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Alzheimer’s Disease Update

Jacob Schor, ND, FABNO

August 1, 2008

Recent news stories about a newly patented drug for Alzheimer’s Disease got my attention the other day.   The drug, Rember, is actually methylthioninium chloride the chemical commonly used as a blue dye in laboratory experiments.

Claude Wischik , the fellow behind the current research, discovered this curious application by accident 20 years ago, when a drop of dye added to a test tube caused the Tau protein he had been working on to disappear. Tau proteins are the current ‘bad guys’ that cause Alzheimer’s.

Reading about this Rember drug made me remember those UCLA doctors, Ringman, Frautschy and Cole, who are running a clinical trial of curcumin on Alzheimer’s patients starting back in 2005, and wonder if  they had gotten around to publishing their findings.  The answer is no, but my search through the literature to find out, turned up some other papers of interest.

In fact there are enough new papers on Alzheimer’s that it is time to write an update.  This is my way force myself to sort through the information and organize my thoughts.

 

One recent paper in the June 28 issue of Neuron has an article by Cheung et al that proposes to explain the underlying molecular mechanisms of the disease. In the simplest terms, it attributes Alzheimer’s Disease development to errant calcium channel function.  These details seem really important if you are trying to develop a new drug to sell but more complicated than I need or care to explain in this newsletter. At this point they don’t appear to help me to decide what to do with patients.

There are other papers which are more clinically relevant, that is they give us information we can use in helping patients now.  Interest is still strong in the phytochemicals that protect the brain, especially those referred to as dietary phytochemicals.  In simpler English this means chemicals found in things we eat rather than in odd plants that are inedible.  Recall the results of the Kame Project in Washington State.  Published in the American Journal of Medicine in 2006, the data from this project gave us some fascinating evidence that certain foods were protective against the disease. Drinking three or more glasses of fruit or vegetable juice a week had a remarkably strong protective effect against developing the disease.   We wrote about this at the time.

http://denvernaturopathic.com/news/alzheimerjuice.html

Several papers focus on a theory explaining why these edible chemicals are so beneficial.  In big words, the papers talk about the neuro-hormetic effect of bio-pesticides as triggering the protective effect of dietary phytochemicals. 

Again, let me translate.  Plants don’t want to be eaten by bugs.  Therefore, plants make chemicals to discourage the bugs from chewing on them, basically chemicals that will kill the bugs if they eat the plant.  Chemicals that kill bugs are called pesticides.  Pesticides made by plants are called bio-pesticides.  The best way to kill a bug is to attack its nervous system.  Well actually the best way to kill a bug is probably to squash it, but if you are a plant, not possessing opposable thumbs or feet, squashing a bug is hard to do.  Frying the bug’s nervous system with poison is your next best option. 

So the bio-pesticides plants make are neurotoxins, they poison the eater’s nerves. 

Hormesis is a term used in toxicology for the backwards effect produced by very low doses of poison.  In many cases a teeny bit of something that is really nasty will have the opposite effect of a full dose.  A little bit of poison may actually be good for you.  I’ve written about this in the past, especially in regard to radiation hormesis.

http://www.naturopathydigest.com/archives/2007/jul/schor.php

and

http://denvernaturopathic.com/revigator.htm

Apparently with tiny doses, there is just enough poison to stimulate a protective response within the cells of the organism.  The protective response overcompensates for the injury and the net result is improved and healthier function.  We choose plants as food because they aren’t poisonous.  To be edible they can’t produce much in the way of biopesticides;  generations of domestication have bred the dangerous levels of nasty stuff out of them.  What we are left with are just small traces of poison that attempt to injure our brain neurons, small enough doses that instead of being injured the neurons are inspired to heal.

Don’t write this off as another one of those outlandish naturopathy theories that Dr. Schor makes up on the spot just because he has an old BS degree on the wall.  I’m simply summarizing and translating into English a paper published in 2006 in Trends in Neuroscience titled “Neurohormetic phytochemicals: Low-dose toxins that induce adaptive neuronal stress responses.”  The authors Mattson and Cheng are no slackers.  They work in the neuroscience lab of the National Institute on Aging in Baltimore.  They point out that it’s not so much the antioxidant effects produced by fruits and vegetables that are so valuable but the “neurohormetic phytochemicals…. that help cells to withstand stress.” 

As examples they use resveratrol, sulforaphane and curcumin as protecting neurons against injury through this mechanism.   These are supplements we typically use in treating cancer.  It makes equally good sense to consider them in treating Alzheimer’s Disease.

Dose Response published a follow up paper by Matteson in 2007 which further details this mechanism. “In several cases neurohormetic phytochemicals have been shown to suppress the disease process in animal models relevant to neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, and can also improve outcome following a stroke.” In it he details their plans to set up screening tests to evaluate the nerve protection effect of these chemicals. 

Writing in this June’s issue of Neuromolecular Medicine Matteson updates us on his work and further details how these chemical mechanisms actually work: “… we describe the hormesis hypothesis of phytochemical actions with a focus on the Nrf2/ARE signaling pathway as a prototypical example of a neuroprotective mechanism of action of specific dietary phytochemicals.” 

I’ve learned over the years that it is relatively easy to explain what big words mean.  Explaining what abbreviations like Nrf2 or ARE stand for is another story and I’m not going to even try.

Italian researchers, Calabrese et al, writing just a few weeks ago in the July issue of Neurochemical Research tell us that these neurohoremtic biopesticides work because they trigger the expression of a group of genes called Vitagenes. “As one of the main intracellular redox systems involved in neuroprotection, the vitagene system is emerging as a neurohormetic potential target for novel cytoprotective interventions. Vitagenes encode for cytoprotective heat shock proteins (Hsp) Hsp70 and heme oxygenase-1, as well as thioredoxin reductase and sirtuins.”  They go on and detail the “… neuroprotective roles of dietary antioxidants including curcumin, acetyl-L -carnitine and carnosine…”  in Alzheimer’s and Parkinson’s Diseases. Back in December 2007 another group of Italian researchers had already published on this idea of triggering the Vitagenes using curcumin, resveratrol and also their favorite acetyl-l-carnitine.   It seems that a lot of research on this form of carnitine originates in Italy.  It makes me wonder if it isn’t manufactured there.

There have been several papers of interest written on curcumin since last October when I first wrote about its use with Alzheimer’s.  There are several other clinical trials of interest using curcumin currently going on besides the UCLA Alzheimer’s study. Human trials are experimenting using curcumin to treat multiple myeloma, pancreatic cancer, myelodysplastic syndromes, colon cancer and psoriasis.    Results from the pancreatic trial were published just two weeks ago. This topic deserves its own write-up so pardon me if I neglect to elaborate further at the moment.

While our UCLA researchers have yet to publish data from their human trial, they recently published a paper comparing the chemical action of curcumin against a more stable metabolite of curcumin.  It isn’t clear whether they were interested in this other chemical because it may have been more effective or because it might have been patentable and would have made them all rich.  In any event, it proved to be less effective than real curcumin.

The big thing in the news stories about the new drug Rember is that it targets the Tau proteins.  Apparently curcumin also targets these tau things.  Park et al writing in the August issue of Food and Chemical Toxicology tells us that curcumin reversed the damage caused by amyloid proteins, decrease oxidative damage and DNA damage to the brain cells.  It also prevented harmful chnges in calcium levels and prevented damaging changes in those Tau proteins. 

Another paper published this month details curcumins effect on the enzymes the liver uses to detoxify and elminate dangerous chemicals in the body.

There’s an article in July’s issue of the Journal of Pharmacology and Experimental Therapuetics comparing curcumin against a metabolite of curcumin called tetrahydrocurcumin (TC) which though more stable and better absorbed than curcumin doesn’t work as well as the real thing.

The UCLA 2005 paper by Ringman et al. still remains the classic at laying out the arguments in support of using curcumin to prevent or treat Alzheimer’s.  While we wait for the follow up to it, there are several other supplements we should consider using.

The idea of using alpha lipoic acid in Alzheimer’s is slowly gaining support. The title of a July 4 paper pretty much says it all: “Lipoic acid as an anti-inflammatory and neuroprotective treatment for Alzheimer's disease.”     This isn’t the first of the clear titled papers on the topic.  In January 2007, Pharmacological Therapeutics published an article with an equally easy to understand title: “Lipoic acid as a novel treatment for Alzheimer's disease and related dementias.”

Research on the protective effect of lipoic acid against oxidative damage to brain cells goes back at least to 2003 when Lovell et al from the University of Kentucky proposed that the damage that occurs in Alzheimer’s is oxidative in nature and that alpha-lipoic acid was protective.

There are several other supplements that may help.  A paper now 6 years old suggests that pycnogenol protects brain neurons form Alzheimer like damage. We tend to readily substitute grape seed extracts for pycnogenol in practice.

Marijuana may also be useful.  So much for the popular message the anti-drug campaigns have tried to instill that marijuana destroys brain cells.  It appears components of marijuana do what we want in terms of protecting brain neurons from damaged from beta mayloid and tau proteins.

Fish oil is also looking pretty good.  Back in 2005 we read that fish oil appeared protective to the brains of mice as they aged. A second paper in 2006 clarified that fish oil protect mice brains against amyloid damage, the sort we see in Alzheimer’s. Then this August we see the publication of a clinical trial using fish oil to treat humans and that produced decent results.   .

This was a 6 month randomized, double-blind placebo-controlled study that tested omega-3 polyunsaturated fatty acids (PUFAs) monotherapy in people with cognitive impairment and its effects on cognitive. Twenty three participants with mild or moderate Alzheimer's disease and twenty three with mild cognitive impairment were randomized to receive omega-3 PUFAs 1.8 g/day or placebo (olive oil). To no one’s surprise there were no severe adverse effects in either group. “The treatment group showed better improvement on the Clinician's Interview-Based Impression of Change Scale (CIBIC-plus) than those in the placebo group over the 24 week follow-up (p=0.008).” …..  the omega-3 fatty acids group showed significant improvement in ADAS-cog compared to the placebo group in participants with mild cognitive impairment (p=0.03),…”   The doses used in this study were lower than typically seen in fish oil research.

There is also a new paper suggesting that green tea will have benefit.  An earlier 2005 paper reported that the epigallocatechin stuff (EGCG) in green tea reduced the cerebral amyloidosis in Alzheimer mice. This past June the same researchers reported that they gave mutant mice who were doomed to develop Alzheimer’s disease, green tea extracts in water for six months.  Drinking their daily green tea halved the amyloid deposited in the brains of these mice.   They gave these mice fairly hefty amounts of EGCG,  50 mg/KG.  Thus for a person weighing in at 75 kilo, that would be a dose of 3,750 mg of EGCG per day.  This sounds like a lot but recall that taking green tea on an empty stomach almost triples absorption.  A dose of 1,000 mg of green tea taken before breakfast sounds well within reason.  

Speaking of tea, people will no doubt ask me about caffeine.  It was reported back in 2006 that a dose of about 500 mg of caffeine a day, about what you’d get in five cups of coffee, is protective against disease development.

I mentioned that Kame study earlier in which that drinking juice more than three times a week lowers disease risk so significantly (reducing the risk by 76%).    There is some info on specific fruit juices.  Again, let me simply quote the titles, “Pomegranate juice decreases amyloid load and improves behavior in a mouse model of Alzheimer's disease” and “Apple juice; “the antioxidant potential of apple products can prevent Abeta-induced oxidative damage””

Resveratrol that is found in grape juice and wine (and the Chinese medicinal herb Polygonum cuspidatum) in particular looks promising. Three papers in 2006 suggested use as a possible treatment but I haven’t noticed much of late on this particular focus.   Most of the excitement surrounding Resveratrol still focuses on using it as a cancer treatment.

We should also keep in mind possible defects in metabolism that might lower folate and SAM-e

And then there is Co-Q-10.  A June article makes me think we should probably also add it to our list of supplements to consider; “Oral CoQ may be a viable antioxidant strategy for neurodegenerative disease, ”  another study where the title gives away the ending of the story.   Don’t ask me which form of Co Q-10 though.

So much for a short update. 

Here is an updated list of supplements to consider for Alzheimer’s Disease.

Curcumin

Alpha Lipoic Acid

Green tea

Acetyl-l-carnitine

Pycnogenol or grape seed extract

Resveratrol

Sulforaphane

Fish Oil (Omega-3 fats)

Coenzyme Q-10

Web Links:

UCLA Curcumin webpage:  http://alzheimer.neurology.ucla.edu/Curcumin.html

DNC NEWS Curcumin and Alzheimer’s Disease: http://denvernaturopathic.com/curcuminandAlzheimers.htm

DNC News: Fruit Juice and Alzheimer’s Disease: http://denvernaturopathic.com/news/alzheimerjuice.html

Radiation Hormesis:

http://www.naturopathydigest.com/archives/2007/jul/schor.php

and

http://denvernaturopathic.com/revigator.htm

DNC News:  Alzheimer’s and Fish Oil (2004): http://denvernaturopathic.com/news/alzheimersfish.html

DNC News: Walking and Diet Protect against Alzheimer’s Disease:

http://denvernaturopathic.com/news/alzheimerswalking.html

DNC News: Miscellaneous abstracts of interest on Alzheimer’s Disease: Niacin, Coffee and Statin drugs offer protection

http://denvernaturopathic.com/news/niacinalzheimerabstracts.html

References:

 

 

http://news.bbc.co.uk/1/hi/health/7525115.stm

Neuron. 2008 Jun 26;58(6):871-83.Click here to read Links

    Mechanism of Ca2+ disruption in Alzheimer's disease by presenilin regulation of InsP3 receptor channel gating.

    Cheung KH, Shineman D, Müller M, Cárdenas C, Mei L, Yang J, Tomita T, Iwatsubo T, Lee VM, Foskett JK.

    Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104, USA.

    Mutations in presenilins (PS) are the major cause of familial Alzheimer's disease (FAD) and have been associated with calcium (Ca2+) signaling abnormalities. Here, we demonstrate that FAD mutant PS1 (M146L)and PS2 (N141I) interact with the inositol 1,4,5-trisphosphate receptor (InsP3R) Ca2+ release channel and exert profound stimulatory effects on its gating activity in response to saturating and suboptimal levels of InsP3. These interactions result in exaggerated cellular Ca2+ signaling in response to agonist stimulation as well as enhanced low-level Ca2+signaling in unstimulated cells. Parallel studies in InsP3R-expressing and -deficient cells revealed that enhanced Ca2+ release from the endoplasmic reticulum as a result of the specific interaction of PS1-M146L with the InsP3R stimulates amyloid beta processing,an important feature of AD pathology. These observations provide molecular insights into the "Ca2+ dysregulation" hypothesis of AD pathogenesis and suggest novel targets for therapeutic intervention.

Am J Med. 2006 Sep;119(9):751-9.Click here to read Click here to read Links

    Fruit and vegetable juices and Alzheimer's disease: the Kame Project.

    Dai Q, Borenstein AR, Wu Y, Jackson JC, Larson EB.

    Department of Medicine, Division of General Internal Medicine and Public Health, Vanderbilt Center for Health Services Research, Vanderbilt-Ingram Cancer Center, Vanderbilt School of Medicine, Nashville, Tenn, USA. qi.dai@vanderbilt.edu

    BACKGROUND: Growing evidence suggests that oxidative damage caused by the beta-amyloid peptide in the pathogenesis of Alzheimer's disease may be hydrogen peroxide mediated. Many polyphenols, the most abundant dietary antioxidants, possess stronger neuroprotection against hydrogen peroxide than antioxidant vitamins. METHODS: We tested whether consumption of fruit and vegetable juices, containing a high concentration of polyphenols, decreases the risk of incident probable Alzheimer's disease in the Kame Project cohort, a population-based prospective study of 1836 Japanese Americans in King County, Washington, who were dementia-free at baseline (1992-1994) and were followed through 2001. RESULTS: After adjustment for potential confounders, the hazard ratio for probable Alzheimer's disease was 0.24 (95% confidence interval [CI], 0.09-0.61) comparing subjects who drank juices at least 3 times per week with those who drank less often than once per week with a hazard ratio of 0.84 (95% CI, 0.31-2.29) for those drinking juices 1 to 2 times per week (P for trend < .01). This inverse association tended to be more pronounced among those with an apolipoprotein Eepsilon-4 allele and those who were not physically active. Conversely, no association was observed for dietary intake of vitamins E, C, or beta-carotene or tea consumption. CONCLUSIONS: Fruit and vegetable juices may play an important role in delaying the onset of Alzheimer's disease, particularly among those who are at high risk for the disease. These results may lead to a new avenue of inquiry in the prevention of Alzheimer's disease.

 

  Trends Neurosci. 2006 Nov;29(11):632-9. Epub 2006 Sep 26.Click here to read Links

    Neurohormetic phytochemicals: Low-dose toxins that induce adaptive neuronal stress responses.

    Mattson MP, Cheng A.

    Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA. mattsonm@grc.nia.nih.gov

    Diets rich in vegetables and fruits are associated with reduced risk of several major diseases, including neurodegenerative disorders. Although some beneficial phytochemicals might function solely as antioxidants, it is becoming clear that many of the beneficial chemicals in vegetables and fruits evolved as toxins (to dissuade insects and other predators) that, at subtoxic doses, activate adaptive cellular stress-response pathways in a variety of cells including neurons. Examples of such 'preconditioning' or 'neurohormesis' pathways include those involving cell-survival signaling kinases, the transcription factors NRF2 and CREB, and histone deacetylases of the sirtuin family. In these ways, neurohormetic phytochemicals such as resveratrol, sulforaphanes and curcumin might protect neurons against injury and disease by stimulating the production of antioxidant enzymes, neurotrophic factors, protein chaperones and other proteins that help cells to withstand stress. Thus, as we discuss in this review, highly conserved longevity and survival pathways in neurons are the targets of many phytochemicals.

Dose Response. 2007 Aug 6;5(3):174-86.Click here to read Links

    Viewpoint: mechanisms of action and therapeutic potential of neurohormetic phytochemicals.

    Mattson MP, Son TG, Camandola S.

    Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD.

    The nervous system is of fundamental importance in the adaptive (hormesis) responses of organisms to all types of stress, including environmental "toxins". Phytochemicals present in vegetables and fruits are believed to reduce the risk of several major diseases including cardiovascular disease, cancers and neurodegenerative disorders. Although antioxidant properties have been suggested as the basis of health benefits of phytochemicals, emerging findings suggest a quite different mechanism of action. Many phytochemicals normally function as toxins that protect the plants against insects and other damaging organisms. However, at the relatively low doses consumed by humans and other mammals these same "toxic" phytochemicals activate adaptive cellular stress response pathways that can protect the cells against a variety of adverse conditions. Recent findings have elucidated hormetic mechanisms of action of phytochemicals (e.g., resveratrol, curcumin, sulforaphanes and catechins) using cell culture and animal models of neurological disorders. Examples of hormesis pathways activated by phytochemicals include the transcription factor Nrf-2 which activates genes controlled by the antioxidant response element, and histone deacetylases of the sirtuin family and FOXO transcription factors. Such hormetic pathways stimulate the production of antioxidant enzymes, protein chaperones and neurotrophic factors. In several cases neurohormetic phytochemicals have been shown to suppress the disease process in animal models relevant to neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, and can also improve outcome following a stroke. We are currently screening a panel of biopesticides in order to establish hormetic doses, neuroprotective efficacy, mechanisms of action and therapeutic potential as dietary supplements.

Neuromolecular Med. 2008 Jun 10. [Epub ahead of print]Click here to read Links

    Hormetic Dietary Phytochemicals.

    Son TG, Camandola S, Mattson MP.

    Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, 5600 Nathan Shock Drive, Baltimore, MD, 21224, USA.

    Compelling evidence from epidemiological studies suggests beneficial roles of dietary phytochemicals in protecting against chronic disorders such as cancer, and inflammatory and cardiovascular diseases. Emerging findings suggest that several dietary phytochemicals also benefit the nervous system and, when consumed regularly, may reduce the risk of disorders such as Alzheimer's and Parkinson's diseases. The evidence supporting health benefits of vegetables and fruits provide a rationale for identification of the specific phytochemicals responsible, and for investigation of their molecular and cellular mechanisms of action. One general mechanism of action of phytochemicals that is emerging from recent studies is that they activate adaptive cellular stress response pathways. From an evolutionary perspective, the noxious properties of such phytochemicals play an important role in dissuading insects and other pests from eating the plants. However at the subtoxic doses ingested by humans that consume the plants, the phytochemicals induce mild cellular stress responses. This phenomenon has been widely observed in biology and medicine, and has been described as 'preconditioning' or 'hormesis.' Hormetic pathways activated by phytochemicals may involve kinases and transcription factors that induce the expression of genes that encode antioxidant enzymes, protein chaperones, phase-2 enzymes, neurotrophic factors, and other cytoprotective proteins. Specific examples of such pathways include the sirtuin-FOXO pathway, the NF-kappaB pathway, and the Nrf-2/ARE pathway. In this article, we describe the hormesis hypothesis of phytochemical actions with a focus on the Nrf2/ARE signaling pathway as a prototypical example of a neuroprotective mechanism of action of specific dietary phytochemicals.

Expert Opin Investig Drugs. 2007 Dec;16(12):1921-31.Click here to read Links

    Natural antioxidants in Alzheimer's disease.

    Mancuso C, Bates TE, Butterfield DA, Calafato S, Cornelius C, De Lorenzo A, Dinkova Kostova AT, Calabrese V.

    Catholic University School of Medicine, Institute of Pharmacology, Largo F Vito, 00168 Roma, Italy.

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by severe cognitive impairment that ultimately leads to death. Current drugs used in AD are acetylcholinesterase inhibitors and antagonists to the NMDA receptors. These drugs may only slightly improve cognitive functions but have only very limited impact on the clinical course of the disease. In the past several years, based on in vitro and in vivo studies in laboratory animals, natural antioxidants, such as resveratrol, curcumin and acetyl-L-carnitine have been proposed as alternative therapeutic agents for AD. An increasing number of studies demonstrated the efficacy of primary antioxidants, such as polyphenols, or secondary antioxidants, such as acetylcarnitine, to reduce or to block neuronal death occurring in the pathophysiology of this disorder. These studies revealed that other mechanisms than the antioxidant activities could be involved in the neuroprotective effect of these compounds. This paper discusses the evidence for the role of acetylcarnitine in modulating redox-dependent mechanisms leading to the upregulation of vitagenes. Furthermore, future development of novel antioxidant drugs targeted to the mitochondria should result in effectively slowing disease progression. The association with new drug delivery systems may be desirable and useful for the therapeutic use of antioxidants in human neurodegenerative diseases.

 

Neurochem Res. 2008 Jul 16. [Epub ahead of print]Click here to read Links

    Cellular Stress Response: A Novel Target for Chemoprevention and Nutritional Neuroprotection in Aging, Neurodegenerative Disorders and Longevity.

    Calabrese V, Cornelius C, Mancuso C, Pennisi G, Calafato S, Bellia F, Bates TE, Giuffrida Stella AM, Schapira T, Dinkova Kostova AT, Rizzarelli E.

    Section of Biochemistry and Molecular Biology, Department of Chemistry, Faculty of Medicine, University of Catania, Viale Andrea Doria 6, 95100, Catania, Italy, calabres@unict.it.

    The predominant molecular symptom of aging is the accumulation of altered gene products. Moreover, several conditions including protein, lipid or glucose oxidation disrupt redox homeostasis and lead to accumulation of unfolded or misfolded proteins in the aging brain. Alzheimer's and Parkinson's diseases or Friedreich ataxia are neurological diseases sharing, as a common denominator, production of abnormal proteins, mitochondrial dysfunction and oxidative stress, which contribute to the pathogenesis of these so called "protein conformational diseases". The central nervous system has evolved the conserved mechanism of unfolded protein response to cope with the accumulation of misfolded proteins. As one of the main intracellular redox systems involved in neuroprotection, the vitagene system is emerging as a neurohormetic potential target for novel cytoprotective interventions. Vitagenes encode for cytoprotective heat shock proteins (Hsp) Hsp70 and heme oxygenase-1, as well as thioredoxin reductase and sirtuins. Nutritional studies show that ageing in animals can be significantly influenced by dietary restriction. Thus, the impact of dietary factors on health and longevity is an increasingly appreciated area of research. Reducing energy intake by controlled caloric restriction or intermittent fasting increases lifespan and protects various tissues against disease. Genetics has revealed that ageing may be controlled by changes in intracellular NAD/NADH ratio regulating sirtuin, a group of proteins linked to aging, metabolism and stress tolerance in several organisms. Recent findings suggest that several phytochemicals exhibit biphasic dose responses on cells with low doses activating signaling pathways that result in increased expression of vitagenes encoding survival proteins, as in the case of the Keap1/Nrf2/ARE pathway activated by curcumin and NAD/NADH-sirtuin-1 activated by resveratrol. Consistently, the neuroprotective roles of dietary antioxidants including curcumin, acetyl-L: -carnitine and carnosine have been demonstrated through the activation of these redox-sensitive intracellular pathways. Although the notion that stress proteins are neuroprotective is broadly accepted, still much work needs to be done in order to associate neuroprotection with specific pattern of stress responses. In this review the importance of vitagenes in the cellular stress response and the potential use of dietary antioxidants in the prevention and treatment of neurodegenerative disorders is discussed.

 

Cell Mol Life Sci. 2008 Jun;65(11):1631-52.Click here to read Links

    Curcumin: from ancient medicine to current clinical trials.

    Hatcher H, Planalp R, Cho J, Torti FM, Torti SV.

    Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.

    Curcumin is the active ingredient in the traditional herbal remedy and dietary spice turmeric (Curcuma longa). Curcumin has a surprisingly wide range of beneficial properties, including anti-inflammatory, antioxidant, chemopreventive and chemotherapeutic activity. The pleiotropic activities of curcumin derive from its complex chemistry as well as its ability to influence multiple signaling pathways, including survival pathways such as those regulated by NF-kappaB, Akt, and growth factors; cytoprotective pathways dependent on Nrf2; and metastatic and angiogenic pathways. Curcumin is a free radical scavenger and hydrogen donor, and exhibits both pro- and antioxidant activity. It also binds metals, particularly iron and copper, and can function as an iron chelator. Curcumin is remarkably non-toxic and exhibits limited bioavailability. Curcumin exhibits great promise as a therapeutic agent, and is currently in human clinical trials for a variety of conditions, including multiple myeloma, pancreatic cancer, myelodysplastic syndromes, colon cancer, psoriasis and Alzheimer's disease.

Clin Cancer Res. 2008 Jul 15;14(14):4491-4499.Click here to read Links

    Phase II Trial of Curcumin in Patients with Advanced Pancreatic Cancer.

    Dhillon N, Aggarwal BB, Newman RA, Wolff RA, Kunnumakkara AB, Abbruzzese JL, Ng CS, Badmaev V, Kurzrock R.

    Authors' Affiliations: Phase I Program, Department of Investigational Cancer Therapeutics, Department of Experimental Therapeutics, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, and Department of Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas and Sabinsa Corporation, Piscataway, New Jersey.

    PURPOSE: Pancreatic cancer is almost always lethal, and the only U.S. Food and Drug Administration-approved therapies for it, gemcitabine and erlotinib, produce objective responses in <10% of patients. We evaluated the clinical biological effects of curcumin (diferuloylmethane), a plant-derived dietary ingredient with potent nuclear factor-kappaB (NF-kappaB) and tumor inhibitory properties, against advanced pancreatic cancer. EXPERIMENTAL DESIGN: Patients received 8 g curcumin by mouth daily until disease progression, with restaging every 2 months. Serum cytokine levels for interleukin (IL)-6, IL-8, IL-10, and IL-1 receptor antagonists and peripheral blood mononuclear cell expression of NF-kappaB and cyclooxygenase-2 were monitored. RESULTS: Twenty-five patients were enrolled, with 21 evaluable for response. Circulating curcumin was detectable as drug in glucuronide and sulfate conjugate forms, albeit at low steady-state levels, suggesting poor oral bioavailability. Two patients showed clinical biological activity. One had ongoing stable disease for >18 months; interestingly, one additional patient had a brief, but marked, tumor regression (73%) accompanied by significant increases (4- to 35-fold) in serum cytokine levels (IL-6, IL-8, IL-10, and IL-1 receptor antagonists). No toxicities were observed. Curcumin down-regulated expression of NF-kappaB, cyclooxygenase-2, and phosphorylated signal transducer and activator of transcription 3 in peripheral blood mononuclear cells from patients (most of whom had baseline levels considerably higher than those found in healthy volunteers). Whereas there was considerable interpatient variation in plasma curcumin levels, drug levels peaked at 22 to 41 ng/mL and remained relatively constant over the first 4 weeks. CONCLUSIONS: Oral curcumin is well tolerated and, despite its limited absorption, has biological activity in some patients with pancreatic cancer.

J Pharmacol Exp Ther. 2008 Jul;326(1):196-208. Epub 2008 Apr 16.Click here to read Links

    Curcumin structure-function, bioavailability, and efficacy in models of neuroinflammation and Alzheimer's disease.

    Begum AN, Jones MR, Lim GP, Morihara T, Kim P, Heath DD, Rock CL, Pruitt MA, Yang F, Hudspeth B, Hu S, Faull KF, Teter B, Cole GM, Frautschy SA.

    Department of Medicine, University of California, Los Angeles, California, USA.

    Curcumin can reduce inflammation and neurodegeneration, but its chemical instability and metabolism raise concerns, including whether the more stable metabolite tetrahydrocurcumin (TC) may mediate efficacy. We examined the antioxidant, anti-inflammatory, or anti-amyloidogenic effects of dietary curcumin and TC, either administered chronically to aged Tg2576 APPsw mice or acutely to lipopolysaccharide (LPS)-injected wild-type mice. Despite dramatically higher drug plasma levels after TC compared with curcumin gavage, resulting brain levels of parent compounds were similar, correlating with reduction in LPS-stimulated inducible nitric-oxide synthase, nitrotyrosine, F2 isoprostanes, and carbonyls. In both the acute (LPS) and chronic inflammation (Tg2576), TC and curcumin similarly reduced interleukin-1beta. Despite these similarities, only curcumin was effective in reducing amyloid plaque burden, insoluble beta-amyloid peptide (Abeta), and carbonyls. TC had no impact on plaques or insoluble Abeta, but both reduced Tris-buffered saline-soluble Abeta and phospho-c-Jun NH(2)-terminal kinase (JNK). Curcumin but not TC prevented Abeta aggregation. The TC metabolite was detected in brain and plasma from mice chronically fed the parent compound. These data indicate that the dienone bridge present in curcumin, but not in TC, is necessary to reduce plaque deposition and protein oxidation in an Alzheimer's model. Nevertheless, TC did reduce neuroinflammation and soluble Abeta, effects that may be attributable to limiting JNK-mediated transcription. Because of its favorable safety profile and the involvement of misfolded proteins, oxidative damage, and inflammation in multiple chronic degenerative diseases, these data relating curcumin dosing to the blood and tissue levels required for efficacy should help translation efforts from multiple successful preclinical models.

 

Food Chem Toxicol. 2008 Aug;46(8):2881-7. Epub 2008 Jun 4.Click here to read Links

    Curcumin protected PC12 cells against beta-amyloid-induced toxicity through the inhibition of oxidative damage and tau hyperphosphorylation.

    Park SY, Kim HS, Cho EK, Kwon BY, Phark S, Hwang KW, Sul D.

    Environmental Toxico-Genomic and Proteomic Center, College of Medicine, Korea University, Anamdong 5, Sungbuk ku, Seoul 136-705, Republic of Korea.

    One of the pathological hallmarks of Alzheimer's disease is the progressive accumulation of beta-amyloid (Abeta) in the form of senile plaques, and Abeta insult to neuronal cells has been identified as one of the major causes of the onset of the disease. Curcumin, the major and most active antioxidant of Curcuma longa, protects neuronal cells against Abeta-induced toxicity. Therefore, in this study, we investigated the neuroprotective mechanisms by which curcumin acts against Abeta (25-35)-induced toxicity in PC12 cells. Following the exposure of PC12 cells to 10muM Abeta (25-35) for 24h, significant increases in the level of antioxidant enzymes, and DNA damage were observed, and these increases were accompanied by a decrease in cell viability, and an increase in intracellular calcium levels and tau hyperphosphorylation. In addition, pretreatment of PC12 cells with 10mug/ml curcumin for 1h significantly reversed the effect of Abeta, by decreasing the oxidative stress, and DNA damage induced by Abeta, as well as attenuating the elevation of intracellular calcium levels and tau hyperphosphorylation induced by Abeta. Taken together, these data indicate that curucmin protected PC12 cells against Abeta-induced neurotoxicity through the inhibition of oxidative damage, intracellular calcium influx, and tau hyperphosphorylation.

 

  Drug Metab Dispos. 2008 Aug;36(8):1594-605. Epub 2008 May 14.Click here to read Links

    Curcuminoids inhibit multiple human cytochromes P450, UDP-glucuronosyltransferase, and sulfotransferase enzymes, whereas piperine is a relatively selective CYP3A4 inhibitor.

    Volak LP, Ghirmai S, Cashman JR, Court MH.

    Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.

    Curcuminoid extract and piperine are being evaluated for beneficial effects in Alzheimer's disease, among other intractable disorders. Consequently, we studied the potential for herb-drug interactions involving cytochrome P450 (P450), UDP-glucuronosyltransferase (UGT), and sulfotransferase (SULT) enzymes. The curcuminoid extract inhibited SULT > CYP2C19 > CYP2B6 > UGT > CYP2C9 > CYP3A activities with IC(50) values ranging from 0.99 +/- 0.04 to 25.3 +/- 1.3 microM, whereas CYP2D6, CYP1A2, and CYP2E1 activities were less affected (IC(50) values > 60 microM). Inhibition of CYP3A activity by curcuminoid extract was consistent with competitive inhibition (K(i) = 11.0 +/- 1.3 microM), whereas inhibition of both CYP2C9 and CYP2C19 activities were consistent with mixed competitive-noncompetitive inhibition (10.6 +/- 1.1 and 7.8 +/- 0.9 microM, respectively). Piperine was a relatively selective noncompetitive inhibitor of CYP3A (IC(50) 5.5 +/- 0.7 microM, K(i) = 5.4 +/- 0.3 microM) with less effect on other enzymes evaluated (IC(50) > 29 microM). Curcuminoid extract and piperine inhibited recombinant CYP3A4 much more potently (by >5-fold) than CYP3A5. Pure synthetic curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin) were also evaluated for their effects on CYP3A, CYP2C9, UGT, and SULT activities. All three curcuminoids had similar effects on CYP3A, UGT, and SULT activity, but demethoxycurcumin (IC(50) = 8.8 +/- 1.2 microM) was more active against CYP2C9 than either curcumin or bisdemethoxycurcumin (IC(50) > 50 microM). Based on these data and expected tissue concentrations of inhibitors, we predict that a p.o. administered curcuminoid/piperine combination is most likely to inhibit CYP3A, CYP2C9, UGT, and SULT metabolism within the intestinal mucosa.

J Pharmacol Exp Ther. 2008 Jul;326(1):196-208. Epub 2008 Apr 16.Click here to read Links

    Curcumin structure-function, bioavailability, and efficacy in models of neuroinflammation and Alzheimer's disease.

    Begum AN, Jones MR, Lim GP, Morihara T, Kim P, Heath DD, Rock CL, Pruitt MA, Yang F, Hudspeth B, Hu S, Faull KF, Teter B, Cole GM, Frautschy SA.

    Department of Medicine, University of California, Los Angeles, California, USA.

    Curcumin can reduce inflammation and neurodegeneration, but its chemical instability and metabolism raise concerns, including whether the more stable metabolite tetrahydrocurcumin (TC) may mediate efficacy. We examined the antioxidant, anti-inflammatory, or anti-amyloidogenic effects of dietary curcumin and TC, either administered chronically to aged Tg2576 APPsw mice or acutely to lipopolysaccharide (LPS)-injected wild-type mice. Despite dramatically higher drug plasma levels after TC compared with curcumin gavage, resulting brain levels of parent compounds were similar, correlating with reduction in LPS-stimulated inducible nitric-oxide synthase, nitrotyrosine, F2 isoprostanes, and carbonyls. In both the acute (LPS) and chronic inflammation (Tg2576), TC and curcumin similarly reduced interleukin-1beta. Despite these similarities, only curcumin was effective in reducing amyloid plaque burden, insoluble beta-amyloid peptide (Abeta), and carbonyls. TC had no impact on plaques or insoluble Abeta, but both reduced Tris-buffered saline-soluble Abeta and phospho-c-Jun NH(2)-terminal kinase (JNK). Curcumin but not TC prevented Abeta aggregation. The TC metabolite was detected in brain and plasma from mice chronically fed the parent compound. These data indicate that the dienone bridge present in curcumin, but not in TC, is necessary to reduce plaque deposition and protein oxidation in an Alzheimer's model. Nevertheless, TC did reduce neuroinflammation and soluble Abeta, effects that may be attributable to limiting JNK-mediated transcription. Because of its favorable safety profile and the involvement of misfolded proteins, oxidative damage, and inflammation in multiple chronic degenerative diseases, these data relating curcumin dosing to the blood and tissue levels required for efficacy should help translation efforts from multiple successful preclinical models.

 

Curr Alzheimer Res. 2005 Apr;2(2):131-6.Click here to read Click here to read Links

    A potential role of the curry spice curcumin in Alzheimer's disease.

    Ringman JM, Frautschy SA, Cole GM, Masterman DL, Cummings JL.

    University of California, Los Angeles, Department of Neurology, Alzheimer's Disease Research Center, Los Angeles, CA 90095, USA. jringman@mednet.ucla.edu

    There is substantial in-vitro data indicating that curcumin has antioxidant, anti-inflammatory, and anti-amyloid activity. In addition, studies in animal models of Alzheimer's disease (AD) indicate a direct effect of curcumin in decreasing the amyloid pathology of AD. As the widespread use of curcumin as a food additive and relatively small short-term studies in humans suggest safety, curcumin is a promising agent in the treatment and/or prevention of AD. Nonetheless, important information regarding curcumin bioavailability, safety and tolerability, particularly in an elderly population is lacking. We are therefore performing a study of curcumin in patients with AD to gather this information in addition to data on the effect of curcumin on biomarkers of AD pathology.

Adv Drug Deliv Rev. 2008 Jul 4. [Epub ahead of print]

    Lipoic acid as an anti-inflammatory and neuroprotective treatment for Alzheimer's disease.

    Maczurek A, Hager K, Kenklies M, Sharman M, Martins R, Engel J, Carlson D, Münch G.

    Department of Pharmacology, School of Medicine, University of Western Sydney, Australia; Department of Biochemistry and Molecular Biology, James Cook University, Townsville, Australia.

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder that destroys patient memory and cognition, communication ability with the social environment and the ability to carry out daily activities. Despite extensive research into the pathogenesis of AD, a neuroprotective treatment - particularly for the early stages of disease - remains unavailable for clinical use. In this review, we advance the suggestion that lipoic acid (LA) may fulfil this therapeutic need. A naturally occurring cofactor for the mitochondrial enzymes pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, LA has been shown to have a variety of properties which can interfere with the pathogenesis or progression of AD. For example, LA increases acetylcholine (ACh) production by activation of choline acetyltransferase and increases glucose uptake, thus supplying more acetyl-CoA for the production of ACh. LA chelates redox-active transition metals, thus inhibiting the formation of hydroxyl radicals and also scavenges reactive oxygen species (ROS), thereby increasing the levels of reduced glutathione. In addition, LA down-regulates the expression of redox-sensitive pro-inflammatory proteins including TNF and inducible nitric oxide synthase. Furthermore, LA can scavenge lipid peroxidation products such as hydroxynonenal and acrolein. In human plasma, LA exists in an equilibrium of free and plasma protein bound form. Up to 150 muM, it is bound completely, most likely binding to high affinity fatty acid sites on human serum albumin, suggesting that one large dose rather than continuous low doses (as provided by "slow release" LA) will be beneficial for delivery of LA to the brain. Evidence for a clinical benefit for LA in dementia is yet limited. There are only two published studies, in which 600 mg LA was given daily to 43 patients with AD (receiving a standard treatment with choline-esterase inhibitors) in an open-label study over an observation period of up to 48 months. Whereas the improvement in patients with moderate dementia was not significant, the disease progressed extremely slowly (change in ADAScog: 1.2 points=year, MMSE: -0.6 points=year) in patients with mild dementia (ADAScog<15). Data from cell culture and animal models suggest that LA could be combined with nutraceuticals such as curcumin, (-)-epigallocatechin gallate (from green tea) and docosahexaenoic acid (from fish oil) to synergistically decrease oxidative stress, inflammation, Abeta levels and Abeta plaque load and thus provide a combined benefit in the treatment of AD.

Pharmacol Ther. 2007 Jan;113(1):154-64. Epub 2006 Sep 20.Click here to read Links

    Lipoic acid as a novel treatment for Alzheimer's disease and related dementias.

    Holmquist L, Stuchbury G, Berbaum K, Muscat S, Young S, Hager K, Engel J, Münch G.

    Department of Biochemistry and Molecular Biology and Comparative Genomics Centre, School of Pharmacy and Molecular Sciences, James Cook University, Townsville, Australia.

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder that destroys patient memory and cognition, communication ability with the social environment and the ability to carry out daily activities. Despite extensive research into the pathogenesis of AD, a neuroprotective treatment - particularly for the early stages of disease - remains unavailable for clinical use. In this review, we advance the suggestion that lipoic acid (LA) may fulfil this therapeutic need. A naturally occurring precursor of an essential cofactor for mitochondrial enzymes, including pyruvate dehydrogenase (PDH) and alpha-ketoglutarate dehydrogenase (KGDH), LA has been shown to have a variety of properties which can interfere with pathogenic principles of AD. For example, LA increases acetylcholine (ACh) production by activation of choline acetyltransferase and increases glucose uptake, thus supplying more acetyl-CoA for the production of ACh. LA chelates redox-active transition metals, thus inhibiting the formation of hydroxyl radicals and also scavenges reactive oxygen species (ROS), thereby increasing the levels of reduced glutathione. Via the same mechanisms, downregulation redox-sensitive inflammatory processes is also achieved. Furthermore, LA can scavenge lipid peroxidation products such as hydroxynonenal and acrolein. The reduced form of LA, dihydrolipoic acid (DHLA), is the active compound responsible for most of these beneficial effects. R-alpha-LA can be applied instead of DHLA, as it is reduced by mitochondrial lipoamide dehydrogenase, a part of the PDH complex. In this review, the properties of LA are explored with particular emphasis on how this agent, particularly the R-alpha-enantiomer, may be effective to treat AD and related dementias.

    PMID: 16989905 [PubMed - indexed for MEDLINE]

 

Brain Res Mol Brain Res. 2002 Jul 15;104(1):55-65.Click here to read Links

    Pycnogenol protects neurons from amyloid-beta peptide-induced apoptosis.

    Peng QL, Buz'Zard AR, Lau BH.

    Department of Microbiology and Molecular Genetics, School of Medicine, Loma Linda University, Loma Linda, CA 92350, USA.

    Neuronal apoptosis is one of the pathological features of Alzheimer's disease (AD). Morphological pathology reveals that neuronal apoptosis is associated with senile plaques containing amyloid-beta peptide (Abeta) in AD brains. Reactive oxygen species (ROS) has been proposed to be involved in the apoptotic mechanism of Abeta-mediated neurotoxicity. In the present study, using a rat pheochromocytoma (PC12) cell line, we investigated the effect of Pycnogenol (PYC), a potent antioxidant and ROS scavenger, on Abeta(25-35)-induced apoptosis and ROS generation. We used vitamin E, a known antioxidant agent, to verify the effect of PYC. Abeta(25-35)-induced apoptosis in PC12 cells was demonstrated by: (1) a dose-dependent loss of cell viability; (2) a time- and dose-dependent increase in the apoptotic cells; (3) an induction of DNA fragmentation; and (4) an increase in caspase-3 activity and cleavage of poly (ADP-ribose) polymerase (PARP). Our data showed that a significant increase in ROS formation preceded apoptotic events after PC12 cells were exposed to Abeta(25-35). We further found that PYC not only suppressed the generation of ROS but also attenuated caspase-3 activation, DNA fragmentation, PARP cleavage, and eventually protected against Abeta-induced apoptosis. Vitamin E also suppressed cell death and caspase-3 activation induced by Abeta(25-35). Taken together, these results suggest that ROS may be involved in Abeta-induced apoptosis in PC12 cells. They further suggest that PYC can reduce apoptosis, possibly by decreasing free radical generation in PC12 cells.

 

J Mol Med. 2006 Mar;84(3):253-8. Epub 2005 Dec 31.Click here to read Links

    The marijuana component cannabidiol inhibits beta-amyloid-induced tau protein hyperphosphorylation through Wnt/beta-catenin pathway rescue in PC12 cells.

    Esposito G, De Filippis D, Carnuccio R, Izzo AA, Iuvone T.

    Department of Experimental Pharmacology, Faculty of Pharmacy, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, Italy.

    Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. A massive accumulation of beta-amyloid (Abeta) peptide aggregates has been proposed as pivotal event in AD. Abeta-induced toxicity is accompanied by a variegated combination of events including oxidative stress. The Wnt pathway has multiple actions in the cascade of events triggered by Abeta, and drugs that rescue Wnt activity may be considered as novel therapeutics for AD treatment. Cannabidiol, a non-psychoactive marijuana component, has been recently proposed as an antioxidant neuroprotective agent in neurodegenerative diseases. Moreover, it has been shown to rescue PC12 cells from toxicity induced by Abeta peptide. However, the molecular mechanism of cannabidiol-induced neuroprotective effect is still unknown. Here, we report that cannabidiol inhibits hyperphosphorylation of tau protein in Abeta-stimulated PC12 neuronal cells, which is one of the most representative hallmarks in AD. The effect of cannabidiol is mediated through the Wnt/beta-catenin pathway rescue in Abeta-stimulated PC12 cells. These results provide new molecular insight regarding the neuroprotective effect of cannabidiol and suggest its possible role in the pharmacological management of AD, especially in view of its low toxicity in humans.

 

J Neurochem. 2004 Apr;89(1):134-41.Click here to read Links

    Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa, on beta-amyloid-induced toxicity in PC12 cells.

    Iuvone T, Esposito G, Esposito R, Santamaria R, Di Rosa M, Izzo AA.

    Department of Experimental Pharmacology, University of Naples Federico II, Naples, Italy.

    Abstract Alzheimer's disease is widely held to be associated with oxidative stress due, in part, to the membrane action of beta-amyloid peptide aggregates. Here, we studied the effect of cannabidiol, a major non-psychoactive component of the marijuana plant (Cannabis sativa) on beta-amyloid peptide-induced toxicity in cultured rat pheocromocytoma PC12 cells. Following exposure of cells to beta-amyloid peptide (1 micro g/mL), a marked reduction in cell survival was observed. This effect was associated with increased reactive oxygen species (ROS) production and lipid peroxidation, as well as caspase 3 (a key enzyme in the apoptosis cell-signalling cascade) appearance, DNA fragmentation and increased intracellular calcium. Treatment of the cells with cannabidiol (10(-7)-10(-4)m) prior to beta-amyloid peptide exposure significantly elevated cell survival while it decreased ROS production, lipid peroxidation, caspase 3 levels, DNA fragmentation and intracellular calcium. Our results indicate that cannabidiol exerts a combination of neuroprotective, anti-oxidative and anti-apoptotic effects against beta-amyloid peptide toxicity, and that inhibition of caspase 3 appearance from its inactive precursor, pro-caspase 3, by cannabidiol is involved in the signalling pathway for this neuroprotection

J Neurosci. 2005 Mar 23;25(12):3032-40.Click here to read Links

    A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model.

    Lim GP, Calon F, Morihara T, Yang F, Teter B, Ubeda O, Salem N Jr, Frautschy SA, Cole GM.

    Department of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA.

    Epidemiological studies suggest that increased intake of the omega-3 (n-3) polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) is associated with reduced risk of Alzheimer's disease (AD). DHA levels are lower in serum and brains of AD patients, which could result from low dietary intake and/or PUFA oxidation. Because effects of DHA on Alzheimer pathogenesis, particularly on amyloidosis, are unknown, we used the APPsw (Tg2576) transgenic mouse model to evaluate the impact of dietary DHA on amyloid precursor protein (APP) processing and amyloid burden. Aged animals (17-19 months old) were placed in one of three groups until 22.5 months of age: control (0.09% DHA), low-DHA (0%), or high-DHA (0.6%) chow. beta-Amyloid (Abeta) ELISA of the detergent-insoluble extract of cortical homogenates showed that DHA-enriched diets significantly reduced total Abeta by >70% when compared with low-DHA or control chow diets. Dietary DHA also decreased Abeta42 levels below those seen with control chow. Image analysis of brain sections with an antibody against Abeta (amino acids 1-13) revealed that overall plaque burden was significantly reduced by 40.3%, with the largest reductions (40-50%) in the hippocampus and parietal cortex. DHA modulated APP processing by decreasing both alpha- and beta-APP C-terminal fragment products and full-length APP. BACE1 (beta-secretase activity of the beta-site APP-cleaving enzyme), ApoE (apolipoprotein E), and transthyretin gene expression were unchanged with the high-DHA diet. Together, these results suggest that dietary DHA could be protective against beta-amyloid production, accumulation, and potential downstream toxicity.

 

Prog Neuropsychopharmacol Biol Psychiatry. 2008 Aug 1;32(6):1538-44. Epub 2008 May 25.Click here to read Links

    The effects of omega-3 fatty acids monotherapy in Alzheimer's disease and mild cognitive impairment: A preliminary randomized double-blind placebo-controlled study.

    Chiu CC, Su KP, Cheng TC, Liu HC, Chang CJ, Dewey ME, Stewart R, Huang SY.

    Department of Psychiatry, Taipei City Psychiatric Center, Taipei City Hospital, Taipei, Taiwan; Department of Psychiatry, Taipei Medical University, Taiwan; King's College London (Institute of Psychiatry), London, United Kingdom.

    A 24-week, randomized, double-blind placebo-controlled study was carried out to test the feasibility of using omega-3 polyunsaturated fatty acids (PUFAs) monotherapy in people with cognitive impairment and to explore its effects on cognitive function and general clinical condition in these participants. Twenty three participants with mild or moderate Alzheimer's disease and twenty three with mild cognitive impairment were randomized to receive omega-3 PUFAs 1.8 g/day or placebo (olive oil). The data of 35 (76%) participants with at least one post-treatment visit was analyzed. There were no severe adverse effects in either group and it suggests that omega-3 PUFAs were well tolerable in this population. The treatment group showed better improvement on the Clinician's Interview-Based Impression of Change Scale (CIBIC-plus) than those in the placebo group over the 24 week follow-up (p=0.008). There was no significant difference in the cognitive portion of the Alzheimer's Disease Assessment Scale (ADAS-cog) change during follow-up in these two groups. However, the omega-3 fatty acids group showed significant improvement in ADAS-cog compared to the placebo group in participants with mild cognitive impairment (p=0.03), which was not observed in those with Alzheimer's disease. Higher proportions of eicosapentaenoic acid on RBC membranes were also associated with better cognitive outcome (p=0.003). Further studies should be considered with a larger-sample size, diet registration, higher dosages, comparisons between different combinations of PUFAs, and greater homogeneity of participants, especially those with mild Alzheimer's disease and mild cognitive impairment.

  J Neurosci. 2005 Sep 21;25(38):8807-14.Click here to read Links

    Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice.

    Rezai-Zadeh K, Shytle D, Sun N, Mori T, Hou H, Jeanniton D, Ehrhart J, Townsend K, Zeng J, Morgan D, Hardy J, Town T, Tan J.

    Silver Child Development Center, Department of Psychiatry and Behavioral Medicine, University of South Florida, Tampa, Florida 33613, USA.

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by deposition of beta-amyloid (Abeta) peptides as senile plaques in the brain. Recent studies suggest that green tea flavonoids may be used for the prevention and treatment of a variety of neurodegenerative diseases. Here, we report that (-)-epigallocatechin-3-gallate (EGCG), the main polyphenolic constituent of green tea, reduces Abeta generation in both murine neuron-like cells (N2a) transfected with the human "Swedish" mutant amyloid precursor protein (APP) and in primary neurons derived from Swedish mutant APP-overexpressing mice (Tg APPsw line 2576). In concert with these observations, we find that EGCG markedly promotes cleavage of the alpha-C-terminal fragment of APP and elevates the N-terminal APP cleavage product, soluble APP-alpha. These cleavage events are associated with elevated alpha-secretase activity and enhanced hydrolysis of tumor necrosis factor alpha-converting enzyme, a primary candidate alpha-secretase. As a validation of these findings in vivo, we treated Tg APPsw transgenic mice overproducing Abeta with EGCG and found decreased Abeta levels and plaques associated with promotion of the nonamyloidogenic alpha-secretase proteolytic pathway. These data raise the possibility that EGCG dietary supplementation may provide effective prophylaxis for AD.

Brain Res. 2008 Jun 12;1214:177-87. Epub 2008 Apr 7.Click here to read Links

    Green tea epigallocatechin-3-gallate (EGCG) reduces beta-amyloid mediated cognitive impairment and modulates tau pathology in Alzheimer transgenic mice.

    Rezai-Zadeh K, Arendash GW, Hou H, Fernandez F, Jensen M, Runfeldt M, Shytle RD, Tan J.

    Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry and Behavioral Medicine, and Department of Neurosurgery, University of South Florida, Tampa, FL 33613, USA.

    We previously reported that intraperitoneal (i.p.) injection (20 mg/kg) of (-)-epigallocatechin-3-gallate (EGCG), the main polyphenolic constituent of green tea, decreased beta-amyloid (Abeta) levels and plaques via promotion of the non-amyloidogenic alpha-secretase proteolytic pathway in "Swedish" mutant amyloid precursor protein overexpressing (APPsw, Tg) mice. Here, we find that EGCG administered orally in drinking water (50 mg/kg) similarly reduces Abeta deposition in these mice. Following a six month treatment of an 8 month old cohort, immunohistochemical analysis of coronal sections reveals that plaque burdens were reduced in the cingulate cortex, hippocampus, and entorhinal cortex by 54%, 43%, and 51%, respectively. Congo red plaque burdens were decreased in the cingulate cortex, hippocampus, and entorhinal cortex by 53%, 53%, and 58%, respectively as well. ELISA of brain homogenates of the treatment Tg mice revealed consistent reductions in both Abeta1-40 and 1-42 soluble and insoluble forms. In the present study we also investigated the effect EGCG administration had on tau pathology and cognition in Tg mice. Both i.p. and orally-treated Tg animals were found to have modulated tau profiles, with markedly suppressed sarkosyl-soluble phosphorylated tau isoforms. Radial arm water maze (RAWM) testing for working memory indicated that EGCG provided cognitive benefit to Tg mice with both i.p. and oral administration, although i.p.-treated animals showed a more pronounced benefit because of the greater impairment of their Tg controls at the time of testing. Taken together, these data further the notion of EGCG dietary supplementation as a potentially safe and effective prophylaxis for Alzheimer's disease.

 

Neuroscience. 2006 Nov 3;142(4):941-52. Epub 2006 Aug 28.Click here to read Links

    Caffeine protects Alzheimer's mice against cognitive impairment and reduces brain beta-amyloid production.

    Arendash GW, Schleif W, Rezai-Zadeh K, Jackson EK, Zacharia LC, Cracchiolo JR, Shippy D, Tan J.

    The Byrd Alzheimer's Center and Research Institute, Tampa, FL 33647, USA. arendash@cas.usf.edu

    A recent epidemiological study suggested that higher caffeine intake over decades reduces the risk of Alzheimer's disease (AD). The present study sought to determine any long-term protective effects of dietary caffeine intake in a controlled longitudinal study involving AD transgenic mice. Caffeine (an adenosine receptor antagonist) was added to the drinking water of amyloid precursor protein, Swedish mutation (APPsw) transgenic (Tg) mice between 4 and 9 months of age, with behavioral testing done during the final 6 weeks of treatment. The average daily intake of caffeine per mouse (1.5 mg) was the human equivalent of 500 mg caffeine, the amount typically found in five cups of coffee per day. Across multiple cognitive tasks of spatial learning/reference memory, working memory, and recognition/identification, Tg mice given caffeine performed significantly better than Tg control mice and similar to non-transgenic controls. In both behaviorally-tested and aged Tg mice, long-term caffeine administration resulted in lower hippocampal beta-amyloid (Abeta) levels. Expression of both Presenilin 1 (PS1) and beta-secretase (BACE) was reduced in caffeine-treated Tg mice, indicating decreased Abeta production as a likely mechanism of caffeine's cognitive protection. The ability of caffeine to reduce Abeta production was confirmed in SweAPP N2a neuronal cultures, wherein concentration-dependent decreases in both Abeta1-40 and Abeta1-42 were observed. Although adenosine A(1) or A(2A) receptor densities in cortex or hippocampus were not affected by caffeine treatment, brain adenosine levels in Tg mice were restored back to normal by dietary caffeine and could be involved in the cognitive protection provided by caffeine. Our data demonstrate that moderate daily intake of caffeine may delay or reduce the risk of AD.

Am J Med. 2006 Sep;119(9):751-9.Click here to read Click here to read Links

    Fruit and vegetable juices and Alzheimer's disease: the Kame Project.

    Dai Q, Borenstein AR, Wu Y, Jackson JC, Larson EB.

    Department of Medicine, Division of General Internal Medicine and Public Health, Vanderbilt Center for Health Services Research, Vanderbilt-Ingram Cancer Center, Vanderbilt School of Medicine, Nashville, Tenn, USA. qi.dai@vanderbilt.edu

    BACKGROUND: Growing evidence suggests that oxidative damage caused by the beta-amyloid peptide in the pathogenesis of Alzheimer's disease may be hydrogen peroxide mediated. Many polyphenols, the most abundant dietary antioxidants, possess stronger neuroprotection against hydrogen peroxide than antioxidant vitamins. METHODS: We tested whether consumption of fruit and vegetable juices, containing a high concentration of polyphenols, decreases the risk of incident probable Alzheimer's disease in the Kame Project cohort, a population-based prospective study of 1836 Japanese Americans in King County, Washington, who were dementia-free at baseline (1992-1994) and were followed through 2001. RESULTS: After adjustment for potential confounders, the hazard ratio for probable Alzheimer's disease was 0.24 (95% confidence interval [CI], 0.09-0.61) comparing subjects who drank juices at least 3 times per week with those who drank less often than once per week with a hazard ratio of 0.84 (95% CI, 0.31-2.29) for those drinking juices 1 to 2 times per week (P for trend < .01). This inverse association tended to be more pronounced among those with an apolipoprotein Eepsilon-4 allele and those who were not physically active. Conversely, no association was observed for dietary intake of vitamins E, C, or beta-carotene or tea consumption. CONCLUSIONS: Fruit and vegetable juices may play an important role in delaying the onset of Alzheimer's disease, particularly among those who are at high risk for the disease. These results may lead to a new avenue of inquiry in the prevention of Alzheimer's disease.

 

Neurobiol Dis. 2006 Dec;24(3):506-15. Epub 2006 Sep 28.Click here to read Links

    Pomegranate juice decreases amyloid load and improves behavior in a mouse model of Alzheimer's disease.

    Hartman RE, Shah A, Fagan AM, Schwetye KE, Parsadanian M, Schulman RN, Finn MB, Holtzman DM.

    Department of Psychology, Loma Linda University, Loma Linda, CA 92354, USA. behavioralneuroscience@gmail.com

    Although there are no proven ways to delay onset or slow progression of Alzheimer's disease (AD), studies suggest that diet can affect risk. Pomegranates contain very high levels of antioxidant polyphenolic substances as compared to other fruits and vegetables. Polyphenols have been shown to be neuroprotective in different model systems. We asked whether dietary supplementation with pomegranate juice (PJ) would influence behavior and AD-like pathology in a transgenic mouse model. Transgenic mice (APP(sw)/Tg2576) received either PJ or sugar water control from 6 to 12.5 months of age. PJ-treated mice learned water maze tasks more quickly and swam faster than controls. Mice treated with PJ had significantly less (approximately 50%) accumulation of soluble Abeta42 and amyloid deposition in the hippocampus as compared to control mice. These results suggest that further studies to validate and determine the mechanism of these effects, as well as whether substances in PJ may be useful in AD, should be considered.

J Alzheimers Dis. 2004 Feb;6(1):27-30.Click here to read Links

    Apple juice prevents oxidative stress induced by amyloid-beta in culture.

    Ortiz D, Shea TB.

    Center for Cellular Neurobiology and Neurodegeneration Research, Department of Biological Sciences, University of Massachusetts Lowell, Lowell, MA 01854, USA.

    Increased oxidative stress contributes to the decline in cognitive performance during normal aging and in neurodegenerative conditions such as Alzheimer's disease. Dietary supplementation with fruits and vegetables that are high in antioxidant potential have in some cases compensated for oxidative stress. Herein, we examined whether apple juice could alleviate the neurotoxic consequences of exposure of cultured neuronal cells to amyloid-beta (Abeta), since at least a portion of the neurotoxicity of Abeta is due to oxidative stress. Apple juice concentrate (AJC; 70 degree brix) was diluted into culture medium of SH-SY-5Y human neuroblastoma cells that had been differentiated for 7 days with 5 microM retinoic acid concurrent with the addition of 20 microM Abeta. AJC prevented the increased generation of reactive oxygen species (ROS) normally induced by Abeta treatment under these conditions. AJC also prevented Abeta-induced calcium influx and apoptosis, each of which results in part due to increased ROS. These findings suggest that the antioxidant potential of apple products can prevent Abeta-induced oxidative damage.

Bioorg Med Chem. 2007 Jan 15;15(2):1160-7. Epub 2006 Oct 1.Click here to read Links

    Inhibitory activity of stilbenes on Alzheimer's beta-amyloid fibrils in vitro.

    Rivière C, Richard T, Quentin L, Krisa S, Mérillon JM, Monti JP.

    Laboratoire de physique et biophysique, Université de Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux cedex, France.

    Polymerization of the amyloid beta-peptide (Abeta) has been identified as one of the major characteristics of Alzheimer's disease (AD). Thus, finding molecules to prevent the aggregation of Abeta could be of therapeutic value in AD. We describe an original routine in vitro assay to search for inhibitors of Abeta(25-35) fibril formation which uses UV-visible measurements and electron microscopy (EM). In particular, this routine assay was used to examine the effects of stilbenes, a well-known polyphenol class, as inhibitors of Abeta fibril formation. The inhibitory properties of resveratrol (RES), piceid (PIC), resveratrol diglucoside (DIG), piceatannol (PIA), astringine (AST), and viniferin (VIN) were characterized and compared. RES and PIC effectively and dose-dependently inhibited Abeta polymerization while other polyphenols exerted less inhibition. Although the mechanism of anti-amyloidogenic activity is still unknown, these results support the hypothesis that stilbenes could be of therapeutic value in AD.

 

Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2006 Aug;31(4):566-9.Links

    [Effect of resveratrol on the cognitive ability of Alzheimeros mice]

    [Article in Chinese]

    Luo L, Huang YM.

    Deparment of Nutrition and Food Hygiene, School of Public Health, Central South University, Changsha 410078, China.

    OBJECTIVE: To explore the effect of resveratrol on the cognition of Alzheimer's mice (AD) and its mechanism, and to assess its action on the reproduction system. METHODS: According to the results of step-down test, 84 Kunming female mice were randomly divided into 6 groups: Group A [sham operated+1% CMC-Na (0.01 mL/g)], Group B [ovariectomy+D-galactose+1% CMC-Na (0.01 mL/g)], Group C [ovariectomy+D-galactose+0.05 mg/(kg.d) Diethylstilbestrol], Group D [ovariectomy+D-galactose+15 mg/(kg.d) Res], and Group E [ovariectomy+D-galactose injected+45 mg/(kg.d) Res], and Group F [ovariectomy+D-galactose +135 mg/(kg.d) Res]. Experimental cycle was 60 days. RESULTS: Resveratrol of every dosage could improve the performance records of behavior tests in AD mice,could inhibit the SOD vitality and the MDA level both in the serum and in the brain, and could suppress the acetylcholinesterase vitality and the bax expression. Resveratrol has no endometrial hyperplasia effect. CONCLUSION: Resveratrol can improve the cognitive ability of AD mice, which may contribute to the resveratrol's antioxidation and antiapoptosis, and can modulate acetylcholinesterase. Resveratrol has no side-effect of endometrial hyperplasia on AD mice.

Brain Res Rev. 2006 Sep;52(2):316-26.Click here to read Links

    Resveratrol--a boon for treating Alzheimer's disease?

    Anekonda TS.

    Neurological Sciences Institute, Oregon Health and Science University, 505 NW 185th Avenue, Beaverton, 97006, USA. anekondt@ohsu.edu

    Resveratrol, a red wine polyphenol, is known to protect against cardiovascular diseases and cancers, as well as to promote antiaging effects in numerous organisms. It also modulates pathomechanisms of debilitating neurological disorders, such as strokes, ischemia, and Huntington's disease. The role of resveratrol in Alzheimer's disease is still unclear, although some recent studies on red wine bioactive compounds suggest that resveratrol modulates multiple mechanisms of Alzheimer's disease pathology. Emerging literature indicates that mechanisms of aging and Alzheimer's disease are intricately linked and that these mechanisms can be modulated by both calorie restriction regimens and calorie restriction mimetics, the prime mediator of which is the SIRT1 protein, a human homologue of yeast silent information regulator (Sir)-2, and a member of NAD+-dependent histone deacetylases. Calorie restriction regimens and calorie restriction-mimetics trigger sirtuins in a wide variety of organisms, ranging from bacteria to mouse. In a mouse model of Huntington's disease, resveratrol-induced SIRT1 was found to protect neurons against ployQ toxicity and in Wallerian degeneration slow mice, resveratrol was found to protect the degeneration of neurons from axotomy, suggesting that resveratrol may possess therapeutic value to neuronal degeneration. This paper mainly focuses on the role of resveratrol in modulating AD pathomechanisms.

J Nutr Health Aging. 2008 Apr;12(4):252-61.Links

    Dietary and genetic compromise in folate availability reduces acetylcholine, cognitive performance and increases aggression: critical role of S-adenosyl methionine.

    Chan A, Tchantchou F, Graves V, Rozen R, Shea TB.

    Center for Cellular Neurobiology and Neurodegeneration Research, Department of Biological Sciences, University of Massachusetts, Lowell, MA 01854, USA.

    Folate deficiency has been associated with age-related neurodegeneration. One direct consequence of folate deficiency is a decline in the major methyl donor, S-adenosyl methionine (SAM). We demonstrate herein that pro-oxidant stress and dietary folate deficiency decreased levels of acetylcholine and impaired cognitive performance to various degrees in normal adult mice (9-12 months of age, adult mice heterozygously lacking 5',10'-methylene tetrahydrofolate reductase, homozygously lacking apolipoprotein E, or expressing human ApoE2, E3 or E4, and aged (2-2.5 year old) normal mice. Dietary supplementation with SAM in the absence of folate restored acetylcholine levels and cognitive performance to respective levels observed in the presence of folate. Increased aggressive behavior was observed among some but not all genotypes when maintained on the deficient diet, and was eliminated in all cases supplementation with SAM. Folate deficiency decreased levels of choline and N-methyl nicotinamide, while dietary supplementation with SAM increased methylation of nicotinamide to generate N-methyl nicotinamide and restored choline levels within brain tissue. Since N-methyl nicotinamide inhibits choline transport out of the central nervous system, and choline is utilized as an alternative methyl donor, these latter findings suggest that SAM may maintain acetylcholine levels in part by maintaining availability of choline. These findings suggest that dietary supplementation with SAM represents a useful therapeutic approach for age-related neurodegeneration which may augment pharmacological approaches to maintain acetylcholine levels, in particular during dietary or genetic compromise in folate usage.

J Alzheimers Dis. 2008 Jul;14(3):323-8.Click here to read Links

    S-adenosylmethionine mediates glutathione efficacy by increasing glutathione s-transferase activity: implications for s-adenosyl methionine as a neuroprotective dietary supplement.

    Tchantchou F, Graves M, Falcone D, Shea TB.

    Department of Biological Sciences, Center for Cellular Neurobiology and Neurodegeneration Research, Umass Lowell, One University Avenue, Lowell, MA 01854, USA.

    When maintained on a folate-deficient, iron-rich diet, transgenic mice lacking in apolipoprotein E (ApoE-/- mice) demonstrate impaired activity of glutathione S-transferase (GST), resulting in increased oxidative species within brain tissue despite abnormally high levels of glutathione. These mice also exhibit reduced levels of S-adenosyl methionine (SAM) and increased levels of its hydrolysis product S-adenosyl homocysteine, which inhibits SAM usage. Supplementation of the above diet with SAM restored GST activity and eliminated reactive oxygen species at the expense of stockpiled glutathione, suggesting that one or more SAM-dependent reactions were required to maintain GST activity. We examined herein the impact of SAM on GST activity using a cell-free assay. SAM stimulated GST activity in a dose-response manner when added to homogenates derived from the above ApoE-/- mice. SAM also increased activity of purified rat liver GST and recombinant GST. Filtering of SAM through a 4kDa cutoff and systematic withholding of reaction components eliminated the possibility of any additional contaminating enzyme. These findings confirm that SAM can exert a direct effect on GST activity. Since Alzheimer's disease is accompanied by reduced GST activity, diminished SAM and increased SAH, these findings underscore the critical role of SAM in maintenance of neuronal health.

 

J Alzheimers Dis. 2008 Jun;14(2):225-34.Click here to read Links

    Evaluation of coenzyme Q as an antioxidant strategy for Alzheimer's disease.

    Wadsworth TL, Bishop JA, Pappu AS, Woltjer RL, Quinn JF.

    Department of Neurology, Oregon Health & Science University, Portland, OR 97239-3098, USA. wadswort@ohsu.edu

    Increasing evidence suggests that Alzheimer's disease (AD) is associated with oxidative damage that is caused in part by mitochondrial dysfunction. Here we investigated the feasibility of modifying Alzheimer pathology with the mitochondrial antioxidant coenzyme Q (CoQ). Exogenous CoQ protected MC65 neuroblastoma cells from amyloid-beta protein precursor C-terminal fragment (APP CTF)-induced neurotoxicity in a concentration dependent manner, with concentrations of 6.25 microM and higher providing near complete protection. Dietary supplementation with CoQ at a dose of 10 g/kg diet to C65/Bl6 mice for one month significantly suppressed brain protein carbonyl levels, which are markers of oxidative damage. Treatment for one month with 2 g lovastatin/kg diet, which interferes with CoQ synthesis, resulted in a significant lowering of brain CoQ10 levels. Mitochondrial energetics (brain ATP levels and mitochondrial membrane potential) were unaffected by either CoQ or lovastatin treatment. Our results suggest that oral CoQ may be a viable antioxidant strategy for neurodegenerative disease. Our data supports a trial of CoQ in an animal model of AD in order to determine whether a clinical trial is warranted.