Journal of the American College of Nutrition

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Alzheimer’s Disease and Parkinson’s Disease: A

Nutritional Toxicology Perspective of the Impact
of Oxidative Stress, Mitochondrial Dysfunction,
Nutrigenomics and Environmental Chemicals

Aayushi Agnihotri & Okezie I. Aruoma

To cite this article: Aayushi Agnihotri & Okezie I. Aruoma (2020) Alzheimer’s Disease and
Parkinson’s Disease: A Nutritional Toxicology Perspective of the Impact of Oxidative Stress,
Mitochondrial Dysfunction, Nutrigenomics and Environmental Chemicals, Journal of the American
College of Nutrition, 39:1, 16-27, DOI: 10.1080/07315724.2019.1683379

To link to this article: https://doi.org/10.1080/07315724.2019.1683379

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JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION
2020, VOL. 39, NO. 1, 16–27
https://doi.org/10.1080/07315724.2019.1683379

Alzheimer’s Disease and Parkinson’s Disease: A Nutritional Toxicology

Perspective of the Impact of Oxidative Stress, Mitochondrial Dysfunction,
Nutrigenomics and Environmental Chemicals
Aayushi Agnihotria and Okezie I. Aruomab
a
School of Medicine, The University of Manchester, Manchester, UK; bDepartment of Chemistry and Biochemistry, College of Natural and
Social Sciences, California State University Los Angeles, Los Angeles, California, USA

ABSTRACT KEYWORDS
Introduction: Alzheimer’s disease is primarily a dementia-related disorder from progressive cogni- Mitochondrial Dysfunction;
tive deterioration and memory impairment, while Parkinson’s disease is primarily a movement dis- Neuropsychiatric disorders;
order illness having movement disorder symptoms, bradykinesia (slowness of movements), metabolic disturbances;
Alzheimer’s disease;
hypokinesia (reduction of movement amplitude), and akinesia (absence of normal unconscious Parkinson’s disease;
movements) along with muscle rigidity and tremor at rest. While aging is the main risk factor, epi- Oxidative stress; Nutritional
demiological evidence suggests that the exposure to environmental toxicants, mainly pesticides, management;
metals and solvents could increase the risk of developing neurodegenerative conditions. Nutrigenomics;
Oxidative stress in neurodegenerative diseases: Mitochondria function impacts cell respiratory Nutraceuticals;
processes, metabolism, energy production, intracellular signaling, free radical production, and Environmental toxicants;
apoptosis. In neurodegenerative diseases, mitochondrial dysfunction is associated with a compro- Pesticides and
mised energy production, impaired calcium buffering, activation of proteases and phospholipases, neurodegeneration.
and increased oxidative stress. Oxidative stress induced microglial cells activation, protein aggrega- Xenobiotics and metabolism
tion, neuroinflammation and mitochondrial dysfunction lead to neuronal deaths in these disorders.
Role of nutrition: Neurodegenerative disease is not curable, but treatment is available to manage the
symptoms and slow down the disease progression. The drugs for treating these diseases only reduce
the cognitive impairment and behavioral problems, but do not stop the progression of neurodegener-
ation. Healthy diet, lifestyle improvement and nutraceuticals targeting of oxidative stress, inflamma-
tion, abnormal mitochondrial dynamics and the mitochondrial interaction with abnormal disease-
related proteins and assessment of impact of environmental contaminants including occupational
exposures to pesticides, can be a promising approach in the treatment of neurodegenerative diseases.
Conclusion: These innovations can be benchmarked on firm understanding of nutrigenomics and
the personalized management of individuals at risk.

Introduction disabling and irreversible disease has two recognizable hall-

Neurodegenerative diseases are a group of chronic disabling
disorders, characterized by the gradual and selective loss of
neurons in the central or peripheral nervous system. The
major age-related neurodegenerative diseases such as
Alzheimer’s disease (AD) and Parkinson’s disease (PD) can
give rise to dementia, which is a leading cause of disability
worldwide and represents a major public health burden with
spiraling healthcare costs (1,2). AD is primarily a dementia-
related disorder from progressive cognitive deterioration and
memory impairment, while PD is primarily a movement dis-
order illness having three major kinesia or movement dis-
order symptoms, bradykinesia (slowness of movements),
hypokinesia (reduction of movement amplitude), and akin-
esia (absence of normal unconscious movements) along with
muscle rigidity and tremor at rest. Alzheimer’s disease is the
major form of dementia in the elderly and possibly contrib-
utes to 60–70% of cases worldwide. (2). This progressive,
marks, the first, familial or of early onset, is directly related
to specific gene mutations in the amyloid precursor protein
(APP) and presenilin (PSEN) 1 and 2 genes, both related to
the amyloid-beta (Ab) peptide synthesis perpetuated by the
neurofibrillary tangles (NFT). The second hypothesis sug-
gests that the hyperphosphorylation of the Tau protein and
its subsequent deposition as NFTs is the ultimate responsible
for the disease. According to Chin-Chan, Navarro-Yepes, &
Quintanilla-Vega (3), the amyloid cascade hypothesis estab-
lishes that Ab aggregation initiates the brain damage leading
to memory loss and to AD. There is no cure for AD, and
therapeutic treatments are basically to ameliorate the symp-
toms. Therefore, an early and opportune diagnosis is indis-
pensable to slow the progression of the disease. Currently
(4), the determination of Tau and Ab levels in blood and
CSF are broadly used for the diagnosis of AD, and several
medical tools are also used to confirm the diagnosis

CONTACT Okezie I. Aruoma oaruoma@calstatela.edu Department of Chemistry and Biochemistry, College of Natural and Social Sciences, California State
University Los Angeles, 5151 State University Drive, Los Angeles, CA 90032, USA.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/uacn.
ß 2019 American College of Nutrition
 JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION 17

Figure 1. Innate Immune response and Tau pathology: a vicious circle. Hyperphosphorylated pathological Tau species can be secreted extracellularly, explaining
the progressive spread of tauopathy (A). Therefore, it promotes microglial activation/reactive astrocytes which release cytokines or neurotoxic inflammatory mole-
cules including IL1b or TNFa (B). By a modulation of Tau kinases (p38, cdk5 … ), glial activation enhances Tau pathology, self-perpetuating the detrimental circle
(C). Microglia may be involved in Tau propagation by releasing exosomal Tau once pathological Tau phagocytosed (D). (Adapted from Laurent, C., Bu
ee, L., Blum, D.
(2018). Tau and neuroinflammation: What impact for Alzheimer’s disease and Tauopathies? Biomedical Journal, 41, 21–33).

including the medical history, mental status tests, and evalu-
ations of the brain structure and function with neuroimag-
ing techniques. Reference (5) has reviewed the concept of
Tau and neuroinflammation exploring the impact this has
on AD. As can be seen in Figure 1, this is a very complex
process, more so because knowledge on AD can only be
derived from postmortem samples. Such postmortem obser-
vation of AD brains reveals a characteristic distribution pat-
tern of NFT lesions in the disease course, starting in the
transentorhinal cortex and progressively affecting the hippo-
campus, temporal cortex and polymodal association areas.
The modalities of the propagation of Tau pathology have
been investigated. Experimental transfer of brain homoge-
nates containing pathologic Tau from transgenic P301S mice
promotes the accumulation of NFT in wild-type recipient
animals in a stereotypical and time-dependent fashion. Tau
spreading occurs at distance of the injection site and con-
cerns area connected anatomically instead of affecting prox-
imal structures. Among the diverse modifications of tau,
phosphorylation induces the most critical change of tau
leading to tau aggregation. Full-length tau protein has 80
serine and threonine residues and 5 tyrosine residues. In an
intact cell, tau is constantly phosphorylated and dephos-
phorylated for the regulation of microtubule assembly. Once
the balance is disrupted, tau is highly phosphorylated. The
additional phosphates disrupt the charge balance between
tau and microtubules, and tau dissociates from microtu-
bules. Therefore, hyper-phosphorylation is the critical event
in the initiation of tau pathology. Tau phosphorylation is
tightly regulated by kinases or phosphatases. Among diverse
enzymes, GSK3b is the most effective tau kinase in the
human brain. Increased GSK3b activity is directly linked to
elevated levels of tau phosphorylation in AD patients
(reviewed by 5).
Mitochondria play important roles in cell respiratory
processes, metabolism, energy production, intracellular sig-
naling, free radical production, and apoptosis. In neurodege-
nerative diseases, mitochondrial dysfunction is associated
with a compromised energy production, impaired calcium
buffering, activation of proteases and phospholipases, and
increased oxidative stress (6–8). Increased level of oxidative
stress and accumulation of mitochondrial DNA mutations
resulting in mitochondrial dysfunction plays an important
role in the aging process and the pathogenesis of many neu-
rodegenerative diseases (9,10). Impaired calcium influx, dis-
sipation of mitochondrial membrane potential, accumulation
of mutant proteins in mitochondria, increased accumulation
of mtDNA deficiencies, and deficiencies in mitochondrial
oxidative phosphorylation are significant cellular changes in
late-onset neurodegenerative diseases (11). Reference (12)
suggested that mitochondrial proteases in the inner mem-
brane perform the quality control surveillance by having
chaperone-like activities and degrading the misfolded pro-
teins and play a crucial role in the pathogenesis of many
neurodegenerative diseases. The m-AAA protease is a key
modulator of mitochondrial quality control system. Loss of
m-AAA protease promotes neurodegeneration through vari-
ous pathways, including decreased mitochondrial protein
synthesis due to impaired maturation of Mrpl32, accumula-
tion of misfolded proteins, defective Opa1-mediated mito-
chondrial fusion, abnormal mitochondrial transport and
reduced assembly and stability of complexes I and III (12).
AD is the most common cause of dementia, characterized
by extracellular accumulation of amyloid-b (Ab) peptides in
18 A. AGNIHOTRI AND O. I. ARUOMA
the form of senile plaques and intracellular aggregation of
microtubules binding protein (tau) as tangles in the brain in
the gray matter (13). The interaction between amyloid-b
and hyperphosphorylated tau aggregates causes metabolic
decline in the limbic structures such as the cingulate, orbito-
frontal, and medial and basal temporal cortices resulting in
imminent neurodegeneration (14). Substantial changes in
mitochondrial size and number in vulnerable neurons sug-
gest a potential alteration in mitochondrial dynamics in AD
(15). Several studies revealed an increased expression of fis-
sion-related genes such as Drp1 and Fis1, and a decreased
expression of fusion-related genes such as Mfn1, Mfn2 and
Opa1, leading to mitochondrial fragmentation in AD
patients. Overexpression of Drp1 interacts with Ab and
hyperphosphorylated tau proteins leading to mitochondrial
fragmentation and neuronal damage (16–18).
PD is the second common age-related neurodegenerative
disease, which causes dementia in about 80% of people dur-
ing the disease (1). Parkinson’s disease dementia (PDD) and
Dementia with Lewy bodies (DLB) are the two separate enti-
ties of the aging population characterized by the similar
morphological features such as a-synuclein accumulation
(Lewy bodies) in cortical and subcortical regions, but differ-
ent clinical profile at onset (19). Postmortem examination
reveals more pronounced cortical atrophy, and elevated cor-
tical and limbic Lewy pathologies in DLB as compared to
PDD (19). The overexpression of wild type a-synuclein pro-
motes neuronal death by inducing Drp-1 dependent mito-
chondrial fragmentation (20). Interestingly, about 90% of
PD cases are sporadic and cannot be attributed only to gen-
etic factors, which suggests that PD have a multifactorial eti-
ology. In addition to the aging, which is the main risk factor
for PD, epidemiological evidence suggests that the exposure
to environmental toxicants, mainly pesticides, metals and
solvents could increase the risk of developing PD, and fac-
tors such as tobacco consumption can protect against PD
development, as depicted in Figure 2 based on several toxi-
cological data at molecular level and reviewed in (as
reviewed in 3). The hypothesis that pesticide exposures may
be related to PD development was prompted by the discov-
ery that intravenous injection of 1-methy l-4 pheny l-1, 2, 3,
6-tetrahydropyridine (MPTP), a by-product of the synthesis
of heroin, developed a Parkinson syndrome clinically indis-
tinguishable from PD and subsequent findings showed that
MPTP selectively damaged dopaminergic neurons in the
substantia nigra (21,22). Environmental factors with similar
toxicological profiles have received attention as potential
risk factors for PD and AD (3). Dieldrin may cross the
blood–brain barrier and remains in lipid-rich tissues such as
the brain, and it has been shown that it is selectively toxic
to dopaminergic neurons and could induce several of the
pathologic mechanisms of PD including the depletion of
brain dopamine levels, increased ROS in nigral dopamin-
ergic neurons, inhibition of mitochondrial oxidative phos-
phorylation that lead to a reduction of cellular ATP
production, alteration of the mitochondrial membrane
potential and cytochrome C release in animal models.
Paraquat is a quaternary nitrogen herbicide used worldwide.
Due to its structural similarity to MPP (the active metabolite
of MPTP), it was thought to be toxic to dopaminergic neu-
rons and thus might be related to PD. Paraquat can be taken
up into dopaminergic terminals by the dopamine transport
and organic cation transporter 3 and have been reported to
cause cellular toxicity by oxidative stress. This may occur
through the cellular redox cycling generating superoxide
radical by the oxidation of NADPH, which in turn impairs
the restauration of GSH levels and thus the activity of sev-
eral antioxidant systems. Rotenone, an OP insecticide has
also been associated with an increased risk of PD. Rotenone
can freely cross the blood–brain barrier and is a well-estab-
lished mitochondrial toxin that specifically inhibits the com-
plex I (NADH–dehydrogenase) of the electron transport
chain leading to ATP depletion, energy failure and mito-
chondrial ROS production, which in turn induces cyto-
chrome C release and apoptotic cell death. Rotenone
treatment in animal models can reproduce features of PD
such as bradykinesia, postural instability and/or rigidity,
reduces the tyrosine hydroxylase-positive neurons in the
substance nigra, induces a loss of striatal dopamine, and the
accumulation of a-syn and poly-ubiquitin positive aggregates
in remaining dopaminergic neurons. Since rotenone recapit-
ulates several mechanisms of PD pathogenesis, this pesticide
is currently used as a toxicological model to study the
underlying mechanisms on the PD development. Reference
(3) reviewed the use of insecticides as depicted in Figure 2.
Their paper indicated that despite the widespread use of
organophosphates (OP) insecticides such as malathion,
methyl parathion, chlorpyriphos and diazinon, not many
studies have evaluated the association between specific OP
and PD risk. Solvents are widespread used due to their com-
mercial applications, including metal degreasing, dry clean-
ing, and as ingredients of paint thinners and detergents.
Some solvents are lipophilic and thus easily absorbed by the
central and peripheral nervous system tissues. There are iso-
lated cases of acute Parkinsonism associated with large solv-
ent exposures such as in workers exposed to n-hexane, and
toluene, among others. There is no consistent evidence of
the association of solvent exposure and PD.
Trichloroethylene (TCE) is one of the specific solvents that
has been investigated in detail. Some clinical case reports
have reported the onset of PD in workers exposed to TCE
through chronic inhalation and dermal exposure by han-
dling TCE, suggesting a potential link between the exposure
to TCE and PD. The two major uses of trichloroethylene are
as a solvent to remove grease from metal parts and as a
chemical that is used to make other chemicals, especially the
refrigerant, HFC-134a. Trichloroethylene has also been used
as an extraction solvent for greases, oils, fats, waxes, and
tars; by the textile processing industry to scour cotton, wool,
and other fabrics; in dry cleaning operations; and as a com-
ponent of adhesives, lubricants, paints, varnishes, paint
strippers, pesticides, and cold metal cleaners. As there is no
consistent evidence from either the toxicological or epide-
miologic perspective that any specific solvent or class of sol-
vents is a cause of PD, toxicological research that addresses
mechanisms of nigral damage from TCE and its metabolites,
 JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION 19

Figure 2. Molecular mechanisms altered by environmental factors related to increased Parkinson’s disease risk. Exposure to environmental toxicants mainly pesti-
cides, metals and solvents may lead to the selective loss of dopaminergic neurons on the substantia nigra pars comp acta (SNpc) through the dysregulation/alter-
ation of the molecular mechanisms implicated on PD development such as mitochondrial dysfunction, impairment of protein quality pathways, microglia activation
and inflammation, which converge in the production of oxidative stress as the main factor in PD. (Copyright # 2015 Chin-Chan, Navarro-Yepes and Quintanilla-
Vega. Chin-Chan M, Navarro-Yepes J, Quintanilla-Vega B. Environmental pollutants as risk factors for neurodegenerative disorders: Alzheimer and Parkinson diseases.
Front Cell Neurosci. 9: 124, 2015).

with exposure routes and doses relevant to human expo-
sures, is recommended (3, 23).
Understanding the pathophysiology of neurodegeneration
may improve the efforts to prevent and treat dementia in
aged population. Today, no neurodegenerative is curable, and
the treatment is available to manage the symptoms and slow
down the disease progression (24). Acetylcholinesterase inhib-
itors are used mainly to alleviate cognitive impairment and
behavioral problems in both AD and PD, but display heavy
side effects such as nausea, vomiting, diarrhea, dizziness, con-
fusion, and cardiac arrhythmias (25,26). Although target-bases
therapies such as stem cells (27), neuroprotective drugs (28),
hormonal replacement therapy (29), neurotrophic factors (30)
and regulators of mRNA processing into disease-causing
mutant proteins (31) have been developed, neutraceuticals
(32) appear to have a safer alternative treatment option to
mitigate the neurodegenerative processes. Recent researches
(33) show that the natural therapeutics with anti-oxidative
and anti-inflammatory properties, including caffeine, trigonel-
line, shogaol, curcumin, resveratrol, baicalein, wogonin, ginse-
nosides, tanshinones, withanolides, picrosides, parthenolide,
cannabinoids, Devil’s claw and white willow bark may play a
crucial role in protecting neurons due to their potential neu-
roprotective, anti-inflammatory, antioxidant, anti-amyloido-
genic and anticholinesterase activities (33,34).
Oxidative stress in neurodegenerative diseases
Several studies (35) have demonstrated the role of chronic
oxidative stress in a common pathogenesis of age-related
20 A. AGNIHOTRI AND O. I. ARUOMA
neurodegenerative diseases such as AD and PD, and an anti-
oxidant therapy for the prevention and treatment of these
diseases. Oxidative stress can induce mitochondrial DNA
mutations, depress the mitochondrial respiratory chain func-
tions, alter membrane permeability, disturb Ca2þ homeosta-
sis, and damage mitochondrial antioxidant system (6,36,37).
A sustained increased production of ROS in mitochondria
promotes calcium uptake by oxidizing thiol groups in pro-
teins and initiates calcium overloaded-induced cell death
that might contribute to the pathogenesis of various neuro-
degenerative diseases (38). A classic mitochondrial free rad-
ical theory of aging suggests that reactive oxygen species
generated due to mitochondrial DNA (mtDNA) mutations
cause persistent DNA damage leading to more mutations
and give rise to further mitochondrial dysfunction and neu-
rodegeneration (39,40).
Over production of reactive oxygen species (ROS) and/or
a defect in the antioxidants systems lead to neuronal loss in
majority of the neurodegenerative diseases. Recently, a
superoxide anion (O2-) generating enzyme i.e. NADPH oxi-
dase 2 (Nox2) has been considered as a major source of age-
ing-related vascular endothelial oxidative damage in
neurodegenerative diseases (41). Under normal metabolic
conditions, mitochondria convert about 1-5% oxygen into
ROS mainly by complex I (NADH dehydrogenase) and
complex III (cytochrome oxidoreductase) (42). Once gener-
ated, superoxide O2.- is dismutated to H2O2 by superoxide
dismutase, and afterwards, H2O2 is fully reduced to water by
GPX (43). The damage and inactivation of Fe-S clusters of
electron transport chain complexes (I, II, and III) (ETC)
and Krebs cycle aconitase due to acute ROS exposure can
shut down the energy production in mitochondria leading
to cell death (44). Neurons are extremely dependent on the
ETC complexes of mitochondria, and impaired functions of
these complexes are related to several neurodegenerative dis-
eases including AD and PD (45). Reduced ETC complex I,
III and IV activities have been found in platelets, lympho-
cytes and postmortem brain tissue of patients with
Alzheimer’s disease, however major change association with
complex IV (46). In Parkinson’s disease, a mild deficiency of
complex I and NADH dehydrogenase has been demon-
strated in substantia nigra, platelets and the skeletal
muscles (47).
Role of nutrition in neurodegenerative diseases
Recently, the role of diet and nutrition in preventing or
delaying the progression of neurodegeneration in aged
population has received a great amount of attention.
Reference (48) reported that consumption of diet rich in
antioxidants (such as fruits, nuts, vegetables and spices),
reduced caloric intake by consuming less carbohydrate and
low consumption of alcohol may lower age-relative cognitive
decline and lessen the risk of developing neurodegenerative
disease. Emerging evidence supports the role of B-vitamins
(vitamin B12, vitamin B6 and riboflavin), vitamin D, folate,
polyphenols, and n-3 polyunsaturated fatty acids (PUFAs) –
eicosapentaenoic acid (EPA) and docosahexaenoic acid
(DHA) in neuroprotection and reducing the risk of cogni-
tive decline (49). In addition to a healthy diet, cooking
methods should also be considered. The cooking procedures
can modify the original dietary ingredients, not only by
destroying the nutrients, but also by generating potential
toxic compounds such as advanced glycation end products
(AGEs) that contribute to the ageing process and neurode-
generative diseases (50). Advanced glycation end products
(AGEs) play a crucial role in neurodegeneration by down
regulating thioredoxin, which as an anti-oxidative and anti-
apoptotic protein accelerates neuronal cells apoptosis (51).
Recent studies (52–54) demonstrate the association
between the Mediterranean-style diet (MsD) and age-related
neurodegenerative diseases especially Alzheimer’s disease.
According to the “Global Strategy on Diet, Physical Activity
and Health”, MsD can prevent many diseases including neu-
rodegenerative diseases and improve the quality of life (55).
MsD includes plenty of plant-based foods (such as fruits,
vegetables, whole grains, legumes and nuts), a moderate to
high intake of fish and sea food, a low to moderate intake
of poultry, eggs, cheese and yogurt, low consumption of red
meat, and a regular intake of red wine during the meals. A
systemic review of the thirty-one population-based studies
by (52) from Australia, China, France, Greece, Scotland,
Spain, Sweden, and USA shows that MsD has the beneficial
effects on cognitive function and reduces the risk of
Alzheimer’s disease and dementia. Similarly, another review
of twenty-four observational-type studies (prospective and
retrospective) by (54) from Australia, Canada, Finland,
France, Japan, Norway and USA summarizes the impact of
MsD on cognition and in Alzheimer’s disease in human
clinical trials. Reference (54) further add that the bioactive
components of MsD have both neuroprotective and neuro-
rescue effects not only through antioxidant activity but also
due to anti-inflammatory, and anti-amyloidogenic activities.
A recent population-based cohort study (56) of older adults
in Greece suggests that the adherence to MsD is associated
with a lower probability of prodromal Parkinson’s disease in
elderly people.
Components of mediterranean-style diet and their
impact on neurodegeneration
Vegetables and fruits
An adequate intake of vegetable and fruits particularly flavo-
noids and carotenoids prevent or delays the age-related cog-
nitive decline and reduces the risk of developing
neurodegenerative diseases (57). These beneficial effects are
not only due to three major antioxidant vitamins such as
a-tocopherol (vitamin E), ascorbic acid (vitamin C), or
b-carotene (vitamin A), but also because of having a large
amount of non-vitamin antioxidants such as polyphenols
and anthocyanins (58). Researches (59,60) show that some
specific vegetable and fruits especially green leafy and nuts
are strongly associated with a reduced rate of age-related
cognitive decline.
 JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION 21

Table 1. Summary of nutraceuticals-targeting age-related neurodegenerative diseases.

S.N. Nutraceuticals Target mechanism Authors (Years)
1. Curcumin Suppress increased production of intracellular ROS (74,75)
Inhibit pro-inflammatory signaling through NF-jB
Inhibit aggregation of misfolded proteins (b-amyloid, a-synuclein)
2. Anthocyanins (Blue berry extract) Improve beta-amyloid induced neurotoxicity by inhibiting calcium influx and (76)
tau hyperphosphorylation.
Modulate inflammatory genes expression.
3. Coenzyme Q10 supplements Protect mitochondrial impairment and oxidative stress (77)
4. Aged garlic extract (AGE) Modulates Nrf2-mediated signaling as well as other oxidative stress- (78)
related pathways.
5. Astaxanthin (Xanthophyll carotenoid) Attenuates microglial activation and the release of pro-inflammatory cytokines. (79,80)
Promotes hippocampal neurogenesis in dose-dependent manner.
6. Epigallocatechin-3-gallate (Green tea) Reduces oxidative stress, regulates signaling pathways and metal chelation (81,82)
7. Alfa-lipoic acid Displays antioxidant, antiapoptotic, and anti-inflammatory properties (83)
8. Vitamin B supplements Improve cognition by lowering homocysteine levels (84)
9 Lycopene Increases glutathione peroxidase and markedly reduces tau (85)
hyperphosphorylation
Has synergistic antioxidant effect with Vitamin E

Seafood Red wine

Seafood is considered to be a highly nutritious food given
its high protein and low-calorie content and associated with
numerous health benefits. Researchers (61) are interested in
omega-3-polyunsaturated fatty acids, such as eicosapenta-
enoic acid (EPA) and docosahexsaenoic acid (DHA) con-
tained in fish and seafood, which are required to maintain
the structural integrity of neuronal membranes. These fatty
acids may decrease with aging that increases the risk of cog-
nitive impairment and dementia. (62) reported that con-
sumption of seafood at least one serving a week results in
less decline in cognitive functions in elderly people. A cross-
sectional analysis of older adults with brain neuropathology
suggests that moderate seafood consumption is correlated
with lesser Alzheimer disease neuropathology. Importantly,
a prospective cohort study by (63) of 5,988 women over a
follow-up period of 4 years concluded that the relationship
of seafood to cognition might depend on the seafood types,
not on the total consumption. The consumption of tuna and
dark-meat fish once weekly or more is strongly associated
with lower cognitive decline (63).
Olive oil
The fatty acid composition (mainly oleic acid - a monoun-
saturated omega-9 fatty acid), vitamins and polyphenols in
olive oil are responsible for longevity, and beneficial for cog-
nitive deficit in age-related neurodegenerative diseases (64).
Olive oil has more than 30 phenolic compounds including
the three major variants oleuropein, hydroxytyrosol and
oleocanthal (65). Oleocanthal, a phenolic component of
extra-virgin olive oil, enhances b-amyloid clearance by up-
regulating major b-amyloid transport proteins (P-glycopro-
tein and LDL lipoprotein receptor related protein-1) at the
blood-brain barrier (BBB) (66), inhibits the aggregation of
tau protein aggregation into neurofibrillary tangles (67), and
thus reduces a risk of Alzheimer’s disease. Oleuropein
Aglycone, another polyphenol present in olive oil, hinders
b-amyloid and tau proteins aggregation, autophagy
impairment, and neuroinflammation (68).
Wine is an alcoholic beverage commonly made from fer-
mented grapes. Reference (69) have reported that moderate
consumption of red wine reduces the risk of many diseases
and protects against various age-related neurodegenerative
diseases such as Parkinson’s or Alzheimer’s diseases. The
neuroprotective effects of red wine are mainly due to the
presence of polyphenols such as quercetin, myricetin, cate-
chins, tannins, anthocyanidins, resveratrol, and ferulic acid
(70). These polyphenols induce endogenous antioxidant
Defense mechanism by modulating transcription factors
such as the nuclear factor erythroid 2-related factor 2 (Nrf2)
and improve cognitive functions (71).
A nutrigenomics perspective and emerging
nutraceuticals targeting neuroprotection
Nutrigenomics is the study of the relationship among nutri-
tion, genome and health that examines how different foods
interact with our gene and how the people respond to food
based on their genetic distinctions. Evidence suggests the
role of nutrition in the genetics of many neurodegenerative
diseases. Epigenetics suggest the involvement of nutrition
in the pathogenesis of age-related cognitive decline.
Nutraceuticals can modulate the specific metabolic pathways
that affect the development of age-related neurodegenera-
tive diseases.
Nutraceuticals are the fortified food products that not
only supplement the diet but also assist in treating and/or
preventing diseases and disorders (72). Neutraceuticals pro-
tect neuronal damage by targeting the four major pathways
– mitochondrial dysfunction, calcium overload, oxidative
stress and inflammation (72). Many neutraceuticals, which
have antioxidant effects by scavenging ROS inducing the
expression of a variety of cytoprotective and detoxification
proteins in the Nrf2/ARE pathway, have been identified as a
potential therapeutic target for neurodegenerative diseases
(73). We have categorized sample nutraceuticals-targeting
neuroprotection based on the available evidences from the
published scientific literature (Table 1).
22 A. AGNIHOTRI AND O. I. ARUOMA

Figure 3. Environmental factors associated with Alzheimer’s disease development through different mechanisms. Several factors including metals, pesticides, nano-
particles, and diet can affect the two targets of AD such as Ab generation and Tau phosphorylation. The figure depicts the molecular targets than can be modified
at different levels following the amyloid hypothesis that ends in Ab senile plaques formation (upper part) or the hyperphosphorylation of Tau protein and its subse-
quent deposition as neurofibrillary tangles (NFTs) (lower part). (Copyright # 2015 Chin-Chan, Navarro-Yepes and Quintanilla-Vega. Chin-Chan M, Navarro-Yepes J,
Quintanilla-Vega B. Environmental pollutants as risk factors for neurodegenerative disorders: Alzheimer and Parkinson diseases. Front Cell Neurosci. 9: 124, 2015).

Influence of the environmental contaminants and
lifestyle on neurodegenerative diseases
Lifestyle factors are crucial in minimizing the risk of devel-
oping age-related neurodegenerative diseases. Continuous
physical and cognitive activity, a balanced or Mediterranean-
style diet with a high proportion of polyunsaturated fatty
acids, proper treatment of hypertension, control diabetes
and cholesterol, and adequate sleep reduce the risk of devel-
oping dementia later in life (86). Given that dietary supple-
ments may fill a void by providing necessary nutrients for
optimizing health, enhancing micronutrient and vitamin lev-
els may be a more pragmatic approach to address stress and
improve psychosocial mood than pharmacological interven-
tions with their associated negative side effects (87).
Environmental factors possibly include inorganic and
organic hazards, exposure to toxic metals (aluminum, cop-
per), pesticides (organochlorine and organophosphate insec-
ticides), industrial chemicals (flame retardants) and air
pollutants (particulate matter). The association between past
occupational exposure to pesticides and low cognitive per-
formance, together with an increase in the risk of developing
Alzheimer’s disease or Parkinson’s disease has been reported
(88,89) and that this may be related to occupational expos-
ure such as vineyards. The possibility of long-term neuro-
logic effects of pesticide use in agricultural settings where
fungicides account for much of the occupational exposure
(3,88,89) can be paralleled with long term exposures to other
environmental contaminants together with bioaccumulation
over an individual’s lifetime. The reader is referred to the
paper by (89) which eminently discussed five categories of

environmental agents, including (i) toxic metals, (ii) insecti-
cides/pesticides, (iii) industrial/commercial pollutants, (iv)
antimicrobials and (v) air pollutants, all known or hypothe-
sized to induce or aggravate AD or AD-like progression
in vitro, in animal models and in human research subjects.
The cognitive disturbances that may persist in occupation-
ally exposed subjects, even long after work cessation, may be
aligned with neuroinflammation and neuropathology paving
the way for developing AD. While epidemiologic associa-
tions between environmental contaminant exposures and
AD are still limited, data from many in vitro and animal
studies have identified toxic effects of environmental con-
taminants at the cellular level, revealing alterations of path-
ways and metabolisms associated with AD pathogenesis of
neuropsychiatric disorders (3,89,90). Neurotoxic metals such
as lead, mercury, aluminum, cadmium and arsenic, as well
as some pesticides and metal-based nanoparticles have been
involved in AD due to their ability to increase beta-amyloid
(Ab) peptide and the phosphorylation of Tau protein (P-
Tau), causing senile/amyloid plaques and neurofibrillary tan-
gles (NFTs) characteristic of AD. The exposure to lead,
manganese, solvents and some pesticides has been related to
hallmarks of PD such as mitochondrial dysfunction, altera-
tions in metal homeostasis and aggregation of proteins such
as a-synuclein (a-syn), which is a key constituent of Lewy
bodies (LB), a crucial factor in PD pathogenesis (3,89–92).
This is an intriguing area for future research, particularly
drawing on how nutrition can play a role in modulating
cognitive decline in the face of advancing pathophysiology
and mitochondrial dysfunction and cognitive decline.
Individuals have variations in the composition of their gen-
etic characteristics (factored on strategies that embrace test-
ing for candidate-genes and genome-wide association) that
will affect the availability of functional proteins which ultim-
ately impacts functional homeostasis and the outcome of
drug therapy. The brain reflex-receptor mechanism in sig-
naling for biomarkers and availability of enzymes for metab-
olism is of critical importance here. If this is altered, cellular
homeostasis will be altered. The context of Figure 3 is edu-
cative. Underlying mechanisms are multiple but can be sum-
marized as a toxic gain of function including Tau
aggregation, release of inflammatory molecules and a loss of
physiological functions such as adult neurogenesis, glial
phagocytosis and trophic factor release, Tau-driven axonal
transport and RNA/DNA integrity. Also, environmental dis-
ease modifiers (for instance obesity, stress, caffeine con-
sumption) can act through an alteration of the
neuroimmune response and impact upon the vicious circle
(3,5,89,90). Environmental factors such as diet (fat-rich),
heavy metals, biogenic metals and pesticides have been
involved in AD development due to their ability to disrupt
metabolic pathways involved in the homeostasis of Ab
(Figure 3). The following summaries are instructive. Lead
(Pb) is a heavy metal well known for its neurological toxic
effects, although a direct association with AD development
has not been reported. Pb affects cognitive abilities, intelli-
gence, memory, speed processing and motor functions in
children, while studies in the elderly are limited. Exposure
JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION 23
to Pb during development is a good example of an environ-
mental contaminant as a risk factor to promote neurodege-
nerative diseases such as AD, supporting the hypothesis that
many adult diseases have a fetal origin. Mercury (Hg) is a
heavy metal with a high potential to cause neurotoxicity.
Early studies about Minamata and Iraq disasters led us to
understand the neurotoxicity of this metal. It is widely
accepted that Hg disrupts the brain development and produ-
ces cognitive and motor disabilities, and in adults, Hg
exposure produces memory loss and cognitive alterations.
The ability of Hg to increase Ab levels has been studied
in vitro and in vivo, and the suggested mechanisms include
an increased production, a reduced degradation and/or a
diminished brain clearance of the peptide. Inorganic arsenic
(As) is a known neurotoxic metalloid with adverse effects in
both the neurodevelopment and cognitive function, although
its effects in elderly have been less studied. A plausible
mechanism for the cognitive and memory alterations
induced by As exposure is by interfering with the amyloid
pathway. The mechanism by which As causes Ab overpro-
duction has not been determined, but As exposure has been
associated with brain inflammatory responses and oxidative
stress, which is in agreement with the inflammatory and oxi-
dative hypotheses of AD. Cadmium is another toxic heavy
metal associated with neurological alterations including
memory loss and mental retardation which may be linked to
Ab overproduction. Aluminum is a neurotoxic element
involved in the etiology of neurodegenerative disorders such
as AD; however, there is no consistent evidence. Reference
(91) reported that chronic oral Al administration in rats
(20 g/day in the food/twice weekly from 6 months of age to
the end of their lives) increases the Ab production by rais-
ing the levels of APP in hippocampal and cortical tissues
(brain regions important for the memory process). The asso-
ciation between chronic pesticide exposure and the preva-
lence of dementias, including AD has not been as well
studied as with other environmental risk factors, and results
are often inconsistent. This is mainly because the difficulty
on getting adequate data on the levels of exposure of indi-
vidual pesticides, which is often indirectly evaluated by
structure questionnaires (exposure index). The role of pesti-
cides in alterations observed in cognitive functions and AD
has been suggested based on epidemiological studies, but the
mechanisms have been poorly explored. Interesting chlor-
pyrifos (CPF), an organophosphate insecticide associated
with cognitive impairment, oxidative stress and neuronal
damage caused a significant increase in Ab levels in the cor-
tex and hippocampus, as well as increased memory loss and
reduced motor activity in Tg2576 mice 6 months after an
acute subcutaneous administration of 50 mg/Kg of CPF (92).
But the work of reference (93) did not find increased Ab
levels nor significant changes in memory acquisition in
Tg2576 mice treated with CPF (25 mg/Kg/twice weekly/
4 weeks, intragastric) and analyzed 6 months later. This indi-
cates that more studies are needed to better understand the
mechanisms by which organochlorines and organophos-
phates and other insecticides are linked to AD and PD.
24 A. AGNIHOTRI AND O. I. ARUOMA
Paraquat (PQ), is a commonly used herbicide that has
been suggested to be involved in AD development (Figure
2). One study showed that treatment of wild type and APP
transgenic (Tg2576) mice with PQ (10 mg/Kg/twice a week/
3 weeks) produced a significant increase in Ab levels that
was associated with mitochondrial oxidative damage in cere-
bral cortex leading to the impairment of learning and mem-
ory (4). The amyloid cascade hypothesis of Alzheimer’s
disease envisages that the initial elevation of amyloid b-pep-
tide (Ab) levels, especially of Ab1-42, is the primary trigger
for the neuronal cell death specific to onset of Alzheimer’s
disease. There is now substantial evidence that brain amyl-
oid levels can be manipulated because of a dynamic equilib-
rium between their synthesis from the amyloid precursor
protein and their removal by amyloid-degrading enzymes
(ADEs) providing a potential therapeutic strategy. Factors
such as lifestyle (antioxidants and exercise) can prevent AD
development. The brain is particularly vulnerable to oxida-
tive stress due to its high glucose-based metabolic rate, low
levels of antioxidants, high levels of polyunsaturated fatty
acids, and high enzymatic activities related to transition
metals that catalyze the formation of free radicals increasing
the oxidative burden. The identification and validation of
accurate biomarkers of individual responses to environmen-
tal toxicants, pharmaceutical agent (prescription drugs) or
biological secondary metabolites in foods remain prerequis-
ite conditions ascribed to the development of personalized
medicine benchmarked on nutrigenomics, toxicogenomics
and pharmacogenomics as well as other evolving therapeutic
strategies (94). The sequence variations in the genes for pro-
teins involved in xenobiotics (from drugs, environmental
toxicants to dietary supplements etc.) as discussed in this
paper on disposition can alter the pharmacokinetics of the
foreign agent, while sequence variations in target genes for
pharmacologic actions can change the pharmacodynamics of
the xenobiotics.
Conclusion
Mitochondrial dysfunction and the aggregation of misfolded
proteins are the key features of age-related neurodegenera-
tive diseases such as AD and PD. The overproduction of
ROS and/or suppression of antioxidant systems in mito-
chondria can induce severe oxidative stress, which plays an
important role in the pathogenesis of neurodegeneration.
Maintenance of the major antioxidant systems predomin-
antly superoxide dismutase and glutathione peroxidase are
crucial for normal function of the mitochondria and limits
the amount of oxidative damage. Modification in the anti-
oxidant systems is an attractive therapeutic strategy for the
treatment of various neurodegenerative diseases. Vitamin E
(a major scavenger of lipid peroxidation in brain), vitamin
C (an intracellular reducing molecule), and CoQ10 (a coen-
zyme that transfers electrons from complexes I and II to
complex III, optimizing the proton gradient of the oxidative
phosphorylation mechanisms) are commonly studied antiox-
idants for the therapeutic purpose. Although antioxidant
administration has been found to effective in number of
neurodegenerative disorders in vitro and in animal models
but does not adequately demonstrate the neuroprotection
efficacy in patients due to the chemical instability of antioxi-
dant. Modifying abnormal mitochondrial dynamics and tar-
geting mitochondrial interaction with disease-specific
proteins can be the promising strategies to treat neurodege-
nerative diseases. Diet and lifestyle changes are thought to
slow down the progression of neurodegeneration and cogni-
tive impairment at a later age. Dietary secondary metabolites
have neuroprotective effects due to their, potential antioxi-
dant activities, abilities to suppress inflammation, minimize
protein aggregation and to modulate several signaling path-
ways. In addition to healthy diet, we should educate the
people about food processing (cooking) in order to get max-
imum benefit from the food nutrients. Further studies are
needed to find a define the link of natural bioactive com-
pounds to prevent neurodegenerative diseases due to envir-
onmental exposure of toxicants and begin understanding
how nutrigenomics can foster the understanding of the indi-
vidual variabilities.
Disclosure statement
Dr Okezie I. Aruoma is a member of the Scientific Advisory Board for
Zurvita, Houston, Texas, USA.
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