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Alzheimer’s disease (AD) is a disease of concern due to its many implications on the individual, family and friends, and even the economy. 1,2 The pathogenesis of AD is not widely understood, but one of the main proposed causes of cognitive impairment in AD is β-amyloid accumulation and toxicity in the brain. This accumulation of β-amyloid proteins in the cortex and hippocampus of individuals with AD causes neurological degeneration. 3 Through our research, we aim to explain resveratrol (Res) action in inhibiting β-amyloid accumulation and toxicity and to propose Res as a potential therapeutic agent in the prevention and treatment of AD. Future long-term research is needed in this area to ensure that Res is a safe and effective treatment on human subjects at risk of developing or suffering from AD. Resveratrol May Reduce β-Amyloid Plaques Aiding in the Treatment and Prevention of Alzheimer's Disease Erin Meyer, Kendra Parker, Mia Matthews Department of Food Science & Human Nutrition, Colorado State University, Fort Collins, CO, USA AD affects 1 in 10 Americans over 65 years old 1 and is accompanied with a loss of memory and language, the inability to learn and perform calculations, and a distorted perception of space. Patients may also experience depression, delusions and other cognitive impairments. AD poses a great emotional and economical burden on those whose lives it effects directly as well as society as a whole. There is currently no cure for the condition and very few FDA approved, efficacious treatments exist. 2 One major feature of AD is the abnormal aggregation of β-amyloid proteins resulting in the accumulation of neuritic plaques causing neuronal damage and loss. 4, 2, 5, 3 Ineffective drugs accompanied with intolerable side effects have perpetuated the demand for alternative treatments. 3 Research has suggested that Res, a polyphenol found in grapes, berries, tea and soy, 6,7 may reduce this accumulation and consequent neuronal deterioration. Therefore, Res may be beneficial in AD treatment and prevention. 2 Introduction myteastories.com Physiology AD is a serious condition accompanied with significant emotional and economic burdens and its prevalence is on the rise. Research aimed towards the treatment and prevention of AD is extremely crucial for our growing older adult population and ineffective drugs with intolerable side effects stimulate the demand for alternative treatments. 3 Research has shown that Res could be a potential therapeutic tool used to combat this disease due to it’s action against β-amyloid accumulation and toxicity via binding to β-amyloid proteins and changing its conformation. This results in the inhibition of their accumulation and formation of neuritic plaques as well as reducing its toxicity. Therefore, Res is an important compound of interest for future research on interventions against the development of AD. Although many studies have been conducted in vitro and in animal models, Res’s effectiveness and long term safety in humans remains unknown and therefore warrants the need for large scale, long-term clinical trials using resveratrol and its derivatives/ synthetics. Res has been theorized to work through several mechanisms including actions as an anti- inflammatory and antioxidant, modulating cell death and cell pathways, preventing telomere shortening and protecting the blood brain barrier. 7, 8, 5, 9 Much of the current research targets Res’s ability to inhibit β-amyloid protein aggregation. 8, 9, 10 In the development of AD, an increase in reactive oxygen species (ROS) contributes to an increase in β-amyloid protein production and related oxidative stress. Additionally, the amyloid precursor protein, a transmembrane glycoprotein, is normally cleaved by β, γ and α-secretase, but in AD, it is abnormally cleaved and the α-secretase does not function. These occurrences result in the formation of neuritic plaques causing neuronal damage to mitochondrial and cellular membranes in the brain. 3 Research has shown that Res may bind to β -amyloid proteins which interferes with their accumulation and changes the conformation to a nontoxic form, thereby decreasing toxicity and reducing neuronal damage. 8 Related studies have demonstrated Res’s ability to stimulate protein kinase C isoforms which may inactivate GSK3B, a protein coding gene which is commonly overexpressed in AD. This further contributes to Res’s protection against Aβ toxicity. 7 Similar Compounds Objectives 1. To explain the implications and pathogenesis of Alzheimer’s disease 2. To explain Resveratrol’s and similar compounds’ role in the treatment and prevention of AD 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. 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 3. 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 4. Brain Tour. Alzheimer’s Association Web site. https://www.alz.org/braintour/plaques.asp . Published 2011. Accessed March 10, 2016. 5. 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 6. 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 7. 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 8. 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 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. Patterson C, Feightner JW, Garcia A, Hsiung GYR, MacKnight C, Sadovnick AD. Diagnosis and treatment of dementia: 1. Risk assessment and primary prevention of Alzheimer disease. CMAJ. 2008; 178: 548-556. 17. Lifelong brain-stimulating habits linked to lower Alzheimer’s protein levels. UC Berkeley Web site. http://news.berkeley.edu/2012/01/23/engaged-brain-amyloid-alzheimers/ Published January 23, 2012. Accessed April 12, 2016. References Compound/ Delivery System Defini5on 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 par5clewater interface, which is stabilized by polysorbate 80. 11 This delivery system may stabilize photolabile substances, control drug release, improve effec5veness, and increase cerebral distribu5on of the compound. They may increase the photostability of resveratrol, beCer target the compound to the brain 5ssue, improve the compound’s an5glioma ac5vity and mi5gate AD (based on the Aβ 142 model). 11 Piceid The glycoside form of resveratrol. 12 Piceid exhibits high scavenging ac5vity against radicals and thus may aid in the treatment of AD. 13 BDPP (bioac5ve dietary polyphenol prepara5on) A combina5on of three bioac5ve and commercially available polyphenol products including Concord grape juice, grape seed extract and resveratrol. 14 It was created to simultaneously affect mul5ple Alzheimer’s targets such as amyloid load, synap5c plas5city and cogni5on. 14, 1 Piceatannol The compound trans3,4,3,5tetrahydroxys5lbene, which has a structure homologous to resveratrol. It is an an5inflammatory s5lbene derived from the seeds of Euphorbia lagascae. 15 It may block Aβ induced accumula5on of reac5ve oxygen species, which ul5mately leads to neuronal cell death. 6 Figure 1: Res ac5on in inhibi5ng βamyloid plaque forma5on Image Adapted from Patterson, C. et al. Conclusions We wish to thank Aaron Magnuson, James Peth, and Dr. Cunningham-Sabo for their advisement in the development of this poster. Research proves Res’s low bioavailability due to it’s rapid metabolism by the liver. 8 To enhance bioavailability, related compounds have been found and synthe5cs have been created 11, 12, 13, 14, 1, 15, 6 Acknowledgements Table 1: Similar Compounds/Synthe5cs Image by Susan Landau and William Jagust
