Resveratrol is a natural compound that may help reduce beta-amyloid plaques and prevent/treat Alzheimer's disease. It has shown to bind to amyloid proteins, changing their shape to non-toxic forms and decreasing their accumulation in the brain. Resveratrol also has antioxidant properties that can reduce oxidative stress associated with amyloid plaque formation. While studies in cells and animals have shown promise, more research is still needed to determine resveratrol's long-term safety and effectiveness in humans for treating Alzheimer's.

1. A Promising New
Background
Alzheimer’s disease is one of the most prevalent forms of
dementia and is expected to rise.1
The following are
some alarming statistics about the disease and its
prevalence:
• Alzheimer’s disease affects 1 in 10 Americans
over 65 years old and almost 1 in 2 Americans
over 85 years old.1
• In 2000, an estimated 25 million people in the
world were diagnosed with AD. Experts project
this number to increase by 114 million by 2050.2
• Currently in the U.S, up to 5 million individuals
have the disease, which is accompanied by a
$100 billion yearly price tag.3
• These projections mean this disease will require
$20 trillion over the next 40 years with the rise in
cases.3
Proposed causes of AD include accumulation of plaques,
neurofibrillary tangles, loss of neurons, and glial
proliferations.4
Two major features of AD are the
abnormal aggregation of β-amyloid plaques (clumps of
β-amyloid proteins) and tau proteins (proteins that
stabilize microtubules).5
Although some pharmaceuticals have been developed to
aid in the symptoms of AD, many have proved to be
ineffective and may induce intolerable side effects,
therefore increasing the demand for alternative
treatments.4
Research has suggested resveratrol for the treatment and
prevention of AD.
• Resveratrol is a natural polyphenolic compound
found in giant knotweeds, peanuts, berries,
grapes, red wine, chocolate, soy and tea.2, 6
• Resvertarol has been shown to play a role as an
antioxidant, vasorelaxant, and anticarcinogen as
well as posses anti-inflammatory,
phytoestrogenic, and cardioprotective
properties.6, 7, 8, 9
• Although many studies have been conducted in
cells and animal models, resveratrol’s
effectiveness and safety in the long term in
humans still requires further research.
Resveratrol May Reduce β-
Amyloid Plaques Aiding in
the in the Prevention and
Treatment of Alzheimer’s
Disease
Image from http://www.all-creatures.org/health/alzheimers.html

2. Physiology
The senile plaques are formed from insoluble deposits of
Aβ peptide. The amyloid precursor protein is cleaved by
β, γ and α-secretase but in AD, it is abnormally cleaved
and the α-secretase does not function. This leads to an
accumulation of Aβ in the cortex and hippocampus of
individuals with Alzheimer’s disease, causing
neurological degeneration. Resveratrol dose dependently
reduces neuronal cell death associated with Aβ plaques.
Individuals with Alzheimer’s maintain an accumulation
of soluble forms of Aβ oligomers in their brain and
cerebrospinal fluid, contributing to neurodegeneration.
Studies demonstrate resveratrol may bind to Aβ proteins
which interferes with their accumulation, changes their
conformation and also decreases their toxicity. Separate
related studies have shown the compound to change the
conformation of Aβ proteins into nontoxic forms.
Stimulating protein kinase C isoforms via resveratrol
may inactivate GSK3B (a protein coding gene commonly
overexpressed in AD) which helps protect against Aβ
toxicity as well.7
Oxidative stress is another cause of AD
primarily because the brain lacks antioxidant systems
when compared to other organs. Research studies have
demonstrated resveratrol’s role in inhibiting Aβ toxicity
via antioxidant properties. Primary reactive oxygen
species produced include iNOS and COX-2 which
damage mitochondrial and cellular membranes. In the
development of AD, an increase in reactive oxygen
species as well as nitrogen oxygen species such as iNOS
and COX-2 contributes to an increase in Aβ production
and Aβ related oxidative stress and therefore, the
formation of neuritic plaques. Resveratrol has been found
to reduce iNOS levels and reduce membrane damage in
neuronal cells.4
Aβ toxicity may also be attributed to the
accumulation of reactive oxygen intermediates.
Resveratrol acts as an antioxidant through the hindering
of reactive oxygen intermediate accumulation by
downregulating NF-kappaB (a family of transcription
factors involved in DNA transcription, the immune
system and other cellular processes) as well as decreasing
tyrosine kinase activity and lipid oxidation, therefore
increasing glutathione, a free-radical scavenger. Another
study found resveratrol plays a role in decreasing
intracellular Aβ peptides through increasing proteasome
activity.10
Because resveratrol is rapidly metabolized by the liver, it has a low bioavailability. Several synthetic compounds have been
developed to solve this problem:
Compound/ Delivery System Definition Benefits
Lipid core nanocapsules with
resveratrol
Made up of an oil core formed by a
dispersion of a liquid lipid and a solid
lipid surrounded by a polymeric wall
and a particle-water interface, which is
stabilized by polysorbate 80.11
This delivery system may stabilize
photolabile substances, control drug
release, improve effectiveness, and
increase cerebral distribution of the
compound. They may increase the
photostability of resveratrol, better
target the compound to the brain tissue,
improve the compound’s antiglioma
activity and mitigate AD (based on the
Aβ 1-42 model).11
Piceid The glycoside form of resveratrol.12
Piceid exhibits high scavenging activity
against radicals and thus may aid in the
treatment of AD.13
BDPP (bioactive dietary polyphenol
preparation)
A combination of three bioactive and
commercially available polyphenol
products including Concord grape juice,
grape seed extract and resveratrol.14
It was created to simultaneously affect
multiple Alzheimer’s targets such as
amyloid load, synaptic plasticity and
cognition.14, 1
Piceatannol The compound trans-3,4,3′,5′-
tetrahydroxystilbene, which has a
structure homologous to resveratrol. It
is an anti-inflammatory stilbene derived
from the seeds of Euphorbia
lagascae.15
It may block Aβ -induced accumulation
of reactive oxygen species, which
ultimately leads to neuronal cell death.2

3. References
1. Pasinetti GM, Wang J, Ho L, Zhao W, Dubner L. Roles of Resveratrol and other grape-derived polyphenols in Alzheimer’s disease prevention and treatment.
Biochemica et Biophysica Acta. 2014; 1852: 1202-1208. doi: http://dx.doi.org/10.1016/j.bbadis.2014.10.006
2. Rege SD, Geetha T, Griffin GD, Broderick TL, Babu JR. Neuroprotective effects of resveratrol in Alzheimer disease pathology. Frontiers in Aging
Neuroscience. 2014; 6: 1-12. doi: 10.3389/fnagi.2014.00218
3. Pasinetti GD. Novel Role of Red Wine-Derived Polyphenols in the Prevention of Alzheimer’s Disease Dementia and Brain Pathology: Experimental
Approaches and Clinical Implications. Planta Med. 2012; 78: 1614-1619. doi: http://dx.doi.org/ 10.1055/s-0032-1315377
4. Ma T, Tan MS, Yu JT, Tan L. Resveratrol as a Therapeutic Agent for Alzheimer’s Disease. BioMed Research International. 2014; 2014: 1-14. doi:
http://dx.doi.org/10.1155/2014/350516
5. Brain Tour. Alzheimer’s Association Web site. https://www.alz.org/braintour/plaques.asp. Published 2011. Accessed March 10, 2016.
6. Yao Y, Li J, Niu Y et al. Resveratrol inhibits oligomeric Aβ-induced microglial activation via NADPH oxidase. Molecular Medicine Reports. 2015; 12: 6133-
6139. doi: 10.3892/mmr.2015.4199
7. Bastianetto S, Menard C, Quirion R. Neuroprotective action of resveratrol. Biochemica et Biophysica Acta. 2014; 1852: 1195-1201. doi:
http://dx.doi.org/10.1016/j.bbadis.2014.09.011
8. Malhotra A, Bath S, Elbarby F. An Organ System Approach to Explore the Antioxidative, Anti-Inflammatory, and Cytoprotective Actions of Resveratrol.
Oxidative Medicine and Cellular Longevity. 2014; 2015: 1-15. doi: http://dx.doi.org/10.1155/2015/803971
9. Zhao HF, Li N, Wang Q, Cheng XJ, Li XM, Liu TT. Resveratrol decreases the insoluble Aβ 1- 42 level in hippocampus and protects the integrity of the
blood-brain barrier in AD rats. Neuroscience. 2015; 310: 641-649. doi: http://dx.doi.org/10.1016/j.neuroscience.2015.10.006
10. Albani D, Polito L, Signorini A, Forloni G. Neuroprotective properties of resveratrol in different neurodegenerative disorders. BioFactors. 2010; 5: 370-376.
doi: 10.1002/biof.118
11. Coradini K, Lima FO, Oliveira CM et al. Co-encapsulation of resveratrol and curcumin in lipid-core nanocapsules improves their in vitro antioxidant effects.
European Journal of Pharmaceutics and Biopharmaceutics. 2014; 88: 178-185. doi: http://dx.doi.org/10.1016/j.ejpb.2014.04.009
12. Fabris S, Momo F, Ravagnan G, Stevanato R. Antioxidant properties of resveratrol and piceid on lipid peroxidation in micelles and monolamellar liposomes.
Biophysical Chemistry. 2008; 135: 76-83. doi: doi:10.1016/j.bpc.2008.03.005
13. Tellone E, Galtieri A, Russo A, Giardina B, Ficarra S. Resveratrol: A Focus on Several Neurodegenerative Disease. Oxidative Medicine and Cellular
Longevity. 2014; 2015: 1-14. doi: http://dx.doi.org/10.1155/2015/392169
14. Zhao W, Wang J, Bi W et al. Novel application of brain-targeting polyphenol compounds in sleep deprivation-induced cognitive dysfunction. Neurochemistry
International. 2015; 89: 191-197. doi: http://dx.doi.org/10.1016/j.neuint.2015.07.023
15. Kim HJ, Lee KW, Lee HJ. Protective Effects of Piceatannol against Beta-Amyloid–Induced Neuronal Cell Death. Annals New York Academy of Sciences.
2007; 1095: 473-482. doi: 10.1196/annals.1397.051
16. Alzheimer’s Disease Can Be Safely Prevented and Treated Now. All Creatures Web site. http://www.all-creatures.org/health/alzheimers.html Accessed April
12, 2016.