ARTICLE
Auteur(s) : Sabrina Florent-Béchard, Violette Koziel,
Jean-Luc Olivier, Thierry Oster,
Thierry Pillot
Lipidomix (JE2482), ENSAIA Institut National Polytechnique de
Lorraine, 15, rue du Bois de la Champelle, 54505
Vandœuvre-lès-Nancy, France
Introduction
Alzheimer’s disease (AD) is a progressive dementia that manifests
in early stages primarily as a profound inability to form new
memories. Mounting evidence suggests that this syndrome begins with
subtle alterations of hippocampal synaptic dysfunction associated
with neuronal cell death involving apoptosis [1]. The molecular
basis for this specificity is unknown, but evidence favors the
involvement of neurotoxins derived from the amyloid-β peptide (Aβ),
a normal product of intracellular proteolysis of a precursor
protein (βAPP) [2]. Indeed, studies from our group have
demonstrated that exposure of cells to soluble Aβ could lead to
neuronal apoptosis following oxidative stress, pro-inflammatory
signals and cytoskeleton perturbation [3, 4]. Such neurotoxicity
strongly suggests that soluble Aβ oligomers could be the proximate
effectors of the neuronal injury and death occurring in the
precocious stages of AD [2]. Due to their amphiphilic properties,
soluble Aβ oligomers may directly interact with the neuronal plasma
membrane and affect its functioning [5], thereby initiating
intracellular pro-apoptotic signaling pathways. It is thus
essential to identify the biological factors that could modulate
these early interactions and their fatal consequences. Also,
considerable attention has been focused in the past several years
on the possible influence of lipid status, especially that of n-3
polyunsaturated fatty acids (PUFA), in the central nervous system
on the development of AD. Docosahexaenoic acid (DHA,
C22:6Δ4,7,10,13,16,19; n-3) represents the longest and
the most unsaturated fatty acid (FA) commonly found in biological
systems and is mainly present in fish and algae. It is the major
n-3 PUFA constituent of the neuronal membranes in the grey matter
of the cerebral cortex and in retinal photoreceptor cells [6].
Because it is highly unsaturated, DHA is expected to increase the
fluidity of neuronal membranes, thereby playing a role in various
neurochemical processes in brain [7].
Given the enormous economical and societal burdens, there is an
enormous medical need for the development of novel therapeutic
strategies that target or even better prevent the molecular
mechanisms leading to AD dementia. In this review, we wished to
provide an overview on the beneficial effect of DHA on brain tissue
in general and in the particular context of AD, leading to the idea
that dietary DHA supplementation could be an efficient preventive
strategy for delaying or preventing AD and other neurodegenerative
diseases.
DHA, an essential fatty acid for the central nervous
system
DHA is the major n-3 PUFA constituent in the neuronal membranes,
present in approximately 30-40% of the phospholipids of the gray
matter of cerebral cortex and photoreceptor cells in the retina
[6]. In the last trimester of fetal life and the first two years of
childhood, the brain undergoes a period of rapid growth termed the
“brain growth spurt”. During this period, the need in this PUFA is
dramatically elevated because of the increase in brain size and in
relative DHA contents. Animal studies have demonstrated that
reductions in perinatal brain DHA accrual are associated with
deficits in neuronal arborisation, multiple indices of synaptic
pathology including deficits in serotonin and mesocorticolimbic
dopamine neurotransmission, neurocognitive deficits, elevated
behavioral indices of anxiety, aggression and depression and
decreased visual acuity [8]. In primates and humans, preterm
delivery has been shown to be associated with the same troubles
which can be reverted by n-3 PUFA supplementation [9]. After the
perinatal brain development, DHA intake remains essential for the
normal maintenance of brain functions including synaptic
plasticity, neurotransmission and vision [10]. Because neurons lack
the enzymes necessary for de novo DHA and arachidonic acid (AA,
C20:4Δ5,8,11,14; n-6) synthesis, these FA are derived
either directly from the diet or are mainly synthesized from the
dietary precursors, α-linolenic acid (ALA,
C18:3Δ9,12,15; n-3) and linoleic acid (LA,
C18:2Δ9,12; n-6) in liver and in a minor way in cerebral
endothelium or in astrocytes from where they are exported to
neuronal cells [7] (figure 1).
DHA and Alzheimer’s disease
Recent findings suggest a possible role of diet in age-related
cognitive decline and impairments. Among the nutritional factors
influencing AD occurrence, moderate fish consumption as a proxi of
n-3 PUFA intake was related to a reduced risk of impaired cognitive
functions [11]. In the same way, a recent population-based study
among middle aged women suggests that dietary cholesterol and to a
lesser extent saturated FA intake was associated with an increased
risk of AD, while consumption of n-3 PUFA such as eicosapentaenoic
acid (EPA ; C20:5Δ5,8,11,14,17) and DHA was
associated with a decreased risk of cognitive impairment,
independently of differences in age, gender, education, smoking,
total energy uptake and cardiovascular risk factor [12].
Importantly, lower contents of n-3 PUFA have also been measured in
the plasma [13] as well as in the brain [14] of AD patients. Recent
in vivo studies have reported that reduction of dietary n-3 PUFA in
Tg2576 AD mouse model resulted in a loss of postsynaptic proteins
and behavioral deficits, while a DHA-enriched diet could prevent
these effects [15]. Furthermore, dietary DHA was not only shown to
be protective against Aβ production, accumulation and toxicity in
Tg2576 mice [16] and AD model rats [17], but it could also
ameliorate cognitive impairments in Aβ-infused rats [18]. This
therefore provides a link between neuronal DHA homeostasis, AD
pathogenesis and Aβ effects.
Neuroprotective effects of DHA
For one simple molecule to affect so many seemingly unrelated
processes, DHA must function at a fundamental level, common to most
cells such as transcription events, membrane structure and
functions and/or signal transduction (figure 2) [19]. A
nutrigenomic approach with high-density microarrays revealed
changes in the expression of brain genes in response to different
PUFA-enriched diets. It emphasised significant changes in the
expression of several genes, as demonstrated by altered
transcription of various genes, including that encoding the
Aβ-scavenger transthyretin, in hippocampus of aged rats fed with
fish oil [20]. Some reports have concluded that DHA or fish oil
supplementation resulted in antioxidant effects in hippocampus and
cortex of an AD model rat [17] as well as in rat hippocampal
cultures exposed to glutamate [21]. It could then be suggested that
the preventive effect described in epidemiological studies could be
due to antioxidant properties of this FA.
We recently demonstrated that DHA strongly protects rat cortical
neurons from soluble Aβ oligomer-induced neurodegeneration and
apoptosis (figure
3) [22]. It is noteworthy that DHA prevents soluble Aβ
oligomer-mediated cytosketelon perturbation [23], as well as
activation of both neutral and acidic sphingomyelinases [24]. We
also reported that DHA pretreatment preserves the capacity of
neurons to phosphorylate ERK1/2 upon exposure to soluble Aβ (figure 4). The
enrichment of membrane in DHA has thus proven its crucial interest
in maintaining a sufficient rate of these phosphorylated/active
proteins, whose associated survival pathways are thereby promoted
in neurons. This suggests that not only DHA is required as an
essential membrane constituent, but it also likely acts as a
sensitive switch of major importance for modulating most signaling
pathways including cell apoptosis and survival. Further experiments
are required to identify the proteins and domains in the plasma
membrane that could act as protective sensors able to induce the
antiapoptotic response triggered by DHA enrichment in neurons.
Focusing on architectural changes PUFA enrichment could induce in
neuronal plasma membrane, the most interesting hypothesis to
explain neuroprotective effects of DHA might concern its impact on
lipid rafts, defined as compositionally distinct platforms for
compartmentalizing dynamically regulated signaling assemblies at
the plasma membrane. DHA and PUFA enrichment is known to be
accompanied by lateral phase separation and local lipid
redistribution, leading to membrane remodeling [25]. In our
experimental model, protection of rat cortical neurons from
Aβ-induced apoptosis was obtained by supplementing the medium with
nanomolar DHA concentrations, likely resulting in DHA enrichment of
specific phospholipids species or membrane microdomains. We thus
hypothesized that subtle changes could have occurred in rafts,
affecting their lipid as well as protein components. Accordingly,
we studied the raft-specific ganglioside M1 and flotillin by
immunocytochemistry and showed that exposition of cortical neurons
to soluble Aβ peptide leads to a membrane disorganisation, whereas
neurons pretreated with DHA still exhibit intense fluorescence
labeling (figure
4). This could suggest that the apoptosis induced by Aβ
oligomers involves structural and qualitative changes in lipid
rafts, which are prevented after DHA pretreatment. These changes
are expected to have functional outcomes in terms of regulating
neuronal signaling cascades.
Conclusion
Diet strongly influences the incidence and outcome in major
age-related disease including cardiovascular diseases, cancer and
dementia such as AD. Several epidemiological and experimental data
suggest that DHA intake and enrichment in neuronal membranes could
provide a substantial protective effect against these devastating
pathologies, which undoubtedly represents one of the most promising
preventive approaches to develop with the aim to prevent or to
delay the onset of AD. Different ways of action could contribute to
the neuroprotective as well as neurotrophic properties of DHA.
Further studies are still necessary to identify the preferential
mechanism(s) with the view to optimize this approach and to improve
its interest on rational and scientifically established bases
instead of nutritional or nutraceutical treatments that are still
often proposed on empirical considerations. Also, it is likely that
the neuroprotective effects of DHA might be further enhanced by
coupling the FA to anti-inflammatory and/or antioxidant molecules
such as polyphenols, given that many papers have also associated
the consumption of vegetables and fruits with a lower AD risk [26].
Original DHA-based formulations might therefore provide essential
health benefits in preventing AD for which no disease-modifying
therapies are currently available.
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