: new insights into
Alzheimer's disease
SoÈnke Arlta, Ulrike Beisiegela and Anatol Kontushb
Imbalances of oxidative homeostasis and lipid peroxidation have
been revealed as important factors involved in
neurodegenerative disorders such as Alzheimer's disease. The
brains of patients with Alzheimer's disease contain increased
levels of lipid-peroxidation products such as 4-hydroxy-2-
nonenal or acrolein, and enhanced lipid peroxidation can also
be detected in cerebrospinal fluid and plasma from such
patients. Recent research revealed that the interplay of
transition metals, amyloid-b peptide and lipid peroxidation might
be responsible for increased oxidative stress and cell damage in
this disease. In particular, the contrasting roles of amyloid-b
peptide, as a possible transition metal-chelating antioxidant for
lipoproteins and a pro-oxidant when aggregated in brain tissue,
has been the focus of discussion recently. In this context, lipid
peroxidation has to be seen as an important part of the
pathophysiological cascade in Alzheimer's disease, and its
measurement in body fluids might serve as a therapy control for
Alzheimer's disease and other neurodegenerative diseases. Curr
Opin Lipidol 13:289±294. # 2002 Lippincott Williams & Wilkins.
a
Department of Molecular Cell Biology, Institute for Medical Biochemistry and
Molecular Biology, University Hospital Hamburg-Eppendorf, Hamburg, Germany and
b
INSERM Unit 551, Pitie Hospital, Paris, France
Correspondence to SoÈnke Arlt MD, Department of Molecular Cell Biology, Institute for
Medical Biochemistry and Molecular Biology, University Hospital Hamburg-
Eppendorf, Martinistraûe 52, D-20246 Hamburg, Germany
Tel: +49 40 42803 3917; fax: +49 40 42803 4592;
e-mail: arlt@uke.uni-hamburg.de
Current Opinion in Lipidology 2002, 13:289±294
Abbreviations
AD Alzheimer's disease
CSF cerebrospinal fluid
HNE 4-hydroxy-2-nonenal
LPO lipid peroxidation
# 2002 Lippincott Williams & Wilkins
0957-9672
Introduction
Oxidative stress is thought to be an important mechan-
ism in many degenerative diseases including athero-
sclerosis [1], diabetes [2] and neurodegenerative
disorders [3]. It can affect biomolecules including
proteins, DNA and lipids and may lead to consecutive
functional disturbance and cell death. The human brain
is especially vulnerable to oxidative stress because of its
high oxygen consumption as well as high concentrations
of easily oxidizable polyunsaturated fatty acids. In
particular, markers of lipid peroxidation (LPO) have
been found to be elevated in brain tissue and body ¯uids
in several neurodegenerative diseases, and the role of
LPO has been extensively discussed in the context of
the pathogenesis of Alzheimer's disease (AD), Parkin-
son's disease, amyotrophic lateral sclerosis, and prion
diseases [3]. It is controversial as to whether elevated
LPO markers in neurodegenerative disorders represent a
feature of the distinct pathomechanisms of these
diseases or are merely a non-speci®cally occurring
epiphenomenon. Whilst our knowledge about the exact
role of LPO in the pathomechanisms of most of the
neurodegenerative diseases remains fragmentary, at least
for AD there seems to be a direct link between the
putative disease-causing agent, amyloid-b peptide, and
LPO processes occurring in the brain and the cerebrosp-
inal ¯uid (CSF) which might lead to a deeper under-
standing of this disease.
Mechanisms of lipid peroxidation
As the uptake of oxidized low-density lipoproteins into
macrophages via the scavenger receptor pathway repre-
sents a key event in the development of artherosclerosis,
most of our knowledge about LPO has been gained from
extensive studies of plasma-lipoprotein oxidation [1].
The main substrates for LPO present in lipoproteins as
well as in membranes are polyunsaturated fatty acids,
primarily linoleic acid, arachidonic acid and docosahex-
aenoic acid. LPO is initiated by reactive oxygen species,
for example, the highly reactive hydroxyl radicals,
peroxynitrite, or hypochlorite. The LPO reaction starts
with the extraction of a relatively weakly bound
hydrogen ion of a double-bond-bearing carbon atom.
After the addition of oxygen, a lipid peroxyl radical is
formed and a chain reaction can be started by the
oxidation of another fatty acid (propagation). LPO is
thought to be especially dangerous, because by this
mechanism one free radical might damage several
289
290 Lipid metabolism
polyunsaturated fatty acid molecules. Oxidized polyun-
saturated fatty acids are further degraded to toxic end-
products including 4-hydroxy-2-nonenal (HNE), acro-
lein, malondialdehyde, and other short-chain aldehydes.
HNE has been shown to disrupt neuronal outgrowth and
neuronal microtubule organization [4], while acrolein is
even more toxic than HNE and is capable of damaging
mitochondria [5]. Further stable end-products of LPO
are F2-isoprostanes, which are speci®c products of non-
enzymatic oxidation of arachidonic acid [6].
Chain-breaking antioxidants such as the most important
lipophilic antioxidant, vitamin E (a major form of which
is a-tocopherol), are capable of aborting the LPO chain
reaction and in this action are supported by co-
antioxidants such as the most important hydrophilic
antioxidant, vitamin C (ascorbate) [7].
There is a wide range of methods capable of re¯ecting
increased LPO in vivo: these include the determination
of polyunsaturated fatty acids as substrates for LPO, the
measurement of in-vitro production of lipid hydroper-
oxides [8] (intermediate products of LPO) in body ¯uids
as an index of the oxidative resistance of lipoproteins,
and measurement of the stable products of LPO (HNE,
malondialdehyde and F2-isoprostanes). Recently, acro-
lein, which is another stable end-product of LPO, has
been introduced to extend the range of tools for
detecting LPO [9]. Acrolein has been shown to be
neurotoxic by inhibiting the uptake of glutamate and
glucose in neuronal cell culture [10].
The role of metal ions in lipid peroxidation
Transition metal ions such as Cu2+ and Fe3+ are capable
of promoting oxidative stress by the production of highly
reactive hydroxyl radicals via the Fenton reaction.
Normally, transition metal ions are tightly bound in a
redox-inactive state to their transport or storage proteins.
Under pathological conditions, transition metals may be
pathologically released and reduced to their highly
active, low-valency form, which makes them potent
oxidants. Recent data show that in-vitro LPO in human
CSF is catalyzed by transition metal ions and can be
totally blocked by chelating agents [11]. There is
increasing evidence that metal-catalyzed oxidation is
particularly important in neurodegenerative diseases, as
pathologically deposited metal ions are a feature of
several neurodegenerative disorders [12].
Lipid peroxidation in brain tissue in
Alzheimer's disease
There are various studies demonstrating elevated
products of LPO, including thiobarbituric acid-reactive
substances [13] and HNE [14], in brain tissue of patients
with AD relative to controls. These studies are
supported by more recent publications which report
increased F2-isoprostanes in the brains of patients with
AD relative to age-matched controls [15]. Interestingly,
the differences in F2-isoprostanes are highest in the
temporal and frontal cortices, brain regions which are
particularly affected in AD. The expression of aldehyde
dehydrogenase, an HNE-detoxifying enzyme, is ele-
vated in the brains of patients with AD [16], probably in
response to increased HNE production. Acrolein,
another end-product of LPO, which is more toxic than
HNE and is produced to a much higher extent, has also
been found to be increased in the brains of patients with
AD [17 .]. It is important to mention that increased
accumulation of oxidation products in AD is not con®ned
to lipids but is also relevant to other biomolecules such
as proteins and DNA [18]. However, lipids typically are
more sensitive to oxidation than are proteins and DNA,
which makes LPO measurement an especially valuable
tool for assessing the early oxidative damage.
In summary, increased parameters of LPO represent a
well-established characteristic of AD. The exact source
of oxidative stress leading to increased LPO in AD is not
known, but recent observations point to a pivotal role for
the interactions between transition metal ions and
amyloid-b [12].
Lipid peroxidation in body fluids in
Alzheimer's disease
The discovery of increased LPO in the brains of
patients with AD led to the measurement of LPO in
body ¯uids, especially in CSF. As in plasma, in CSF
most lipids are transported in lipoprotein particles. CSF
lipoproteins differ from plasma lipoproteins and are in
the density range of plasma high-density lipoprotein
[19±21]. It has been shown that CSF lipoproteins can
be oxidatively modi®ed in vitro and that vitamin C, the
most abundant hydrophilic antioxidant in CSF and the
brain [22], fully protects them against in-vitro oxidation
[11]. Case-control studies in patients with AD reveal a
set of alterations in LPO in CSF that correspond to the
observations made in brain. The lipoproteins of patients
with AD are more sensitive to in-vitro oxidation than
are those of controls; this has been demonstrated in a
post-mortem study [23] as well as in an ante-mortem
study [24]. Corresponding decreases in the antioxidative
vitamins C and E as well as in the polyunsaturated fatty
acid content have been observed in CSF from patients
with AD [24]. In addition, F2-isoprostanes, which are
stable markers of the peroxidation of arachidonic acid,
are increased in CSF from patients with AD [15,25].
Elevated LPO in AD is not restricted to the brain and
CSF compartments but to some extent is also observed
as systemic oxidative stress in plasma [24] and urine
[26], both of which are more easily available for the
possible monitoring of antioxidant pharmacotherapy
[27].

Oxidation of CSF lipoproteins can have pathophysiolo-
gical consequences similar to those of the oxidation of
brain lipids. Oxidized lipids have a plethora of toxic
effects on neuronal cells [28]. Accordingly, it has been
demonstrated that oxidized lipoproteins of human CSF
are neurotoxic by disrupting neuronal microtubule
organization in neuronal cell culture [23].
Amyloid-b and lipid peroxidation
Although the physiological function of amyloid-b, the
major component of senile plaques, which is normally
produced by neurons, astrocytes and many other cells
[29,30], remains unclear, it is important to note that
amyloid-b is associated with lipoproteins in body ¯uids
like CSF and plasma and can therefore be considered to
be an apolipoprotein [31]. It is not yet clear to date
whether amyloid-b is secreted together with lipoproteins
or alone.
Amyloid-b has been thought to be the disease-causing
agent in AD for a long time. Oxidation of various
biomolecules induced by micromolar amounts of
amyloid-b in cell-culture settings has been widely
used as a model for neuronal degeneration in AD. In
recent years it has become evident that amyloid-b
induces oxidation not by itself but through interactions
with metal ions [32 .]. Amyloid-b possesses three
histidine residues (at positions 6, 13 and 14) and one
tyrosine residue (at position 10); all can ef®ciently
chelate transition metal ions. As a result, amyloid-b
strongly binds copper, zinc and other transition metals
and can be aggregated by them [33]. Transition metals
are highly enriched in senile plaques, where they are
likely to be bound to amyloid-b [12]; chelation of
transition metals ef®ciently resolves aggregated amy-
loid-b and senile plaques in vitro [34]. Amyloid-b±
metal aggregates have pro-oxidative properties through
reduction of transition metals to their highly active,
low-valency state with a concomitant production of
reactive oxygen species and induction of LPO [35]. It
is most important to state that this mechanism is only
relevant when amyloid-b concentrations are in the
micromolar range.
In contrast, at the peptide concentrations normally found
in biological ¯uids (0.1±1.0 nM) amyloid-b functions as a
strong antioxidant via its metal-chelating ability [36 .].
Exogenously added amyloid-b inhibits metal-catalyzed
oxidation of lipoproteins from human CSF and plasma
[36 .]. Endogenous amyloid-b present in CSF also acts as
an antioxidant, as suggested by the positive correlation
between the resistance of CSF lipids to peroxidation and
the CSF levels of amyloid-b [37]. This is in accordance
with the decreased resistance to oxidation of CSF from
patients with AD relative to controls, and with its
decreased amyloid-b level [23,24,37].
Lipid peroxidation in Alzheimer's disease Arlt et al. 291
An antioxidant role for amyloid-b in vivo is in agreement
with recent data on the distribution of oxidative damage to
neurons in AD. Unexpectedly, an increase in amyloid-b
deposition in the cortex in AD is associated with a
decrease in the neuronal level of oxidized DNA, that is,
with decreased oxidative damage, indicating that the
formation of amyloid plaques may be considered as a
compensatory response designed to reduce oxidative
stress [38 . .]. Another ®nding that supports the hypoth-
esis of amyloid-b production as a response to oxidative
stress is that an increase in F2-isoprostanes is observed
before the formation of amyloid-b plaques in the brain
tissue of a transgenic mouse model of AD [39 . .].
Various stress conditions, primarily oxidative stress, are
known to raise amyloid-b production [40,41]. This may
be aimed at chelating the potentially harmful transition
metal ions that can be released, for example, from metal-
binding proteins, during abnormal cellular metabolism
and which would otherwise catalyze adverse oxidation of
biomolecules, as has been recently proposed [42].
Indeed, metabolism of transition metals is heavily
impaired in the brains of patients with AD [12]. Thus,
amyloid-b can function as a preventive lipoprotein-
associated antioxidant that binds transition metal ions in
an inactive form and prevents them from catalyzing LPO
(Fig. 1a).
Assuming that oxidative stress causes an increase in
amyloid-b generation in AD, the question of the source
of the oxidative stress becomes central to an explanation
of this pathology. Mitochondria may represent an
important source of reactive oxygen species in aging
and AD [18,43]. Increased production of reactive oxygen
species may lead to increased generation of amyloid-b as
a compensatory response (Fig. 1b). The amyloid-b±
metal complexes formed must be removed ef®ciently;
this may occur via lipoprotein receptors expressed in the
central nervous system [21]. The removal is likely to be
ef®cient in the young and in the absence of the
genetically linked increases in amyloid-b production
observed in familial AD. In contrast, increased oxidative
stress in the aged brain can lead to increased production
of amyloid-b, which can, in turn, lead to increased
production of amyloid-b±metal complexes. At some
stage, ef®cient removal of these complexes can be
overtaken by their disproportionately high generation,
resulting in their accumulation and in the formation of
toxic amyloid-b aggregates (Fig. 1b).
When sequestration of metal in a redox-inactive form
becomes ineffective, the antioxidant activity of amyloid-b
evolves into pro-oxidant activity, representing a typical
gain-of-function transformation. This can further stimu-
late amyloid-b production, providing a feedback loop
mechanism accelerating plaque growth. Accordingly,
292 Lipid metabolism
Figure 1. Antioxidant and pro-oxidant actions of lipoprotein-
associated amyloid-b
b in the physiological and the pathological
situation
(a)
Astrocyte
Metal-binding
Neuron Aβ
Lipoproteins proteins
(b)
Cytotoxicity
Astrocyte OH
Aggregated Aβ
Neuron
(a) Amyloid-b (Ab) is normally produced by astrocytes and neurons
[29,30] and is found in association with lipoproteins in cerebrospinal
fluid [31]. To date, it is not clear whether Ab is secreted alone or in
association with lipoproteins; lipoprotein secretion has been shown for
astrocytes but not yet for neurons [19]. It seems likely that astrocytes
produce Ab as a part of lipoprotein complexes, whereas neurons
secrete lipoprotein-free Ab, which then associates with lipoproteins.
Physiologically, Ab can bind transition metal ions such as Cu2+ (shown
here as white circles) which might be released from metal-binding
proteins. Via this mechanism, Ab could serve as an antioxidant on
lipoproteins by inhibiting metal-ion-induced oxidation. (b) In the
pathological situation, the release of metal ions from their binding
proteins might be increased, and free radical (e.g. hydroxyl radical,
OH .) generation can be induced. It has been proposed that, in response
to this increase in oxidative stress mediated by metal ions, Ab production
might be abnormally increased, leading to Ab aggregation and plaque
formation in Alzheimer's disease [36 .]. Ab±metal-ion aggregates are
capable of producing free radicals which can induce further oxidative
stress and lipid peroxidation and can enhance cytotoxicity.
massive accumulation of amyloid-b in the brains of
patients with AD might be considered as a hyper-
response to increased oxidative stress in aging, and
might lead to further oxidative stress and LPO.
Accumulation of amyloid-b, especially of the 1-42
isoform, in brain tissue might be responsible for its
decreased level in the CSF of patients with AD.
Antioxidant therapy in Alzheimer's disease
As oxidative stress is involved in the development of
AD, there have been numerous studies and proposals for
antioxidant therapies, including non-steroidal antiphlo-
gistics, estrogens and substances that speci®cally inhibit
LPO [44]. The chain-breaking antioxidants that are
known to inhibit LPO and have been most intensively
studied include a-tocopherol and ascorbate [7]. In a large
clinical trial, Sano and co-workers [45] reported that
a-tocopherol is ef®cient in delaying the progression of
AD. Recently, it has been shown that supplementation
with vitamins C and E ef®ciently delays the in-vitro
oxidation of CSF lipids in patients with AD and is
superior to supplementation with vitamin E only [46].
The clinical relevance of this ®nding remains to be
determined in long-term studies.
In recent years, another promising therapy concept has
been developed which may also be considered as an
antioxidant approach. This is the treatment of patients
with AD with chelators for transition metal ions ±
compounds that can theoretically compete with
amyloid-b for transition metals in vivo, thereby reducing
the formation of amyloid-b±metal aggregates. This can,
in turn, reduce the amyloid plaque load and lead to
reduced production of reactive oxygen species. Accord-
ingly, treatment with desferoxamine, a potent chelator
for iron, has been found to delay disease progression in
patients with AD [47]. In a more recent study,
clioquinol, a copper/zinc chelator, ef®ciently reduced
amyloid deposition in the brains of APP2576 transgenic
mice (an animal model for AD) [48 . .]. The ®rst short
clincal study covering the use of clioquinol in patients
with AD has been performed recently; it showed a
slight clinical improvement throughout a 3-week period
[49]. Long-term studies will have to be performed to
con®rm this effect. In order to prove a causal association
between metal-chelating therapy and oxidative mechan-
isms, it will be critical to investigate whether the
reduction of amyloid plaques by metal chelators is
accompanied by decreased LPO, a question that should
also be addressed in future studies.
Lipid peroxidation in other
neurodegenerative diseases
Increased oxidative stress and elevated LPO parameters
have been found not only in AD, but also in Parkinson's
disease, amyotrophic lateral sclerosis and other neurode-
generative diseases [3].
The occurrence of LPO in the brains of patients with
Parkinson's disease has been the subject of research
work for several years. Malondialdehyde and HNE have
been shown to be elevated in the substantia nigra of
such patients [50]. In addition, increased levels of HNE
were detected in CSF and plasma from patients with

Parkinson's disease [51]. Pathological iron accumulation,
which may lead to enhanced oxidative stress and LPO, is
thought to play an important role in the pathogenesis of
Parkinson's disease [52].
Elevated HNE adducts have been measured in the
spinal chords of patients with amyotrophic lateral
sclerosis [53], and elevated thiobarbituric acid-reactive
substances have been observed in their plasma [54]. In
this disease, LPO is currently thought to occur
secondarily to superoxide dismutase dysfunction and
altered intracellular copper homeostasis [3].
Recent research has also revealed a role for oxidative
stress in prion diseases. In parallel with amyloid-b, the
prion protein, PrP, has been considered as acting as a
physiological antioxidant because of its ability to bind
Cu2+ ef®ciently [55]. The loss of antioxidant potency by
aggregated PrP might therefore be relevant in prion
diseases [56]. Measurements in animal models revealed
a higher extent of LPO in PrP 7/7 [57] as well as in
scrapie-infected mice [58 . .]. Assessment of LPO in the
tissues or body ¯uids of patients with Creutzfeldt±Jakob
disease and other prion diseases is rare and the results
are partly contradictory. While F2-isoprostanes are found
to be elevated in patients with Creutzfeldt±Jakob
disease [59], no difference was observed in CSF levels
of malondialdehyde between patients and controls [60].
Investigations in our laboratory showed a strongly
increased susceptibility of CSF lipids to in-vitro
oxidation, and corresponding decreases in CSF concen-
trations of ascorbate and a-tocopherol (S. Arlt, A.
Kontush, S. Poser, U. Beisiegel, unpublished observa-
tion).
Conclusion
Pathological LPO can be detected in various neurode-
generative diseases. However, our understanding of the
exact pathophysiological functions remains incomplete.
Most knowledge of the role of LPO has been gained
from research into AD. The hypothetical order of
pathophysiological events in this disease is as follows:
(1) increased intracellular oxidative stress, possibly due
to mitochondrial dysfunction; (2) increased production of
amyloid-b as a metal-chelating antioxidant; (3) patholo-
gical aggregation of amyloid-b due to its interactions
with transition metal ions; and (4) further enhancement
of oxidative stress, leading to oxidation of lipids and
other biomolecules and to neurotoxicity [61 .]. Thus,
LPO has to be considered within the framework of
pathophysiological mechanisms as a secondary process
that might lead to further neuronal damage, by means of
its toxic end-products, (HNE or acrolein) for example. In
this context, the reduction of LPO by ef®cient
antioxidant therapy might be of special relevance in
decelerating disease progression. As LPO can be
Lipid peroxidation in Alzheimer's disease Arlt et al. 293
detected not only in brain tissue but also in body ¯uids,
it might serve as a useful marker of disease progression
and as a therapy control.
Acknowledgements
The work of the authors was supported by the Deutsche Forschungs-
gemeinschaft (DFG grant FOR 267/2).
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Unexpectedly, an increase in amyloid-b deposition in the cortex in AD is shown to
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example with decreased oxidative damage. This work supports the hypothesis that
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This is an important study showing that 8-12-iso-isoprostane-F2a, a stable product
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mouse model of AD before amyloid-b accumulation is detectable in the brain,
supporting the hypothesis that increased oxidative stress is an event that occurs
prior to amyloid-b deposition in AD.
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This is a highly relevant in-vivo study that demonstrates efficient inhibition of
amyloid-b plaque formation by a copper/zinc chelator in a mouse model of AD.
This work represents an excellent link between previous in-vitro data (from the
same group) on the amyloid-b±metal interaction and brain physiology in vivo, and
provides a basis for metal-chelating therapy in AD.
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55 Brown DR. Copper and prion disease. Brain Res Bull 2001; 55:165±173.
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The innovative hypothesis in this paper summarizes data relating to the role of
amyloid-b in oxidative processes. It suggests that increased production of amyloid-
b because of increased oxidative stress in aging, subsequent chelation of
transition metal ions by amyloid-b, accumulation of toxic amyloid-b±metal
complexes, production of reactive oxygen species, and neurotoxicity represent
the temporal sequence of events in the development of AD.