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Sönke Arlt Anatol Kontush

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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 Introduction

been revealed as important factors involved in Oxidative stress is thought to be an important mechan-
neurodegenerative disorders such as Alzheimer's disease. The ism in many degenerative diseases including athero-
brains of patients with Alzheimer's disease contain increased sclerosis [1], diabetes [2] and neurodegenerative
levels of lipid-peroxidation products such as 4-hydroxy-2- disorders [3]. It can affect biomolecules including
nonenal or acrolein, and enhanced lipid peroxidation can also proteins, DNA and lipids and may lead to consecutive
be detected in cerebrospinal fluid and plasma from such functional disturbance and cell death. The human brain
patients. Recent research revealed that the interplay of is especially vulnerable to oxidative stress because of its
transition metals, amyloid-b peptide and lipid peroxidation might high oxygen consumption as well as high concentrations
be responsible for increased oxidative stress and cell damage in of easily oxidizable polyunsaturated fatty acids. In
this disease. In particular, the contrasting roles of amyloid-b particular, markers of lipid peroxidation (LPO) have
peptide, as a possible transition metal-chelating antioxidant for been found to be elevated in brain tissue and body ¯uids
lipoproteins and a pro-oxidant when aggregated in brain tissue, in several neurodegenerative diseases, and the role of
has been the focus of discussion recently. In this context, lipid LPO has been extensively discussed in the context of
peroxidation has to be seen as an important part of the the pathogenesis of Alzheimer's disease (AD), Parkin-
pathophysiological cascade in Alzheimer's disease, and its son's disease, amyotrophic lateral sclerosis, and prion
measurement in body fluids might serve as a therapy control for diseases [3]. It is controversial as to whether elevated
Alzheimer's disease and other neurodegenerative diseases. Curr LPO markers in neurodegenerative disorders represent a
Opin Lipidol 13:289±294. # 2002 Lippincott Williams & Wilkins. 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
Department of Molecular Cell Biology, Institute for Medical Biochemistry and neurodegenerative diseases remains fragmentary, at least
Molecular Biology, University Hospital Hamburg-Eppendorf, Hamburg, Germany and for AD there seems to be a direct link between the
INSERM Unit 551, Pitie Hospital, Paris, France
putative disease-causing agent, amyloid-b peptide, and
Correspondence to SoÈnke Arlt MD, Department of Molecular Cell Biology, Institute for LPO processes occurring in the brain and the cerebrosp-
Medical Biochemistry and Molecular Biology, University Hospital Hamburg-
Eppendorf, Martinistraûe 52, D-20246 Hamburg, Germany inal ¯uid (CSF) which might lead to a deeper under-
Tel: +49 40 42803 3917; fax: +49 40 42803 4592; standing of this disease.

Current Opinion in Lipidology 2002, 13:289±294 Mechanisms of lipid peroxidation

Abbreviations As the uptake of oxidized low-density lipoproteins into
AD Alzheimer's disease macrophages via the scavenger receptor pathway repre-
CSF cerebrospinal fluid sents a key event in the development of artherosclerosis,
HNE 4-hydroxy-2-nonenal
LPO lipid peroxidation most of our knowledge about LPO has been gained from
extensive studies of plasma-lipoprotein oxidation [1].
# 2002 Lippincott Williams & Wilkins
0957-9672 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
290 Lipid metabolism

polyunsaturated fatty acid molecules. Oxidized polyun- increased F2-isoprostanes in the brains of patients with
saturated fatty acids are further degraded to toxic end- AD relative to age-matched controls [15]. Interestingly,
products including 4-hydroxy-2-nonenal (HNE), acro- the differences in F2-isoprostanes are highest in the
lein, malondialdehyde, and other short-chain aldehydes. temporal and frontal cortices, brain regions which are
HNE has been shown to disrupt neuronal outgrowth and particularly affected in AD. The expression of aldehyde
neuronal microtubule organization [4], while acrolein is dehydrogenase, an HNE-detoxifying enzyme, is ele-
even more toxic than HNE and is capable of damaging vated in the brains of patients with AD [16], probably in
mitochondria [5]. Further stable end-products of LPO response to increased HNE production. Acrolein,
are F2-isoprostanes, which are speci®c products of non- another end-product of LPO, which is more toxic than
enzymatic oxidation of arachidonic acid [6]. HNE and is produced to a much higher extent, has also
been found to be increased in the brains of patients with
Chain-breaking antioxidants such as the most important AD [17 .]. It is important to mention that increased
lipophilic antioxidant, vitamin E (a major form of which accumulation of oxidation products in AD is not con®ned
is a-tocopherol), are capable of aborting the LPO chain to lipids but is also relevant to other biomolecules such
reaction and in this action are supported by co- as proteins and DNA [18]. However, lipids typically are
antioxidants such as the most important hydrophilic more sensitive to oxidation than are proteins and DNA,
antioxidant, vitamin C (ascorbate) [7]. which makes LPO measurement an especially valuable
tool for assessing the early oxidative damage.
There is a wide range of methods capable of re¯ecting
increased LPO in vivo: these include the determination In summary, increased parameters of LPO represent a
of polyunsaturated fatty acids as substrates for LPO, the well-established characteristic of AD. The exact source
measurement of in-vitro production of lipid hydroper- of oxidative stress leading to increased LPO in AD is not
oxides [8] (intermediate products of LPO) in body ¯uids known, but recent observations point to a pivotal role for
as an index of the oxidative resistance of lipoproteins, the interactions between transition metal ions and
and measurement of the stable products of LPO (HNE, amyloid-b [12].
malondialdehyde and F2-isoprostanes). Recently, acro-
lein, which is another stable end-product of LPO, has Lipid peroxidation in body fluids in
been introduced to extend the range of tools for Alzheimer's disease
detecting LPO [9]. Acrolein has been shown to be The discovery of increased LPO in the brains of
neurotoxic by inhibiting the uptake of glutamate and patients with AD led to the measurement of LPO in
glucose in neuronal cell culture [10]. body ¯uids, especially in CSF. As in plasma, in CSF
most lipids are transported in lipoprotein particles. CSF
The role of metal ions in lipid peroxidation lipoproteins differ from plasma lipoproteins and are in
Transition metal ions such as Cu2+ and Fe3+ are capable the density range of plasma high-density lipoprotein
of promoting oxidative stress by the production of highly [19±21]. It has been shown that CSF lipoproteins can
reactive hydroxyl radicals via the Fenton reaction. be oxidatively modi®ed in vitro and that vitamin C, the
Normally, transition metal ions are tightly bound in a most abundant hydrophilic antioxidant in CSF and the
redox-inactive state to their transport or storage proteins. brain [22], fully protects them against in-vitro oxidation
Under pathological conditions, transition metals may be [11]. Case-control studies in patients with AD reveal a
pathologically released and reduced to their highly set of alterations in LPO in CSF that correspond to the
active, low-valency form, which makes them potent observations made in brain. The lipoproteins of patients
oxidants. Recent data show that in-vitro LPO in human with AD are more sensitive to in-vitro oxidation than
CSF is catalyzed by transition metal ions and can be are those of controls; this has been demonstrated in a
totally blocked by chelating agents [11]. There is post-mortem study [23] as well as in an ante-mortem
increasing evidence that metal-catalyzed oxidation is study [24]. Corresponding decreases in the antioxidative
particularly important in neurodegenerative diseases, as vitamins C and E as well as in the polyunsaturated fatty
pathologically deposited metal ions are a feature of acid content have been observed in CSF from patients
several neurodegenerative disorders [12]. with AD [24]. In addition, F2-isoprostanes, which are
stable markers of the peroxidation of arachidonic acid,
Lipid peroxidation in brain tissue in are increased in CSF from patients with AD [15,25].
Alzheimer's disease Elevated LPO in AD is not restricted to the brain and
There are various studies demonstrating elevated CSF compartments but to some extent is also observed
products of LPO, including thiobarbituric acid-reactive as systemic oxidative stress in plasma [24] and urine
substances [13] and HNE [14], in brain tissue of patients [26], both of which are more easily available for the
with AD relative to controls. These studies are possible monitoring of antioxidant pharmacotherapy
supported by more recent publications which report [27].
Lipid peroxidation in Alzheimer's disease Arlt et al. 291

Oxidation of CSF lipoproteins can have pathophysiolo- An antioxidant role for amyloid-b in vivo is in agreement
gical consequences similar to those of the oxidation of with recent data on the distribution of oxidative damage to
brain lipids. Oxidized lipids have a plethora of toxic neurons in AD. Unexpectedly, an increase in amyloid-b
effects on neuronal cells [28]. Accordingly, it has been deposition in the cortex in AD is associated with a
demonstrated that oxidized lipoproteins of human CSF decrease in the neuronal level of oxidized DNA, that is,
are neurotoxic by disrupting neuronal microtubule with decreased oxidative damage, indicating that the
organization in neuronal cell culture [23]. formation of amyloid plaques may be considered as a
compensatory response designed to reduce oxidative
Amyloid-b and lipid peroxidation stress [38 . .]. Another ®nding that supports the hypoth-
Although the physiological function of amyloid-b, the esis of amyloid-b production as a response to oxidative
major component of senile plaques, which is normally stress is that an increase in F2-isoprostanes is observed
produced by neurons, astrocytes and many other cells before the formation of amyloid-b plaques in the brain
[29,30], remains unclear, it is important to note that tissue of a transgenic mouse model of AD [39 . .].
amyloid-b is associated with lipoproteins in body ¯uids
like CSF and plasma and can therefore be considered to Various stress conditions, primarily oxidative stress, are
be an apolipoprotein [31]. It is not yet clear to date known to raise amyloid-b production [40,41]. This may
whether amyloid-b is secreted together with lipoproteins be aimed at chelating the potentially harmful transition
or alone. metal ions that can be released, for example, from metal-
binding proteins, during abnormal cellular metabolism
Amyloid-b has been thought to be the disease-causing and which would otherwise catalyze adverse oxidation of
agent in AD for a long time. Oxidation of various biomolecules, as has been recently proposed [42].
biomolecules induced by micromolar amounts of Indeed, metabolism of transition metals is heavily
amyloid-b in cell-culture settings has been widely impaired in the brains of patients with AD [12]. Thus,
used as a model for neuronal degeneration in AD. In amyloid-b can function as a preventive lipoprotein-
recent years it has become evident that amyloid-b associated antioxidant that binds transition metal ions in
induces oxidation not by itself but through interactions an inactive form and prevents them from catalyzing LPO
with metal ions [32 .]. Amyloid-b possesses three (Fig. 1a).
histidine residues (at positions 6, 13 and 14) and one
tyrosine residue (at position 10); all can ef®ciently Assuming that oxidative stress causes an increase in
chelate transition metal ions. As a result, amyloid-b amyloid-b generation in AD, the question of the source
strongly binds copper, zinc and other transition metals of the oxidative stress becomes central to an explanation
and can be aggregated by them [33]. Transition metals of this pathology. Mitochondria may represent an
are highly enriched in senile plaques, where they are important source of reactive oxygen species in aging
likely to be bound to amyloid-b [12]; chelation of and AD [18,43]. Increased production of reactive oxygen
transition metals ef®ciently resolves aggregated amy- species may lead to increased generation of amyloid-b as
loid-b and senile plaques in vitro [34]. Amyloid-b± a compensatory response (Fig. 1b). The amyloid-b±
metal aggregates have pro-oxidative properties through metal complexes formed must be removed ef®ciently;
reduction of transition metals to their highly active, this may occur via lipoprotein receptors expressed in the
low-valency state with a concomitant production of central nervous system [21]. The removal is likely to be
reactive oxygen species and induction of LPO [35]. It ef®cient in the young and in the absence of the
is most important to state that this mechanism is only genetically linked increases in amyloid-b production
relevant when amyloid-b concentrations are in the observed in familial AD. In contrast, increased oxidative
micromolar range. stress in the aged brain can lead to increased production
of amyloid-b, which can, in turn, lead to increased
In contrast, at the peptide concentrations normally found production of amyloid-b±metal complexes. At some
in biological ¯uids (0.1±1.0 nM) amyloid-b functions as a stage, ef®cient removal of these complexes can be
strong antioxidant via its metal-chelating ability [36 .]. overtaken by their disproportionately high generation,
Exogenously added amyloid-b inhibits metal-catalyzed resulting in their accumulation and in the formation of
oxidation of lipoproteins from human CSF and plasma toxic amyloid-b aggregates (Fig. 1b).
[36 .]. Endogenous amyloid-b present in CSF also acts as
an antioxidant, as suggested by the positive correlation When sequestration of metal in a redox-inactive form
between the resistance of CSF lipids to peroxidation and becomes ineffective, the antioxidant activity of amyloid-b
the CSF levels of amyloid-b [37]. This is in accordance evolves into pro-oxidant activity, representing a typical
with the decreased resistance to oxidation of CSF from gain-of-function transformation. This can further stimu-
patients with AD relative to controls, and with its late amyloid-b production, providing a feedback loop
decreased amyloid-b level [23,24,37]. mechanism accelerating plaque growth. Accordingly,
292 Lipid metabolism

Figure 1. Antioxidant and pro-oxidant actions of lipoprotein- Antioxidant therapy in Alzheimer's disease
associated amyloid-b
b in the physiological and the pathological
As oxidative stress is involved in the development of
AD, there have been numerous studies and proposals for
antioxidant therapies, including non-steroidal antiphlo-
(a) 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
Astrocyte 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
Metal-binding superior to supplementation with vitamin E only [46].
Neuron Aβ
Lipoproteins proteins The clinical relevance of this ®nding remains to be
determined in long-term studies.

In recent years, another promising therapy concept has

(b) been developed which may also be considered as an
antioxidant approach. This is the treatment of patients
Cytotoxicity with AD with chelators for transition metal ions ±
Astrocyte OH 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
Aggregated Aβ reduced production of reactive oxygen species. Accord-
ingly, treatment with desferoxamine, a potent chelator
for iron, has been found to delay disease progression in
Neuron 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
(a) Amyloid-b (Ab) is normally produced by astrocytes and neurons clincal study covering the use of clioquinol in patients
[29,30] and is found in association with lipoproteins in cerebrospinal with AD has been performed recently; it showed a
fluid [31]. To date, it is not clear whether Ab is secreted alone or in
association with lipoproteins; lipoprotein secretion has been shown for
slight clinical improvement throughout a 3-week period
astrocytes but not yet for neurons [19]. It seems likely that astrocytes [49]. Long-term studies will have to be performed to
produce Ab as a part of lipoprotein complexes, whereas neurons con®rm this effect. In order to prove a causal association
secrete lipoprotein-free Ab, which then associates with lipoproteins.
Physiologically, Ab can bind transition metal ions such as Cu2+ (shown
between metal-chelating therapy and oxidative mechan-
here as white circles) which might be released from metal-binding isms, it will be critical to investigate whether the
proteins. Via this mechanism, Ab could serve as an antioxidant on reduction of amyloid plaques by metal chelators is
lipoproteins by inhibiting metal-ion-induced oxidation. (b) In the
pathological situation, the release of metal ions from their binding
accompanied by decreased LPO, a question that should
proteins might be increased, and free radical (e.g. hydroxyl radical, also be addressed in future studies.
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
Lipid peroxidation in other
formation in Alzheimer's disease [36 .]. Ab±metal-ion aggregates are neurodegenerative diseases
capable of producing free radicals which can induce further oxidative Increased oxidative stress and elevated LPO parameters
stress and lipid peroxidation and can enhance cytotoxicity.
have been found not only in AD, but also in Parkinson's
disease, amyotrophic lateral sclerosis and other neurode-
generative diseases [3].
massive accumulation of amyloid-b in the brains of
patients with AD might be considered as a hyper- The occurrence of LPO in the brains of patients with
response to increased oxidative stress in aging, and Parkinson's disease has been the subject of research
might lead to further oxidative stress and LPO. work for several years. Malondialdehyde and HNE have
Accumulation of amyloid-b, especially of the 1-42 been shown to be elevated in the substantia nigra of
isoform, in brain tissue might be responsible for its such patients [50]. In addition, increased levels of HNE
decreased level in the CSF of patients with AD. were detected in CSF and plasma from patients with
Lipid peroxidation in Alzheimer's disease Arlt et al. 293

Parkinson's disease [51]. Pathological iron accumulation, detected not only in brain tissue but also in body ¯uids,
which may lead to enhanced oxidative stress and LPO, is it might serve as a useful marker of disease progression
thought to play an important role in the pathogenesis of and as a therapy control.
Parkinson's disease [52].
Elevated HNE adducts have been measured in the The work of the authors was supported by the Deutsche Forschungs-
gemeinschaft (DFG grant FOR 267/2).
spinal chords of patients with amyotrophic lateral
sclerosis [53], and elevated thiobarbituric acid-reactive
substances have been observed in their plasma [54]. In
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35 Huang X, Atwood CS, Hartshorn MA, et al. The A b peptide of Alzheimer's 54 Oteiza PI, Uchitel OD, Carrasquedo F, et al. Evaluation of antioxidants,
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36 Kontush A, Berndt C, Weber W, et al. Amyloid-b is an antioxidant for 55 Brown DR. Copper and prion disease. Brain Res Bull 2001; 55:165±173.
. lipoproteins in cerebrospinal fluid and plasma. Free Radic Biol Med 2001;
56 Wong BS, Pan T, Liu T, et al. Prion disease: a loss of antioxidant function?
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1.0 nM) which is abolished at higher concentrations of the peptide. defense in mice lacking cellular prion protein. Free Radic Biol Med 2001;
37 Kontush A, Donarski N, Beisiegel U. Resistance of human cerebrospinal fluid
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activities. J Neurochem 2001; 79:689±698.

38 Nunomura A, Perry G, Aliev G, et al. Oxidative damage is the earliest event in
. . Alzheimer disease. J Neuropathol Exp Neurol 2001; 60:759±767. This is an outstanding study demonstrating for the first time a loss of antioxidant
function of prion protein in vivo that is accompanied by oxidative alterations,
Unexpectedly, an increase in amyloid-b deposition in the cortex in AD is shown to
including increased LPO, in the brains of scrapie-infected mice.
be associated with a decrease in the neuronal level of 8-hydroxyguanosine, for
example with decreased oxidative damage. This work supports the hypothesis that 59 Minghetti L, Greco A, Cardone F, et al. Increased brain synthesis of
increased amyloid-b production is an event that is secondary to increased oxidative prostaglandin E2 and F2-isoprostane in human and experimental transmis-
stress on a cellular level, and that amyloid-b might serve as an antioxidant. sible spongiform encephalopathies. J Neuropathol Exp Neurol 2000; 59:866±
39 Pratico D, Uryu K, Leight S, et al. Increased lipid peroxidation precedes amyloid
. . plaque formation in an animal model of Alzheimer amyloidosis. J Neurosci 2001; 60 Bleich S, Kropp S, Degner D, et al. Creutzfeldt±Jakob disease and oxidative
21:4183±4187. stress. Acta Neurol Scand 2000; 101:332±334.
This is an important study showing that 8-12-iso-isoprostane-F2a, a stable product
61 Kontush A. Amyloid-b: an antioxidant that becomes a pro-oxidant and critically
of lipid peroxidation, is elevated in brain tissue, plasma and urine from a transgenic . contributes to Alzheimer's disease. Free Radic Biol Med 2001; 31:1120±1131.
mouse model of AD before amyloid-b accumulation is detectable in the brain,
The innovative hypothesis in this paper summarizes data relating to the role of
supporting the hypothesis that increased oxidative stress is an event that occurs
amyloid-b in oxidative processes. It suggests that increased production of amyloid-
prior to amyloid-b deposition in AD.
b because of increased oxidative stress in aging, subsequent chelation of
40 Olivieri G, Brack C, Muller-Spahn F, et al. Mercury induces cell cytotoxicity transition metal ions by amyloid-b, accumulation of toxic amyloid-b±metal
and oxidative stress and increases b-amyloid secretion and tau phosphoryla- complexes, production of reactive oxygen species, and neurotoxicity represent
tion in SHSY5Y neuroblastoma cells. J Neurochem 2000; 74:231±236. the temporal sequence of events in the development of AD.