The effect of curcumin (turmeric) on
Alzheimer's disease: An overview
Abstract
This paper discusses the
effects of curcumin on patients with Alzheimer's disease (AD). Curcumin
(Turmeric), an ancient Indian herb used in curry powder, has been extensively
studied in modern medicine and Indian systems of medicine for the treatment of
various medical conditions, including cystic fibrosis, haemorrhoids, gastric
ulcer, colon cancer, breast cancer, atherosclerosis, liver diseases and
arthritis. It has been used in various types of treatments for dementia and
traumatic brain injury. Curcumin also has a potential role in the prevention
and treatment of AD. Curcumin as an antioxidant, anti-inflammatory and
lipophilic action improves the cognitive functions in patients with AD. A
growing body of evidence indicates that oxidative stress, free radicals, beta
amyloid, cerebral deregulation caused by bio-metal toxicity and abnormal
inflammatory reactions contribute to the key event in Alzheimer's disease
pathology. Due to various effects of curcumin, such as decreased Beta-amyloid
plaques, delayed degradation of neurons, metal-chelation, anti-inflammatory,
antioxidant and decreased microglia formation, the overall memory in patients
with AD has improved. This paper reviews the various mechanisms of actions of
curcumin in AD and pathology.
Keywords: Alternative approach to Alzheimer's, beta
amyloid plaques, curcumin, curcumin and dementia, epidemiology, turmeric
Introduction
Alzheimer's disease
Alzheimer's disease (AD) is
a progressive neurodegenerative disease. It is characterized by progressive
cognitive deterioration together with declining activities of daily living and
behavioral changes. It is the most common type of pre-senile and senile
dementia. According to the World Health Organization (WHO), 5% of men and 6% of
woman of above the age of 60 years are affected with Alzheimer's type dementia
worldwide.[
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control1] In India, the total
prevalence of dementia per 1000 people is 33.6%, of which AD constitutes
approximately 54% and vascular dementia constitutes approximately 39%. AD
affects approximately 4.5 million people in the United States or approximately
10% of the population over the age of 65, and this number is projected to reach
four times by 2050. The frequency increases to 50% by the age of 80 years.
Every year more than $100 billion is spent for health care in the U.S. to treat
AD in primary care settings alone.
Neuropathology of AD:
The neuropathological
process consists of neuronal loss and atrophy, principally in the
temporoparietal and frontal cortex, with an inflammatory response to the
deposition of amyloid plaques and an abnormal cluster of protein fragments and
tangled bundles of fibres (neurofibillary tangles). Neurotic plaques are
relatively insoluble dense cores of 5-10 nm thick amyloid fibrils with a pallor
staining “halo” surrounded by dystrophic neuritis, reactive astrocytes and
activated microglia. There is an increased presence of monocytes/macrophages in
the cerebral vessel wall and reactive or activated microglial cells in the
adjacent parenchyma.[
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control3] The main protein
component of amyloid in AD is the 39-42 amino acid (beta) amyloid peptide
(A-beta) [Figure 1].
Figure 1
Neuritic
plaques are one of the characteristic structural abnormalities found in the
brains of Alzheimer patients
Curcumin
Curcumin (Curcuma longa -
Haldi) is the source of the spice Turmeric [Figure 2] and is used in curries
and other spicy dishes from India, Asia and the Middle East. Similar to many
other herbal remedies, people first used curcumin as a food and later
discovered that it also had impressive medicinal qualities. It has been used
extensively in Ayurveda (Indian system of Medicine) for centuries as a pain
relieving, anti-inflammatory agent to relieve pain and inflammation in the skin
and muscles. It has also proven to have anti-cancer properties.[
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control5] Curcumin holds a high
place in Ayurvedic medicine as a “cleanser of the body,” and today, science is
finding a growing list of diseased conditions that can be healed by the active
ingredients of turmeric.[
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Figure 2
(2a)
Turmeric, (2b) Turmeric plant, (2c) Keto and enol form of curcumin
The Plant
Botanical name: Curcuma
longa; Family: Zingiberaceae, the ginger family. Turmeric is a sterile plant
and does not produce any seeds [Figure 2]. The plant grows up to
3-5 ft tall and has dull yellow flowers. The underground rhizomes or roots of
the plant are used for medicinal and food preparation. The rhizome is an
underground stem that is thick and fleshy ringed with the bases of old leaves.
Rhizomes are boiled and then dried and ground to make the distinctive bright
yellow spice, turmeric.
Turmeric History:
Probably originating from
India, turmeric has been used in India for at least 2500 years. It is most
common in southern Asia and particularly in India. Turmeric was probably
cultivated at first as a dye and later on it was used as cosmetic and as an
auspicious and aromatic food substance. It possesses antiseptic,
anti-inflammatory detoxifying properties as well as carminative properties.
Turmeric has a long history of medicinal use in South Asia and was widely used
in Ayurvedic, Siddha and Unani systems. It is thought to be a hybrid selection
and vegetative propagation of wild turmeric (Curcuma aromatica), which is
native to India, Sri Lanka and the eastern Himalayas and some other closely
related species.
Curcumin and Alzheimer's Disease
Worldwide, there are over
1000 published animal and human studies, both in vivo and in
vitro in which the effects of curcumin on various diseases have been
examined. Studies include epidemiological, basic and clinical research on AD.
Bio
Chemical properties
Epidemiological Studies
Various studies and
research[
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control10] results indicate a lower
incidence and prevalence of AD in India. The prevalence of AD among adults aged
70-79 years in India is 4.4 times less than that of adults aged 70-79 years in
the United States.[
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control9] Researchers investigated
the association between the curry consumption and cognitive level in 1010
Asians between 60 and 93 years of age. The study found that those who occasionally
ate curry (less than once a month) and often (more than once a month) performed
better on a standard test (MMSE) of cognitive function than those who ate curry
never or rarely.[
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Mechanism of action of
curcumin on Alzheimer's disease:
The process through which
AD degrades the nerve cells is believed to involve certain properties:
inflammation, oxidative damage and most notably, the formation of beta-amyloid
plaques, metal toxicity [Figure 3]. There have been several
studies on effects of curcumin on AD. Outlined below are some of the studies
and their conclusions.
Figure 3
Different
mechanisms of action of curcumin in AD
Effects of Curcumin on Macrophages
A study conducted at UCLA
found that curcumin may help the macrophages to clear the amyloid plaques found
in Alzheimer's disease. Macrophages play an important role in the immune
system. They help the body to fight against foreign proteins and then
effectively clear them. Curcumin was treated with macrophages in blood taken
from nine volunteers: six AD patients and three healthy controls. Beta amyloid
was then introduced. The AD patients, whose macrophages were treated with
curcumin, when compared with patients whose macrophages were not treated with curcumin,
showed an improved uptake and ingestion of the plaques. Thus, curcumin may
support the immune system to clear the amyloid protein.[
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Curcumin on glial
cells:
Recent histological studies
reveal the presence of activated microglia and reactive astrocytes around
A-beta plaques in brains from patients with AD. The chronic activation of
microglia secretes cytokines and some reactive substances that exacerbate
A-beta pathology. So neuroglia is an important part in the pathogenesis of AD.
Curcumin has a lipophilic property and can pass through all cell membranes and
thus exerts its intracellular effects. Curcumin has anti-proliferative actions
on microglia. A minimal dose of curcumin affects neuroglial proliferation and
differentiation. Its inhibition of microglial proliferation and differentiation
were studied and researched by the University of Southern California Los
Angeles (UCLA). Researchers[
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control12] using doses of 4, 5, 10,
15, 20 microM concentration of curcumin in C-6 rat glioma 2B-clone cells, a
mixed colony of both neuroglial cells in a six- day trial, showed that curcumin
dose dependently stops the proliferation of neuroglial cells, by differentiate
into a mature cell or undergo apoptosis. It inhibits neuroglial cells
proliferation dose dependently (i.e.) higher the concentration, the greater the
inhibition. It has shown to decrease the glutamine synthetase (GS) assay, a
marker enzyme for astrocytes. In the same study, curcumin was shown to increase
CNP (2′3′- cyclic Nucleotide 3′-phosphohydrolase), a marker enzyme for
oligodendrocytes. The overall effect of curcumin on neuroglial cells involves
decreased astrocytes proliferation, improved myelogenesis and increased
activity and differentiation of oligodendrocytes.
Curcumin as an Anti Inflammatory in
Alzheimer's
One of the important
pathogenesis in Alzheimer's disease is the chronic inflammation of nerve cells.
Several studies have demonstrated the associated inflammatory changes such as
microgliosis, astrocytosis and the presence of pro-inflammatory substances that
accompany the deposition of amyloid-β (Aβ) peptide. Patients with the prolonged
use of certain nonsteroidal anti-inflammatory (NSAID) drugs such as ibuprofen
have been shown to have a reduced risk of developing the symptoms of AD;
however, the chronic use of NSAID can cause a toxic effect on the kidneys,
liver and GI track. Curcumin has a potent anti-inflammatory effect. Through its
various anti-inflammatory effects, it may have a role in the cure of AD.
Curcumin inhibits Aβ-induced expression of Egr-1 protein and Egr-1 DNA-binding
activity in THP-1 monocytic cells. Studies have shown the role of Egr-1 in
amyloid peptide-induced cytochemokine gene expression in monocytes. By
inhibition of Egr-1 DNA-binding activity by curcumin, it reduces the inflammation.
The chemotaxis of monocytes, which can occur in response to chemokines from
activated microglia and astrocytes in the brain, can be decreased by curcumin.[
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Curcumin is found to
inhibit cyclooxygenase (COX-2), phospholipases, transcription factor and
enzymes involved in metabolizing the membrane phospholipids into
prostaglandins. The reduction of the release of ROS by stimulated neutrophils,
inhibition of AP-1 and NF-Kappa B inhibit the activation of the
pro-inflammatory cytokines TNF (tumor necrosis factor)-alpha and IL
(interleukin)-1 beta.[
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control16] Overall, curcumin
decreases the main chemical for inflammation and the transcription of
inflammatory cytokines. Curcumin inhibits intracellular IL-12 p40/p70 and IL-12
p70 expression. The exposure to curcumin also impaired the production of
pro-inflammatory cytokines (IL-1, IL-6 and TNF-). These studies indicate a
potent inhibitor of pro-inflammatory cytokine production by curcumin and it may
differ according to the nature of the target cells.
Curcumin as an Anti-oxidant
Curcumin inhibits the
activity of AP-1, a transcription factor involved in expression of amyloid,
which is linked to AD. Curcuminoids are proven to have strong antioxidant
action demonstrated by the inhibition of the formation and propagation of free
radicals. It decreases the low-density lipoprotein oxidation and the free
radicals that cause the deterioration of neurons, not only in AD but also in
other neuron degenerative disorders such as Huntington's and Parkinson's
disease.[
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control16] In one study, curcuma oil
(500 mg Kg(-1) i.p.) was given 15 min before 2 h middle cerebral artery
occlusion, followed by 24 h reflow in rats. This significantly diminished the
infarct volume, improved neurological deficit and counteracted oxidative
stress.[
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A study conducted at
Nanjing Medical University (China) showed that a single injection of curcumin
(1 and 2 mg/kg, i.v.) after focal cerebral ischemia/reperfusion in rats
significantly diminished the infarct volume, improved neurological deficit,
decreased mortality and reduced the water content in the brain.[
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Curcumin has powerful
antioxidant and anti-inflammatory properties; according to the scientists,
these properties believe help ease Alzheimer's symptoms caused by oxidation and
inflammation.[
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control19] A study conducted at
Jawaharlal Nehru University (India) demonstrated that the administration of
curcumin significantly reduced lipid peroxidation and lipofuscin accumulation
that is normally increased with aging.[
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control20] It also increased the
activity of superoxide dismutase, sodium-potassium ATPase that normally
decreased with aging. In another study, curcumin has been shown to protect the
cells from betaA (1-42) insult through antioxidant pathway.[
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control21] Curcumin protects brain
mitochondria against various oxidative stress. Pre-treatment with curcumin
protects brain mitochondria against peroxynitrite (a product of the reaction of
nitric oxide with superoxide) a potent and versatile oxidant that can attack a
wide range of cells in vitro by direct detoxification
and in vivo by the elevation of total cellular glutathione
levels.[
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Curcumin on Haemoxygenase Pathway
Natural antioxidant
curcumin has been identified as a potent inducer of hemoxygenase, a protein
that provides efficient cytoprotection against various forms of oxidative
stress. By promoting the inactivation of Nrf2-keap1 complex and increased
binding to no-1ARE, curcumin induces hemoxygenase activity. The incubation of
astrocytes with curcumin at a concentration that promoted hemoxygenase activity
resulted in an early increase in reduced glutathione, followed by a significant
elevation in oxidized glutathione content.[
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control25] Glutathione is an
important water-phase antioxidant and essential cofactor for antioxidant
enzymes protecting the mitochondria against endogenous oxygen radicals. Its
level reflects the free radical scavenging capacity of the body. GSH depletion
leads to tissue damage due to lipid peroxidation and oxidative damage.
Beta-Amyloid Plaques
The most prominent
characteristic feature in AD is the presence of beta-amyloid plaques. These
plaques are basically an accumulation of small fibers called beta amyloid
fibrils. Because the deposition of beta-amyloid protein is a consistent
pathological hallmark of brains affected by AD, the inhibition of A-beta
generation, prevention of A-beta fibril formation, destabilization of
pre-formed A-beta would be an attractive therapeutic strategy for the treatment
of AD. The levels of beta-amyloid in AD mice that were given low doses of
curcumin were decreased by around 40% in comparison to those that were not
treated with curcumin. In addition, low doses of curcumin also caused a 43%
decrease in the so-called “plaque burden” that these beta-amyloid have on the
brains of AD mice. Surprisingly low doses of curcumin given over longer period
were actually more effective than high doses in combating the neurodegenerative
process of AD.[
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control26] At higher concentration,
curcumin binds to amyloid beta and blocks its self assembly. The key chemical
features in amyloid beta are the presence of two aromatic end groups and any
alterations in these groups has profound effect on its activity.
Because of the lipophilic
nature of curcumin, it crosses the blood brain barrier and binds to plaques.
Curcumin was a better A-beta 40 aggregation inhibitor and it destabilizes the
A-beta polymer. In in vitro studies, curcumin inhibits
aggregation as well as disaggregates to form fibrillar A-beta 40. A Japanese
study showed that using fluorescence spectroscopic analysis with thioflavin T
and electron microscopic studies, curcumin destabilizes the fA-beta(1-40) and
fA-beta(1-42) as well as their extension.[
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control27] Curcumin-derived
isoxazoles and pyrazoles bind to the amyloid beta peptide (Abeta) and inhibit
amyloid precursor protein (APP) metabolism.[
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control28] Curcumin given to
APPswe/PS1dE9 mice for 7 days crosses the blood-brain barrier as demonstrated
by muliti-photon microscopy and reduces the existing senile plaques.[
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control29] In another study,
curcumin has been shown to increase the phagocytosis of amyloid-beta,
effectively clearing them from the brains of patients with AD.[
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Metal Chelation
Studies showed that metals
can induce A-beta aggregation and toxicity and are concentrated on Alzheimer's
brain. Chelators' desferroxamine and cliquinol have exhibited anti-Alzheimer's
effects. A study at Capital University Beijing demonstrated the toxicity of
copper on neurons. A greater amount of H2O2 was released when
copper (2)-A(beta)-40 complexes were added to the xanthene oxidase system.
Copper was bound to A(beta)1-40 and was observed by electron paramagnetic
resonance spectroscopy. In addition, copper chelators could cause a structural
transition of A(beta). There was an increase on beta sheet as well as
alpha-helix when copper was introduced.[
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control31] Another study reveals
that copper and zinc bind A-beta inducing aggregation and give rise to reactive
oxygen species. There was a conformational change from beta sheet to alpha
helix followed by peptide oligomerization and membrane penetration, when copper
(or) zinc is added to A-beta in a negatively charged lipid environment.[
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control32] Brain iron deregulation
and its association with amyloid precursor protein plaque formation are
implicated in the pathology of AD.[
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Curcumin, by interaction
with heavy metals such as cadmium and lead, prevents neurotoxicity caused by
these metals. The intraperitoneal injection of lead acetate in rats in the
presence of curcumin was studied microscopically. The results show lead-induced
damage to neurons was significantly reduced in rats injected with curcumin.[
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control34] A study at Chinese
University of Hong Kong showed that by using spectrophotometry, the curcumin
effectively binds to copper, zinc and iron. In addition, curcumin binds more
effectively with redox-active metals such as iron and copper than the
redox-inactive zinc. It is suggested that curcumin suppresses inflammatory
damage by preventing metal induction of NF-kappa.[
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Cholesterol Lowering Effect
High-fat diets and
increased blood cholesterol are linked to increased amyloid plaques by the intracellular
accumulation of cholestryl esters.[
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control37] Researchers believe that
by inhibiting cholesterol formation and decreasing serum peroxides, curcumin
might exert beneficial effects on AD.[
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Safety
Oral bioavailability:
Curcumin has poor
bioavailability. Because curcumin readily conjugated in the intestine and liver
to form curcumin glucuronides.[
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control39] In a clinical trial
conducted in Taiwan, serum curcumin concentrations peaked one to two hours
after an oral dose. Peak serum concentrations were 0.5, 0.6 and 1.8
micromoles/L at doses of 4, 6 and 8 g/day respectively.[
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control40] It is also measured in
urine at a dose of 3.6 g/day. Absorption is poor following ingestion in mice
and rats. 38% to 75% of an ingested dose of curcumin is excreted in the feces.
Absorption appears to be better with food. Curcumin crosses the blood brain
barrier and is detected in CSF.
Side Effect
No apparent side effects
have been reported thus far. GI upset, chest tightness, skin rashes, swollen
skin are said to occur with high dose. A few cases of allergic contact
dermatitis from curcumin have been reported.[
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The chronic use of curcumin
can cause liver toxicity. For this reason, turmeric products should probably be
avoided by individuals with liver disease, heavy drinkers and those who take prescription
medications that are metabolized by liver. Curcumin was found to be
pharmacologically safe in human clinical trials with doses up to 10 g/day. A
phase 1 human trial with 25 subjects using up to 8000 mg of curcumin per day
for three months found no toxicity from curcumin.[
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Interaction
Curcumin is said to
interact with certain drugs such as blood thinning agents, NSAIDs, reserpin.
Co-supplementation with 20 mg of piperine (extracted from black pepper)
significantly increase the bioavailablity of curcumin by 2000%.[
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Contraindication
Curcumin is not recommended
for persons with biliary tract obstruction because it stimulates bile
secretion. It is also not recommended for people with gallstones, obstructive
jaundice and acute biliary colic. Curcumin supplementation of 20-40 mg have
been reported to increase gallbladder contractions in healthy people.[
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Human
Epidemiological studies
have shown that prevalence of AD is 4.4 lower amongst Indian Asians as compared
to people of western origin.[
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control9] D ementia
incidence in western countries (P < 0.21) and East Asian
countries were lower than that of Europe (P < 0.0004).[
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Experimental
studies: Statistical significance
Clinical -Vivo: Blood from six
patients with AD and three healthy controls was taken and the macrophage cells
were isolated. After treatment of macrophages with curcuminoids, Aβ uptake by
macrophages of three of the six AD patients was found to have significantly increased
(P < 0.001 to 0.081).[
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Five animal and two human
studies showed statistically significant P values.
Conclusion
Based on the main findings
detailed above, curcumin will lead to a promising treatment for Alzheimer's
disease. The clinically studied chemical properties of curcumin and its various
effects on AD shows the possibility to do further research and develop better
drugs based on curcumin for treating AD. The recent review paper of John
Ringman also supports some of the abovementioned properties of curcumin in AD;[
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control50] however, large-scale
human studies are required to identify the prophylactic and therapeutic effect
of curcumin.
Several unanswered
questions remain: What is the one main chemical property of curcumin that can
be exploited in treating AD? What is the role of curcumin in other neurological
disorders such as Parkinson's, Huntington's and other dementias? How does
curcumin interact with neuronal plaques? Is it effective only as a food
additive? Would it be effective when used alone or with other anti inflammatory
drugs?
Footnotes
Source of Support: Nil
Conflict of
Interest: Nil
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