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Molecular Aspects of Medicine 28 (2007) 591–606

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Review

Vitamin E and neurodegenerative diseases

Roberta Ricciarelli *, Francesca Argellati,
Maria A. Pronzato, Cinzia Domenicotti
Department of Experimental Medicine, via L.B. Alberti 2, 16132 Genoa, Italy

Received 7 December 2006; revised 3 January 2007; accepted 3 January 2007

Abstract

Vitamin E is essential for neurological function. This fact, together with a growing body of
evidence indicating that neurodegenerative processes are associated with oxidative stress, lead
to the convincing idea that several neurological disorders may be prevented and/or cured by
the antioxidant properties of vitamin E.
In this review, some aspects related to the role of vitamin E against Alzheimer’s disease,
Parkinson’s disease, amyotrophic lateral sclerosis and ataxia with vitamin E deficiency will
be presented.
Ó 2007 Elsevier Ltd. All rights reserved.

Keywords: Vitamin E; Neurodegenerative disease; Oxidative stress; AD; PD; ALS; AVED

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 592
2. Alzheimer’s disease (AD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 593
2.1. The oxidative hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 593
2.2. The role of vitamin E in AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 594
3. Parkinson’s disease (PD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 596
3.1. The oxidative hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 596
3.2. The role of vitamin E in PD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597

*
Corresponding author. Tel.: +39 010 3538831; fax: +39 010 3538836.
E-mail address: ricciarelli@medicina.unige.it (R. Ricciarelli).

0098-2997/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.mam.2007.01.004
592 R. Ricciarelli et al. / Molecular Aspects of Medicine 28 (2007) 591–606

4. Amyotrophic lateral sclerosis (ALS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 599

5. Ataxia with vitamin E deficiency (AVED) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 599
6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601

1. Introduction

Neurodegenerative diseases are defined by the progressive loss of specific neuro-

nal cell populations and are associated with protein aggregates. A growing body of
evidence suggests that oxidative stress plays a key role in the pathophysiology of
neurodegenerative disorders (Evans, 1993; Jenner, 1994; Knight, 1997). Reactive
oxygen species (ROS), comprising superoxide anions, hydroxyradicals and hydro-
gen peroxide, are produced as a result of normal and aberrant cellular reactions
(Coyle and Puttfarcken, 1993; Halliwell, 1992). ROS are known to cause cell dam-
age by way of three main mechanisms: lipid peroxidation, protein oxidation and
DNA oxidation. Therefore, cells have developed several defense and repair mech-
anisms to deal with oxidative stress: antioxidants represent the first line of defense
and comprise enzymes such as superoxide dismutase, catalase, glutathione peroxi-
dase and small molecules, as vitamins E and C, which are able to neutralise ROS
and can be regenerated by the cellular antioxidant network (Halliwell, 1999). The
role of vitamin E in the central nervous system (CNS) has not fully elucidated, but
it acts protecting cell membranes from oxidative damage by neutralising the effects
of peroxide and oxygen free radicals. In addition to its antioxidant properties,
tocopherol can act as an anti-inflammatory agent, which may also be neuroprotec-
tive, and can regulate specific enzymes, thus changing the properties of membranes
(Martin et al., 1999).
Evidence suggests that the cellular free radical scavenger systems lose efficiency
with aging and that the age-associated increase in oxidative stress plays a major role
in neurodegenerative processes. The CNS is especially vulnerable to free radical
damage because it has a high oxygen consumption rate, an abundant lipid content
and a relative deficit in antioxidant systems, compared with other tissues (Coyle
and Puttfarcken, 1993; Smith et al., 2000).
It is still unclear whether oxidative stress is the primary initiating event associated
with neurodegeneration or a secondary effect related to other pathological pathways,
but a growing body of evidence implicates it as being involved in the propagation of
cellular injury (Jenner, 2003).
The appealing feature of the oxidative stress hypothesis for neurodegenerative dis-
eases is that cumulative oxidative damage over time could account for the late life
onset and the slowly progressive nature of these disorders. Since vitamin E is the only
lipid-soluble, chain-breaking antioxidant in biological membranes (Burton et al.,
1983; Ingold et al., 1987), it is reasonable to propose that vitamin E may play a role
in the treatment of some of these diseases.
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Although the consequences of oxidative damage have been implicated in many

neurodegenerative disorders, this review will focus on Alzheimer’s disease, Parkin-
son’s disease, amyotrophic lateral sclerosis and ataxia with vitamin E deficiency.

2. Alzheimer’s disease (AD)

AD is the most common neurodegenerative disease associated with aging; actu-

ally, it affects nearly 20–30 million people worldwide (Selkoe, 2005) and is present
in almost half of individuals over the age of 85 (Puglielli et al., 2003). AD may have
a genetic component (familial), where the onset of symptoms occurs relatively early
in life (40s–50s); or may be sporadic (late-onset), where symptoms occur in individ-
uals older than 60s (Law et al., 2001).
AD is clinically characterized by memory dysfunction, loss of lexical access,
spatial and temporal disorientation and impairment of judgment. Histopathologi-
cally, AD brain shows synaptic loss, neuronal loss (mostly in the cerebral cortex,
in the hippocampus and in the amigdala), extracellular deposition of b-amyloid
(Ab) protein in senile plaques, and intraneuronal precipitation of hyperphospho-
rylated tau protein forming neurofibrillary tangles (NFT) (Tanzi and Bertram,
2001).
Aggregated Ab is composed of small peptides with 39–43 aminoacid residues pro-
duced from a large precursor protein (APP), and plays a pivotal role in the neuronal
dysfunction and death; among different subtypes of Ab, Ab1–40 is the most predom-
inant form accounting for more than 90% of the total Ab, whereas amyloid Ab1–42 is
the most toxic form.
Intracellular NFT are, at their core, formed by a hyper-phosphorylated form of
the microtubule-associated protein named tau (Grundke-Iqbal et al., 1986); tau
phosphorylation is thought to cause a destabilization of microtubular dynamics in
the adult neurons, resulting in neuronal dysfunction (Alonso et al., 1996).

2.1. The oxidative hypothesis

The exact biochemical mechanism of the pathogenesis of AD is still unknown, but

much attention is given to the role of the massive loss of the neurotransmitter ace-
tylcholine and to the possible implication of oxidative stress in its development.
In AD, a ‘‘two hit’’ hypothesis has been postulated in which either oxidative stress
or alterations of mitotic signaling serve as initiators and are also crucial to propagate
disease pathogenesis (Longo and Massa, 2004; Zhu et al., 2004).
Age is a risk factor for AD and several studies show logarithmic age-dependent
increases in oxidized proteins, lipids and DNA in AD patients (Floyd and Hensley,
2002).
Oxidative injury may play a role in Ab deposition and the complex relationships
between this event, excitoxicity, calcium dysregulation and ROS generation in AD
have been recently summarized (Canevari et al., 2004; Mattson, 2004). Oxidizing
conditions cause protein cross-linking and aggregation of Ab peptides (Dyrks
et al., 1993) and also contribute to aggregation of tau (Troncoso et al., 1993) and
594 R. Ricciarelli et al. / Molecular Aspects of Medicine 28 (2007) 591–606

other cytoskeletal proteins. Behl and coll. have demonstrated that Ab aggregates,
upon interaction with the neuronal cell membrane, induce a sequence of events that
leads to the intracellular accumulation of ROS (Behl et al., 1994).
In addition to the direct induction of oxidative stress, Ab can also indirectly gen-
erate an oxidative microenvironment mediated by the local immune response;
indeed, cellular and soluble mediators of inflammation are found in post-mortem
AD tissue (McGeer et al., 2000).
It is worthy to mention a quite recent alternative hypothesis that considers Ab as
a protective consequence with many physiological roles, some of which include
redox-active metal sequestration (Smith et al., 1997) and SOD-like activity (Curtain
et al., 2001).
Several markers of oxidative damage to DNA, lipids and proteins have been
widely studied in AD (Markesbery and Carney, 1999). A significant increase of 8-
hydroxy-2 0 -deoxyguanosine (8-OHdG) in nuclear DNA (nDNA) and mitochondrial
DNA (mtDMA) was found in the parietal cortex of AD patients. These levels were
much higher in mtDNA than in nDNA, showing an elevated susceptibility of mito-
chondria to oxidative stress (Mecocci et al., 1994); elevated levels of 8-OHdG were
also detected in lymphocyte DNA from AD donors (Mecocci et al., 1998; Nunomura
et al., 2001).
In AD brains, lipid peroxidation has been quantitatively assessed by measuring
thiobarbituric acid-reactive substances (TBARS), 4-hydroxy-2-nonenal (HNE), mal-
ondialdehyde (MDA), lipid hydroperoxides, and isoprostanes. TBARS were found
to be increased in AD frontal and temporal cortices (Lovell et al., 1995; Subbarao
et al., 1990) and several reports showed an increase in free HNE in multiple AD
brain regions including cerebellum, amigdala and hippocampus (Markesbery,
1997; Markesbery and Lovell, 1998; Zarkovic et al., 2003).
Regarding protein oxidation, Smith and coll. found that brain carbonyl levels
increase with age, but no difference was observed between aged and AD brains
(Smith et al., 1991). On the other hand, it has also been demonstrated that, consis-
tently with the regional pattern of AD histopathology, protein carbonyls are signif-
icantly increased in both hippocampus and inferior parietal lobule (Hensley et al.,
1995).
Elderly subjects with mild cognitive impairment (MCI) and AD subjects show
lower levels of vitamin A, vitamin C, vitamin E, uric acid, alpha-carotene and lower
activities of plasma and erythrocyte superoxide dismutase (SOD) as well as glutathi-
one peroxidase (Rinaldi et al., 2003). These findings suggest that subjects developing
MCI and AD may have an antioxidant enzymatic activity inadequate to counteract
the hyperproduction of free radicals. Therefore, antioxidant therapies for both pre-
vention and treatment of neurodegenerative diseases currently appear to be a prom-
ising field of research.

2.2. The role of vitamin E in AD

Vitamin E has been frequently tested in vitro, in animal studies and in epidemio-
logical and clinical trials.
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In culture of embryonic hippocampal neurons, a-tocopherol can modulate the

Ab-induced oxidative damage of creatine kinase, which is significantly impaired in
brain of AD patients (Yatin et al., 1999). Moreover, when Ab25-35 is administered
in the hippocampus of rats previously treated with vitamin E, neuronal damage and
lipoperoxidation are efficiently prevented (Montiel et al., 2006).
In vitro exposure of neuronal cells to vitamin E also decreases Ab induced lipid
peroxidation and oxidative stress and suppresses inflammation-signalling cascades
(Butterfield et al., 2002).
Sung and coll. investigated the vitamin E mediated effects in the young transgenic
mouse model of AD (Tg2576), finding that early vitamin E supplementation signif-
icantly reduces Ab levels and deposition. Conversely, mice receiving vitamin E sup-
plementation at a later age do not show any significant difference in either markers
when compared with placebo (Sung et al., 2004).
Yokota and coll. have recently generated the a-tocopherol transfer protein knock-
out (Ttpa/) mouse, which shows marked lipid peroxidation due to lack of a-
tocopherol, and is therefore considered as a model for chronic oxidative stress
(Yokota et al., 2001). The double-mutants obtained by crossing of AD transgenic
mice (Tg2576) with Ttpa/ mice showed earlier and more severe cognitive dysfunc-
tion and increased Ab deposits in the brain (Nishida et al., 2006).
In line with these results, a different study demonstrated that the focal neurotox-
icity associated with the senile plaques is partially reversed by antioxidant therapies.
In fact, both Ginkgo biloba extract and vitamin E oral administration reduced the
oxidative stress in APPswe/PS1d9 transgenic mice. Both treatments also led to a pro-
gressive reversal of the structural changes in dystrophic neurites (Garcia-Alloza
et al., 2006).
In a recent investigation, the gene chip technology was utilised to establish the
impact of chronic vitamin E deficiency on hippocampal gene expression. The
study, conducted on male rats fed a vitamin E deficient diet for 9 months, indi-
cated that the vitamin strongly affects the expression of an array of genes directly
or indirectly involved in the clearance of Ab (Rota et al., 2005). In line with this
observation, another interesting work demonstrated that microglial cells isolated
from adult animals are not able to degrade extracellular material very efficiently,
and that this can be partially overcome by tocopherol supplementation (Stolzing
et al., 2006).
The protective activity of vitamin E against AD, underscored by results gained
from animal studies, suggested the need of epidemiological and clinical trials.
Perkins and coll. analyzed the association between the level of serum antioxidants
(vitamins E, C, A, carotenoids, selenium) and memory performance in an elderly,
multiethnic sample of 4809 subjects. After adjustment for age, education, income
and vascular risk factors, they found a decreased serum level of vitamin E consis-
tently associated with memory deficit. Serum levels of other antioxidants (vitamins
A and C, b-carotene, and selenium) did not correlate with memory performance
(Perkins et al., 1999).
In another study, 2889 elderly subjects were asked to complete a food question-
naire; dietary or supplementary intake of vitamin E correlated with less cognitive
596 R. Ricciarelli et al. / Molecular Aspects of Medicine 28 (2007) 591–606

decline with age. Little evidence of association with vitamin C or carotene was found
(Morris et al., 2002).
Data from the Rotterdam study, a prospective cohort study among elderly, have
been analyzed to examine the influence of diet on the risk of dementia (Engelhart
et al., 2002). High dietary intake of vitamin E and C was associated with lower risk
of AD, and the correlation was most pronounced among current smokers subjects.
The association did not vary by education or apolipoprotein E (ApoE) genotype.
Whereas epidemiological studies have indicated a putative role of vitamin E in
preventing cognitive impairment, intervention trials have produced contradictory
results.
The Alzheimer’s Disease Cooperative Study completed a multicenter clinical trial
of vitamin E and selegiline supplementation of patients with moderate AD (Sano
et al., 1997). Selegiline is a monoamine oxidase B inhibitor with antioxidant proper-
ties, at least in some experimental model systems. The primary objective of this study
was to determine whether vitamin E or selegiline could slow functional decline. A
total of 341 patients with moderately severe disease were enrolled in a double-blind,
placebo-controlled, trial. Patients were randomly assigned to receive either vitamin
E (2000 IU/d), selegiline (10 mg/d), both selegiline and vitamin E, or placebo. The
primary outcome measure was the time to reach anyone of the following endpoints:
institutionalization, loss of basic activities of daily living, severe dementia, or death.
The risk of reaching the primary outcome was significantly reduced by vitamin E
treatment, selegiline treatment, and combined treatment. There was no evidence of
additional improvement with combined treatment over each treatment alone. The
effect of vitamin E on each of the individual endpoints making up the primary out-
come measure was also examined. Compared with the placebo group, the vitamin E
group had a favorable hazard ratio and a prolonged time to event for all endpoints.
However, no significant benefit was shown with cognitive tests.
In a more recent double-blind study, 769 subjects with MCI were randomly
assigned to receive 2000 IU of vitamin E daily, 10 mg of donepezil daily, or placebo
for three years. Donepezil therapy was associated with a lower rate of progression to
AD only during the first 12 months of treatment. In this study, vitamin E therapy
had no benefits (Petersen et al., 2005).

3. Parkinson’s disease (PD)

PD is a chronic progressive neurodegenerative disease clinically characterized by

bradykinesia, postural instability and tremor (Samii et al., 2004). Histopathologi-
cally, PD brains show intraneuronal deposition of alpha synuclein proteins (Lewy
bodies) and irreversible loss of nigrostriatal dopaminergic neurons (Mark, 2001).

3.1. The oxidative hypothesis

The mechanisms of cell death in PD have not yet been fully elucidated, but
increased oxidative stress, abnormal mitochondrial function and excitotoxicity are
 R. Ricciarelli et al. / Molecular Aspects of Medicine 28 (2007) 591–606 597

considered as the most likely initiators or mediators of neuronal damage (Abou-Slei-

man et al., 2006).
The evidence of an involvement of free radicals in PD comes from the observation
that oxidation of dopamine yields potentially toxic semiquinones, and that the accel-
erated metabolism of dopamine by monoamine-oxidase-B may induce an excessive
formation of hydrogen peroxide, superoxide anions and hydroxyradicals (Dexter
et al., 1989; Fahn and Cohen, 1992; Jenner, 1991; Lei et al., 1992).
Further evidence for the role of oxidative stress in PD patients comes from the
selective toxicity against the substantia nigra of 1-methyl-4-phenyl-1,2,3,6-tetrahy-
dropyridine (MPTP), which induces Parkinson’s like symptoms in primates. MPTP
acts through its metabolite MPP+, which inhibits Complex I of the mitochondrial
respiratory chain and acts by increasing the vulnerability of cells to oxidative stress
(Lee et al., 2000). Mitochondrial complex I defects have been also found in muscle
(Penn et al., 1995) and platelets (Blake et al., 1997) of PD patients.
As for other neurodegenerative diseases, a fundamental molecular pathway to PD
development is the abnormal folding, function and metabolism of proteins such as
alpha synuclein and parkin, which are simultaneously source and target of oxidative
and nitrative stresses (Bossy-Wetzel et al., 2004).
Increased protein carbonyls were detected in the substantia nigra, basal ganglia,
frontal cortex and cerebellum (Alam et al., 1997) and another evidence for oxidative
damage to proteins is the increased expression of neural heme-oxygenase-1 (Castel-
lani et al., 1996).
A marked enhancement of 8-OHdG in caudatum and substantia nigra (Beal,
1995) and also in the serum and cerebrospinal fluids (CSF) of PD patients has
been described (Kikuchi et al., 2002). Migliore and coll. found that patients with
untreated PD show an increase in chromosomal, primary DNA damage and oxi-
dative DNA damage in peripheral blood lymphocytes (Migliore et al., 2002).
Moreover, lipid peroxidation markers as MDA and cholesterol lipid hydroperox-
ides are increased in parkinsonian substantia nigra (Dexter et al., 1989) and lipo-
protein oxidation is found in CSF and plasma of PD patients (Dexter et al.,
1994).
Glutathione (GSH) is an important intracellular antioxidant; of particular note,
in support to the oxidative hypothesis for the pathogenesis of PD, is the finding of
a significant GSH decrease in PD patients (Li et al., 1997).
Recent studies show that neurons from PD affected brains accumulate mitochon-
drial DNA deletions that cause impaired cellular respiration (Savitt et al., 2006). The
putative role of mitochondrial dysfunction and oxidative stress in PD pathogenesis
has lead to trials of antioxidant and promitochondrial compounds, including coen-
zyme Q10, vitamin E and creatine (Weber and Ernst, 2006).

3.2. The role of vitamin E in PD

Using in vitro and in vivo experimental models, studies have demonstrated both
vitamin E-mediated protection and lack of protection. In the MPTP-induced PD
mouse model (C57/B1), vitamin E deficiency increased MPTP toxicity, measured
598 R. Ricciarelli et al. / Molecular Aspects of Medicine 28 (2007) 591–606

in terms of lethality and dopamine metabolite depletion in the substantia nigra

(Odunze et al., 1990). Subsequent studies have reported that MPTP-induced
depletion of striatal dopamine could not be attenuated by pre-treatment of mice
with a daily oral administration of a-tocopherol (48 mg/kg) (Chi et al., 1992;
Gong et al., 1991). Moreover, in a very recent study, MPTP-induced neurodegen-
eration in Ttpa/ mice was not worsened by genetic vitamin E deficiency (Ren
et al., 2006).
The reason for the conflicting findings on vitamin E protection in vivo is unknown
but it may be related to the high acute dose of a-tocopherol administered and the
ability of MPTP to compromise the blood–brain barrier, enabling a pronounced
delivery of vitamin E from the plasma to the brain (Adams and Wang, 1994; Perry
et al., 1985).
Because it is difficult to increase GSH concentration in the brain (Zeevalk et al.,
2006), and vitamin C is not altered in PD, vitamin E (readily augmented with oral
supplements) was selected in the late 1980s for the first clinical trial of neuroprotec-
tion in PD, the DATATOP study (1989). DATATOP (Deprenyl and tocopherol
antioxidative therapy of parkinsonism) was a placebo-controlled clinical trial
designed to test the hypothesis that long-term treatment of patients with early Par-
kinson’s disease with deprenyl 10 mg/d and/or a-tocopherol 2000 IU/d may extend
the time until disability requires therapy with levodopa (primary end point). At 28
US and Canadian sites, 800 eligible patients in the early stages of untreated Parkin-
son’s disease were enrolled in DATATOP and randomized to receive deprenyl,
tocopherol, deprenyl and tocopherol, or placebo treatments. After a follow-up of
14 ± 6 months, there was no beneficial effect of tocopherol or any interaction
between tocopherol and deprenyl. Conversely, the beneficial and still unexplained
effects of deprenyl significantly delayed the onset of disability requiring levodopa
therapy (Parkinson Study Group, 1993).
On the other hand, it was previously shown that high-dose a-tocopherol, in asso-
ciation with ascorbic acid, may delay the progression of PD by an average of 2.5
years versus the time required in the placebo group (Fahn, 1992). In this study,
the patients that had been diagnosed with PD were assigned to receive both
a-tocopherol (3200 IU) and ascorbate (3000 mg) daily and were compared with a
control population.
More recently, Zhang and coworkers reported that a diet rich in vitamin E
reduces the risk of developing PD. The researchers showed that the protective effects
were not observed neither taking vitamin E supplements, nor with dietary vitamin C
or carotenoids (Zhang et al., 2002).
Other studies have shown contradictory results about dietary intake of vitamin E,
vitamin C and carotenoids and their efficacy to prevent PD progression (Etminan
et al., 2005; Pham and Plakogiannis, 2005; Weber and Ernst, 2006).
Experimental evidence has illustrated that oxidative stress is responsible for dam-
age in the substantia nigra and subsequent PD development; vitamin E is considered
to protect against oxidative damage, due to its antioxidants properties. However,
based on the available literature, there are many disputes about the efficacy of
a-tocopherol in the prevention and/or treatment of PD.
 R. Ricciarelli et al. / Molecular Aspects of Medicine 28 (2007) 591–606 599

4. Amyotrophic lateral sclerosis (ALS)

ALS is a neurodegenerative disorder characterized by the selective death of upper

and lower motor neurons, leading to profound muscle weakness and death, mostly
by respiratory failure. The etiology of most ALS cases remains unknown, but 2% of
instances are due to mutations in Cu/Zn superoxide dismutase (SOD1) (Rosen et al.,
1993). The identification of sod1 (the gene encoding SOD1 protein) as a causative
gene in ALS allowed the generation of multiple lines of transgenic mice, which exhi-
bit a transgene dose-dependent ALS-like pathology (Bruijn et al., 1998; Ripps et al.,
1995; Wong et al., 1995). Interestingly, recent data from mutant SOD1 mice showed
that motor neurons do not die following a cell-autonomous insult (Clement et al.,
2003). While normal motor neurons surrounded by mutant SOD1-expressing cells
are prone to die, those harboring an ALS-linked SOD1 mutation, placed in a
wild-type background, are not (Clement et al., 2003), suggesting that the cellular
environment of motor neurons is crucial to activate the pathological process. On
the other hand, increasing experimental evidences support the idea that mitochon-
dria are key players in ALS pathogenesis (see review in Dupuis et al., 2004). Mito-
chondria constitute a primary site of intracellular production of ROS, and therefore
a major source of oxidative stress. In turn, oxidative damage to mitochondrial com-
ponents may impair the normal function of mitochondria (Lenaz et al., 2002), cor-
roborating the hypothesis that oxidative stress may be either directly or indirectly
linked to the pathogenesis of ALS.
In 1996, data from SOD1 transgenic mice showed that vitamin E intake slowed
the onset and the progression of the disease (Gurney et al., 1996). More recently,
a large prospective study that involved 508,334 men and 676,288 women, indicated
that individuals who regularly used vitamin E supplements for 10 or more years had
less than half the risk of death from ALS than nonusers (Ascherio et al., 2005).
Like for Alzheimer’s and Parkinson’s disease, however, the results are controver-
sial. Two double-blind, placebo-controlled, randomised trials have been performed,
administering to sporadic ALS patients 500 and 5000 mg of vitamin E per day,
respectively. Both trials demonstrated no significant differences with respect to pla-
cebo, although a trend toward improvement was shown in those patients receiving
vitamin E (Desnuelle et al., 2001; Graf et al., 2005).
A lack of significant associations between intakes of antioxidant vitamins and
ALS risk was also reported in two case-control studies, but both were too small
to estimate the specific effect of vitamin E supplementation (Longnecker et al.,
2000; Nelson et al., 2000).

5. Ataxia with vitamin E deficiency (AVED)

Mutations of the a-tocopherol transfer protein (a-TTP) gene, located on chromo-

some 8q, lead to reduced a-tocopherol concentrations in plasma and tissues, which
lead ultimately to a severe syndrome named ataxia with vitamin E deficiency
(AVED) (Ben Hamida et al., 1993). These patients show loss of neurons, symptoms
600 R. Ricciarelli et al. / Molecular Aspects of Medicine 28 (2007) 591–606

of retinal atrophy, massive accumulation of lipofuscin in neurons including dorsal

root ganglions, and retinitis pigmentosa (Yokota et al., 2000). The symptoms of
AVED are similar to those of Friedreich’s ataxia, but these two conditions can be
distinguished by analysis of the frataxin gene on chromosome 9, where large GAA
repeats are found in the first intron of Friedreich’s ataxia patients (Koenig and Man-
del, 1997) and by measurement of the plasma a-tocopherol levels. In fact, AVED
patients have normal intestinal vitamin E absorption but, because of a-TTP lack,
intrahepatocytic vitamin E incorporation into very low density lipoproteins before
release in blood circulation is defective, leading to important reduction of the serum
vitamin E level.
The largest group of AVED patients is found in North Africa; they share one
of the most common mutation for the a-TTP gene (744delA). However, different
mutations have been found among various ethnic groups in Europe, North Amer-
ica and Asia (Yokota et al., 1997). In a recent study, the first case of ataxia with
isolated vitamin E deficiency has been identified in the Netherlands (Ponten et al.,
2006).
An Italian study conduced by Mariotti and coll. involved 16 patients from 12
families; they have the most common mutations 744delA and 513insTT, but two
novel pathogenic mutations have been identified, a truncating mutation (219insAT)
and a missense mutation (Gly246Arg). In spite of the development of spasticity and
retinitis pigmentosa in a few patients during therapy, the vitamin E supplementation
allowed a stabilization of the neurological conditions in most of the patients (Mar-
iotti et al., 2004). This result suggests that a prompt genetic characterization of
AVED may promote an early effective treatment of the disease.
Different pathological conditions, e.g. hepatocellular carcinoma, which compro-
mise a-TTP gene expression, lead to reduced plasma level of a-tocopherol. More-
over, the uptake of dietary antioxidants (tocopherols, carotenoids, flavonoids) and
transport by chylomicrons from intestine to the liver is impaired in abetalipoprotein-
emia and lipid malabsorption syndromes such as cholestatic liver disease, shortbowel
syndrome, and cystic fibrosis, which often show symptoms similar to AVED (Kay-
den and Traber, 1993).
It is unknown whether the degenerative neurological symptoms in patients with
vitamin E deficiency syndromes are the result of insufficient protection by antioxi-
dants or are due to a lack of specific and non-antioxidant effects mediated by a-
tocopherol. In these diseases, the transport of a-tocopherol is impaired in either
the liver or intestine by the complete absence of a transport pathway, leading to
extreme low plasma a-tocopherol levels (Traber et al., 1992).
It can be assumed that conditions may exist with partially impaired vitamin E
uptake and transport, such as heterozygotic mutation of vitamin E binding proteins
(Gotoda et al., 1995) or less penetrant mutations, with consequent less severe symp-
toms or delayed outcome. In fact, the age of symptom onset in AVED patients
depends on the type of mutation in the a-TTP gene (Cavalier et al., 1998).
Individuals with an inherent lower efficiency of tocopherol uptake may benefit
most from supplemental intake of a-tocopherol. Moreover, if polymorphisms in
transport and/or action of vitamin E exist, they could significantly affect the outcome
 R. Ricciarelli et al. / Molecular Aspects of Medicine 28 (2007) 591–606 601

of epidemiological studies, in which the initial plasma level and the individual effi-
ciency of uptake and transport of a-tocopherol often are not known.

6. Conclusion

Two relevant questions can be posed from this study. (1) What can be the basis
for the contradictory results obtained by different clinical trials? (2) Should we aban-
don the idea that a-tocopherol may help protect against neurodegenerative diseases,
or should we improve the trial conditions?
Although biochemical, cellular, and molecular biology data about a-tocopherol
have increased dramatically, many molecular phenomena are still far from being
fully elucidated.
The clinical intervention studies discussed above have not considered important
factors such as Apo E polymorphisms, possibly influencing the effect of a-tocopherol
treatment. They also neglected to measure the basal level of a-tocopherol in plasma
before and after the supplementation or to consider the possibility that pro-oxidant
effects of a-tocopherol may be protected by ascorbic acid.
Finally, the existence of a-tocopherol binding proteins should be taken into con-
sideration: the complexities of a-tocopherol absorption and metabolism are another
variable in the puzzle of in vivo a-tocopherol function.
Clinical aspects are also worth some comments. It is possible that the wrong stage
of disease (irreversible) was chosen in some studies; age is not the sole element in
determining the phase of the disease.
It appears that vitamin E treatments should be started much earlier, continue for
a longer period, and be consumed with vitamin C for its effect to become measurable.
The population of choice should be selected according to age, Apo E genotype, gen-
der, and vitamin E status.
a-Tocopherol is beginning to reveal important, non-antioxidant functions (see
review in Ricciarelli et al., 2001). It is possible that novel reactions and novel genes,
found to be under a-tocopherol control, may help and clarify the relationships
between molecular and clinical events.

Acknowledgements

Research in the authors’ laboratory is supported by grants from PRIN no.

2006065711_002.

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