Alzheimer's disease

1. ROLE OF CURCUMIN
IN TREATMENT OF
ALZHEIMER’S DISEASE
By :- Khushboo Thakur
Academic Writing
khushithakur874@gmail.com

2. CONTENT
1.Introduction
2. Pathophysiology of Alzheimer’s disease
3. Amyloid β and Tau Protein in Alzheimer’s disease
4. Current Pharmacotherapies for Alzheimer’s disease
5. Curcumin
5.1. History of Curcumin
5.2. Bioavailability and Potency of Curcumin and its Metabolites
5.2.1. Strategies to Increase Bioavailability of Curcumin
5.3. Role of Curcumin in Alzheimer’s disease
5.3.1. Mechanism of Action of Curcumin in Alzheimer’s disease
5.3.1.1. Aβ inhibition
5.3.1.2. Tau inhibition

3. 5.3.1.3. Acetylcholinesterase Inhibition
5.3.1.4. Cholesterol lowering ability
6. Limitation and Future Research
7. Reference

4. 1.Introduction
• Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common
cause of dementia in adults.
• Alzheimer’s disease (AD), accounting for 60 to 80% of dementia cases, is an irreversible,
progressive brain disorder characterized by behavioral changes and loss of cognitive functions.
Common symptoms include short-term memory loss, cognitive deficits, and an inability to
perform tasks of daily living.
• The life expectancy following diagnosis ranges from an average of three to nine years.
• Globally, approximately 46 million people are afflicted with dementia and the population ages,
the number is projected to increase to 131.5 million by 2050.
• The deposition of senile plaques composed by fibrillar aggregates of amyloid β peptide (Aβ) is a
characteristic hallmark of the pathology and is considered fundamental in disease
pathogenesis.(fig 1.)

5. Fig.1 Neuropathological-characteristics-of-Alzheimers-disease-amyloid-plaques-and neurofibrillary tangles.

6. • Curcumin has been reported historically in ayurvedic medicine especially in India and other oriental
countries to have potential to treat many diseases like acute dermatitis, hepatitis, erectile dysfunction,
hirsutism, baldness, cancer and neurodegenerative diseases.
• It is a hydrophobic polyphenol derived from the rhizome of the herb Curcuma longa has a wide range
of biological and pharmacological activities. Traditionally turmeric is used as a curry spice in foods
in India.
• Though curcuminoids have got great attention as it consist major medicinal property of turmeric
which is rather mixture of curcumin, a diferuloylmethane (75-80%), demethoxycurcumin (15-20%)
and bisdemethoxy-curcumin (3-5%) (Figure 2.).
• Curcumin also acts as a hepato and nephro-protective, thrombosis suppressing, myocardial infarction
protective, hypoglycaemic and antirheumatic agent.

7. Figure 1. (A) Structures of natural curcumin derivatives, curcuminoids, (1–4). (B) Structures of main curcumin
metabolites (5–7).

8. 2. Pathophysiology of Alzheimer’s disease
• The main histological features of AD include neuronal loss, senile
plaques, neurofibrillary tangles, and accumulation of cytosolic lipids.
• The loss of neurons and synapses results in atrophy of the cerebral cortex
and subcortical regions, principally in the temporal lobe, parietal lobe, and
frontal cortex.
• The other disease mechanism hypotheses are contingent on two proteins:
amyloid-β (Aβ) peptide and tau, the former forming plaques and the latter
forming tangles.
• Aβ peptides easily aggregate into oligomers around cells and have a
crucial role in pathogenic events. These events include increased calcium
influx, oxidative stress, inflammatory processes, altered kinase and
phosphatase activities.

9. AβPP
Aβ40 Aβ42
BACE-1&γ-SECRETASE
β-APP cleaving enzyme 1 (BACE1)
amyloid-β precursor protein (AβPP)

11. 3. Amyloid β and Tau Protein in Alzheimer’s
disease
• Amyloid beta (Aβ) is one of the indications of AD pathogenesis.
• Alzheimer’s disease patients mainly possess:
senile plaques,
neurofibrillary tangles and
extensive neuronal loss in brain (Figure 3.).
• Aβ is responsible for senile plaque formation and tau protein responsible
for neurofibrillary tangles.

12. Figure 3. Diagrammatic representation of brain showing senile plaques and tangles at
one side and normal morphology on another side.

13. • In AD brain a high amount of Aβ fibril deposition leads to neuropathology including depletion of
neuron and deterioration of neuronal functions .
• Some occurrence of mutation are also reported near the Aβ region of the coding sequence of APP
gene which further deteriorated by the enzyme proteases called α-, β- and γ-secretases .
• Therefore conversion in APP metabolism through secretases or abnormal nature of APP
metabolism might be a key for AD pathogenesis.

14. 4. Current Pharmacotherapies for
Alzheimer’s disease
• The oldest hypothesis for the etiology of the disease, is the cholinergic
hypothesis on which four present drug treatments are founded upon.
• It proposes that AD is caused by loss of cholinergic neurons, and a
decrease in Ach levels results in short term memory loss and confusion.
• Acetyl cholinesterase (AchE) inhibitors (Table 1.) are a class of drugs that
reduce the rate at which Ach is degraded in the synapse, thus increasing
the concentration of Ach in the brain.

15. Table 1. Drug treatment of Alzheimer's disease.

16. • Memantine is a NMDA receptor antagonist that inhibits over stimulation by glutamate and has also
be indicated for the treatment of AD.
• While AchE inhibitors and NMDA antagonists are prescribed for AD, none of these drugs are
curative.
• The available treatments target the symptoms of the disease, have a small benefit, and are
palliative in nature.
• The efficacy of AchE inhibitors declines as cholinergic neurons degenerate during the progression
of the disease.
• Current therapies also have other disadvantage such as cost, side effects, the need for a
prescription, and lack of accessibility. As such, there is a need to explore other pharmacotherapies
that are more accessible and alter the disease process.

17. 5. Curcumin
5.1. History of Curcumin
• Curcumin is a polyphenol obtained from turmeric (Curcuma longa), an
herb native to southern Asia.
• It is basically used as a spice in south eastern Asian cuisine, as a food-
coloring agent, and has been utilized in conventional medicine practices.
• In Ayurveda, curcumin has been reported for centuries to treat respiratory
conditions, liver disorders, anorexia, cough, rheumatism, among other
disorders.
• The past decade has shown a gush in research in exploring the
compound’s antifungal, antiviral, antioxidant, and anti-inflammatory
properties.

18. • In epidemiological studies, India has been accepted to have one of the
lowest prevalence rates of AD in the world.
• Since India has widespread turmeric utilization, with individuals
consuming 21.7 to 28.6 gm per month, the neuroprotective function of
curcumin in AD is a possibility.
• Since the relationship between curcumin utilization and a lower
prevalence of AD been noticed, basic scientific investigation has focused
on the mechanisms of action in which curcumin may act in AD to confirm
its potential benefit.

19. 5.2. Bioavailability and Potency of
Curcumin and its Metabolites.
• An agent primarily show the reduced bioavailability DUE TO
 low intrinsic activity,
poor absorption,
high rate of metabolism,
 inactivity of metabolic products,
 rapid elimination and clearance from the body.
• When curcumin is taken orally it is conjugated with glutathione,
glucuronate or sulphate to give water soluble compounds in liver and
intestine.

20. • Alternatively, reduced to hexahydrocurcumin and tetra hydrocurcumin
when taken through intraperitoneal injection. These metabolites are less
bioactive than curcumin itself (Fig.4).
Fig 4. Curcumin Metabolite

21. 5.2.1. Strategies to Increase Bioavailability
of Curcumin
• Some new strategies have come up to overcome this problem including:
complex formation with nanoparticle,
liposome,
micelle, and
phospholipids .
which are capable to keep up longer circulation, better permeability, and
resistance to metabolic processes.
• They are mostly polymer-based nanoparticle of curcumin with less than
100 nm size.

22. • Later Tiyaboonchai et al. have reported curcuminoid loaded Solid Lipid
Nanoparticle (SLNs) having 450 nm sizes showing prolonged in vitro
release of curcuminoids.
• Thereafter in vivo study with healthy volunteers showed the improved
efficacy of SLNs loaded curcuminoid over free curcumin.
• Liposomal curcumin activity against human pancreatic carcinoma via in
vitro and in vivo analysis where curcumin liposome inhibits pancreatic
carcinoma growth and exhibit antiangiogenic activity.
• Micelle and phospholipid complexes also have a significant role to
improve gastrointestinal absorption of natural drugs maintaining higher
concentration at plasma level and a lower rate of elimination.

23. • Another study done by Sui et al illustrated the activity of curcumin an in
vitro inhibitor of HIV1 and HIV-2 proteases where curcumin complex
with boron showed 10 fold enhancement compare to curcumin alone.
Curcumin boron complex (Fig.5) also lowered the IC50 values
significantly.
• Further, they concluded that the complex might be useful as a
neuroprotective agent to treat acute brain pathologies associated with
NO-induced neurotoxicity and oxidative stress-induced neuronal
damage like epilepsy, stroke and traumatic brain injury.

24. Fig. 5. Curcumin boron complex

25. 5.3. Role of Curcumin in Alzheimer’s
disease
• Brain inflammation in Alzheimer’s disease (AD) patients is characterized
by increased cytokines and activated microglia.
• Epidemiological studies suggest reduced AD risk is associated with long-
term use of nonsteroidal anti-inflammatory drugs (NSAIDs).
• Whereas chronic ibuprofen suppressed inflammation and plaque-related
pathology in an Alzheimer transgenic APPSw mouse model (Tg2576).
• Excessive use of NSAIDs targeting cyclooxygenase I can cause
gastrointestinal, liver, and renal toxicity. One alternative NSAID is
curcumin.

26. • With low-dose, curcumin treatment, the astrocytic marker glial fibrillary
acidic protein was reduced, soluble Aβ, and plaque burden were
significantly decreased, by 43 to 50%.

27. 5.3.1. Mechanism of Action of Curcumin in
Alzheimer’s disease
Curcumin’s mechanisms of action are pleiotropic (Fig. 6.). It targets the two
histological markers of AD, Aβ and tau.
Additionally, curcumin modulates other aspects of the disease process. It
also binds copper, lowers cholesterol, modifies microglial activity, inhibits
acetyl cholinesterase, enhances the insulin-signaling pathway, and is an
antioxidant.

28. Figure 6. This flowchart illustrates the diverse mechanisms of action by which curcumin offers neuroprotection in AD. The
compound inhibits the production and neurotoxicity of the two histological markers of AD, amyloid-β and hyper phosphorylated tau.
Additionally, curcumin modulates other aspects of the disease process. It binds copper, lowers cholesterol, modifies microglial
activity, inhibits acetyl cholinesterase, enhances the insulin-signalling pathway, and is an antioxidant.

29. 5.3.1.1. Aβ inhibition
• Since the deposition of Aβ plaques is the characteristic feature of AD,
curcumin has been studied for its ability to prevent the formation and
accumulation of Aβ.
• Intragastric curcumin administration to a mice model of AD reduced Aβ
formation by downregulating BACE1 expression, the enzyme that cleaves
AβPP to Aβ.

30. • Identified curcumin as inhibitor of BACE1 in vitro. Another enzymatic
target for the production of Aβ is presenilin-1 (PS-1), a protein in the γ-
secretase complex and a substrate for glycogen synthase kinase-3β (GSK-
3β). γ-secretase and GSK-3 are both implicated in the generation of Aβ.
• When human neuroblastoma SHSY5Y cells were treated with curcumin,
there was a marked reduction in the production of Aβ. There was also a
decrease in PS-1 and GSK-3β protein levels in a dose- and time-dependent
manner, suggesting that curcumin decreased Aβ production through
inhibition of GSK- 3β-dependent PS1 activation.

31. • In addition to inhibiting Aβ production, curcumin has been demonstrated to inhibit aggregation
and promote disaggregation of fibrillar Aβ in vivo and in vitro.
• This mechanism may be due to the structure of curcumin: an in vitro study postulated that the
the hydrophobicity of curcumin or the inter- actions between the keto or enol rings of curcumin
and aromatic rings of Aβ dimers destabilized the attractions requisite for the formation of beta-
sheets in Aβ plaques.
• A study of human neuroblastoma SHSY5Y cells showed that curcumin protected against Aβ
membrane-mediated neurotoxicity by reducing the rate of Aβ insertion into the plasma
membrane.
• Curcumin impaired Aβ-membrane interactions and reduced Aβ-induced membrane disruption in
artificial lipid bilayers, thereby potentially avoid high calcium influx and cell death.

32. 5.3.1.2. Tau inhibition
• Hyper phosphorylated tau and its aggregation into neurofibrillary tangles
are crucial to the pathogenesis of AD, and numerous studies have shown
that curcumin to prevent tau hyper phosphorylation and neurotoxicity.
• GSK-3β is an enzyme that adds phosphate groups onto serine and
threonine amino acid residues and regulates the phosphorylation of tau.
• In human neuroblastoma SHSY5Y261 cells, curcumin inhibited tau hyper
phosphorylation through the phosphatase and tensin homologue
(PTEN)/protein kinase B (Akt)/GSK-3β pathway, a cellular signalling
pathway induced by Aβ.
• Curcumin may also have a role in tau tangle clearance and alleviating tau-
induced neurotoxicity.
• BCL2 associated athanogene 2 (BAG2) is a molecular protector that
delivers tau to the proteasome for degradation.

33. 5.3.1.3. Acetylcholinesterase Inhibition
• Curcumin has also been revealed to modulate AchE in a mechanism
similar to the first-line prescribed drugs for AD, AchE inhibitors.
• Cadmium poisoned rats had higher levels of AchE activity, and curcumin
treatment reversed this activity to control levels.
• Curcumin did not prevent the effect of chronic cadmium administration on
AchE activity in the cerebral cortex synaptosomes of rats, but was able to
inhibit AchE in the cortex and striatum.
• Similar to cadmium, monosodium glutamate (MSG) also causes
neurotoxicity.

34. • Rats orally administered MSG had a significant elevation in AchE level
compared to the control group.
• However, when rats were administered MSG and curcumin, they showed a
significant decrease in AchE activity when compared to the MSG only
group.
• Curcumin prevented the cognitive deficits associated with chronic alcohol
consumption in rats, partially by attenuating alcohol-induced activation of
AchE activity.

35. 5.3.1.4. Cholesterol lowering ability
• Plasma cholesterol levels are approximately 10% higher in AD patients in
comparison with healthy controls, and high cholesterol levels alter AβPP
metabolism to increase Aβ production.
• Individuals with the ε4 allele of ApoE are at an increased risk of
developing AD.
• The ApoE protein transports cholesterol in the brain and aids in the
aggregation of Aβ.
• Curcumin has been shown to inhibit sterol regulatory element binding
proteins (SREBPs). These are transcription factors that upregulate the
synthesis of enzymes involved in glycolysis, energy production,
lipogenesis, and cholesterol production.

36. • In vitro, curcumin inhibited SREBP expression in hepatocytes, thereby
decreasing the biosynthesis of cholesterol and fatty acid.
• In vivo, in vascular smooth muscle cells, curcumin inhibited cholesterol
accumulation by inhibiting the nuclear translocation of SREBP-1.
• Curcumin downregulated pro- protein convertase subtilisin/kexin type 9
(PCSK9) gene expression, a protein involved in LDL receptor breakdown.
• Thus, when curcumin lowered PCSK9 expression, more LDL receptors
were available to uptake cholesterol-rich LDL.

37. 6. Limitation and Future Research
• The key obstacle to utilizing curcumin as a therapeutic compound in
humans is its low oral bioavailability.
• Accordingly, future research should focus on improving the bioavailability
of curcumin.
• Presently, curcumin analogs, conjugation to nano particles, the use of
micelles, cyclodextrins, and phospholipid complexes, and consumption
with an adjuvant can increase serum concentrations, improve solubility,
reduce metabolism, and increase bioavailability.
• Thus, an area for further research is the analysis of different oral
formulations in the context of a clinical study to treat AD. In addition,
both toxicological and pharmacokinetic profiles should be required for any
new curcumin formulations including the oral ones.

38. Figure 8. This flowchart categorizes the directions for future research of curcumin’s effects in AD into two categories:
clinical research and basic research. The key barrier to clinical utility is curcumin’s lack of oral bioavailability. While
oral formulations that improve bioavailability are available, there exists a need to apply these formulations in a clinical
trial. Additionally, future clinical trials should investigate the efficacy of curcumin in AD when it is consumed with
high-lipid and/or digestible carbohydrate- rich foods, two dietary factors that enhance curcumin absorption. In basic
research, certain mechanisms of action of curcumin need further elucidation. As such, more in vivo studies need to
be conducted, especially in animal models of AD. Furthermore, curcumin has shown to interfere with assay readouts,
so researchers should be prudent to exclude or account for such interference to avoid reports of false activity.

39. • Another area needing further investigation is the analysis of biomarkers and
behaviour as a means of evaluating AD progress when treatment with
curcumin is applied in vivo.
• Further studies could investigate the levels of SREBPs, LDL receptors, or
transporters alongside behavioural outcomes in animal models of AD.

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