Diet and HD:
- About Diet and HD
- Weight Loss: Demystifying a Medical Mystery
- Red Wine
- Diet and Neurogenesis
- The Mediterranean Diet
- Curcumin, the Curry Spice
- Fatty Acids
- Cholesterol and HD
While Huntington’s disease is traditionally thought of as a disease of the brain, its effects are much more widespread: many people with HD lose a dangerous amount of weight, complicating a disease that is already complicated enough. Although weight loss is one of the most serious non-neurological problems of HD, scientists don’t fully understand why it occurs. This medical mystery has driven scientists deep into the biology underlying weight loss in HD. Researchers have recently turned up a few potential explanations, and our increased understanding of this symptom is leading scientists to look at possible new ways of treating the disease.
People with HD tend to weigh less than those without the disease. A group of researchers from the Huntington Study Group followed 927 people with early-stage HD. For a description of the stages of HD, please click here. The investigators found that people with early-stage HD weighed an average of 10 kilograms (22 pounds) less than age-matched controls, which are people of the same age who don’t have the disease. Another study found that people with HD lose an average of 0.9 pounds per year, which stands in stark contrast to the average American, who gains 0.4-2 pounds yearly.
Unfortunately, while 0.9 pounds doesn’t seem like much, that’s just an average; some people with HD lose so much weight that their health is impacted. Weight loss worsens other aspects of the disease as underweight patients become malnourished and weak. Underweight patients are more susceptible to infection, and take longer to recover from illness, operations, and wounds. Weight loss also increases the likelihood of developing pressure ulcers, commonly known as bedsores, as bedridden patients have less fat tissue to cushion them from pressure. Patients who lose the most weight report a lower quality of life, and are more likely to feel apathetic and depressed. In the late stages of the disease, some patients lose so much weight that they need a feeding tube to stay healthy, as described here. On the other hand, people who start out heavier fare better; people who have a high body-mass index (BMI) when symptoms begin progress more slowly through the disease. Visit this website for an explanation of BMI and a for BMI calculator.
While weight loss is one of the most serious non-neurological problems associated with HD, doctors don’t understand why it happens. Many suggestions have been put forth, but most of them have been disproved, forcing researchers to dig deeper to understand this phenomenon.
Doctors once believed that weight loss was due to chorea, the uncontrolled movements characteristic of HD. Doctors thought that people with HD lost weight because they burned extra energy as a result of the involuntary movements of chorea. However, three experiments indicate that chorea can’t be fully responsible for weight loss.
The first piece of evidence comes from looking at the early stages of the disease. People who have just been diagnosed with HD – and therefore have very mild symptoms – already weigh less than people without the disease. As mentioned earlier, people in early-stage HD weigh an average of 10 kg less than those who are not affected by the disease. Another group of researchers arrived at similar results; a study of 361 people with early-stage HD found that they have BMIs an average of 2 points lower than those without the disease, even if the patients had just been diagnosed with HD within that year and hadn’t yet begun to experience choreic movements. Researchers concluded that chorea alone could not explain why people with HD have lower BMIs, and that other factors are at play.
Other studies suggest that chorea may not have as much of an impact as doctors once thought. Pratley et al. measured how much movement chorea caused, in an attempt to quantify how much weight patients lose due to choreic movement. After measuring the movements of 17 people with mild to moderate HD for a week, they found that chorea caused people with HD to move more than people without the disease when sedentary: people with HD moved 14% more than people without HD while sitting or lying down. However, people with HD do less voluntary activity. Study participants with HD walked around and exercised less than people without the disease. In the end, Pratley et al. were surprised to discover that sedentary over-activity balanced out voluntary under-activity: people in the early and middle stages of HD don’t actually move more than people without the disease.
A similar study by the European Huntington’s Disease Initiative Study Group (EHDI) measured weight loss in 517 people with HD, and found no correlation between the amount of weight people lost and the severity of their motor symptoms; people with good scores on tests measuring motor symptoms (such as the UHDRS) were just as likely to lose weight as those with bad motor scores. For more information on diagnostic tests like the UHDRS, click here.
The final strike against the chorea theory comes from observations of people with late-stage HD. Weight loss is most drastic in the final stages of HD, despite the fact that chorea has usually ceased and patients are largely bedridden. So while chorea contributes to weight loss in HD, it cannot stand as the sole explanation.
Others suggest that people with HD lose weight because they have trouble eating; as the disease progresses, it becomes increasingly difficult to perform the complicated series of movements needed to eat, chew, and swallow.
However, this theory is also not enough to fully explain the weight loss. Studies have shown that people with HD actually tend to eat more than people without the disease; a study of 25 people with HD found that they ate an average of almost 400 calories more each day than people without the disease. Others report that they’ve had patients who eat up to 5000 calories a day – over twice the average daily caloric intake – just to maintain their weight.
So two popular explanations for weight loss in HD – chorea and insufficient diet – cannot entirely explain why people with HD lose so much weight.
Though the reasons for the mysterious weight loss are unclear, scientists are currently testing a few ideas.
One leading idea has to do with metabolism, the way the body burns calories to produce energy. HD researchers have long suspected that the disease-causing form of huntingtin (hereafter described as mutant huntingtin) interferes with energy metabolism, as described here. Results from a recent study suggest that this interference might contribute to weight loss.
After discovering that weight loss is not correlated with motor symptoms, scientists from the EHDI Study Group looked for other factors that might be to blame. They found that weight loss could be partially predicted by the number of CAG repeats on a patient’s copy of the mutant huntingtin gene; for every additional CAG repeat a patient had, they lost on average an extra 0.136 BMI points (0.8 pounds) over the course of the three year period that the study was conducted. For an explanation of CAG repeats, please click here.
The same holds true in mouse models of HD. The EHDI Study Group found that the more CAG repeats an HD mouse had, the more it tended to eat. Yet paradoxically, the mice with the most CAG repeats lost the most weight. So people and mice with more CAG repeats lose more weight.
The EHDI investigators suspect that this is due to the long tail of the mutant huntingtin protein. People with more CAG repeats produce mutant huntingtin with a longer tail, as described here. The EHDI investigators suggest that the mutant huntingtin protein interferes with the way cells make energy, and that longer-tailed proteins cause more problems. Mutant huntingtin has been shown to disrupt proteins that are needed to make energy and can damage mitochondria, the “energy factory” of our cells, as described here. In support of the theory that proteins with longer tails are more problematic, scientists at the MacDonald lab in Boston studied cells engineered to express mutant huntingtin. They found that cells with more CAG repeats made less ATP, the energy currency of the cell. So it seems possible that the more CAG repeats individuals have, the less efficient their cells are at converting calories to energy.
A second school of thought suggests that weight loss is due to hormonal disturbances in people with HD. Hormones are the body’s chemical messengers, and are important for regulating physiological processes, like hunger. The hypothalamus secretes many hormones, so when HD causes cells in the hypothalamus to malfunction and die, hormone production is disturbed.
Some of the hormonal signals that the hypothalamus sends out go to the gut and fat tissue, and direct processes like eating and burning energy – processes that are very important in maintaining a healthy weight. Therefore, some scientists think that cell death in the hypothalamus causes hormonal changes that might contribute to weight loss and other problems such as sleep disturbances, as described here.
Further insights have come from studying the way mutant huntingtin interacts with the digestive system. Certain symptoms of HD have hinted that the disease might affect the gut; apart from weight loss, people with HD often experience nutritional deficiencies, cramps, and wasting of skeletal muscles. People with HD are also prone to gastritis, a disease where the stomach lining becomes irritated or swollen.
Despite these symptoms, many HD researchers have traditionally thought that mutant huntingtin only affected the brain – a belief that struck some as strange because the protein is made and found throughout the body. However, results from a recent study suggest that mutant huntingtin in the gut might interfere with important digestive processes, thus contributing to weight loss.
In the study, van der Burg and colleagues looked at R6/2 mice, which are mouse models of HD described in greater detail here. They noticed several physiological changes that could all impact digestion. First, they noticed that the small intestines of HD mice were 10-15% shorter than those of normal mice, and that they had smaller villi, the tiny finger-like projections in the gut that take up nutrients. On top of that, scientists noticed that the mucus lining of the gut of the HD mice was 20-30% thinner. Since all of these structures are needed for nutrient absorption, these findings suggest that HD mice can’t take up nutrients as efficiently as normal mice.
Furthermore, the group found that the HD mice were missing a few key hormones that control the speed at which food passes through the body. This caused an increase in ‘transit time’: the food passed more slowly through the gut. Longer transit time might foster bacterial growth; if food takes longer to pass through the gut, harmful bacterial have more time and a better opportunity to flourish. This could make the small intestine irritated and inflamed, which could cause malabsorption of nutrients, chronic diarrhea, nausea, bloating, flatus, and weight loss. Those bacteria might also use up nutrients that the body would have otherwise taken up.
To see whether these physiological differences actually have an impact on digestion, researchers then compared the feces of HD mice to those of normal mice. They found that HD mice excreted more of what they ate, suggesting that they absorbed fewer calories and nutrients from their food. Notably, the mice that were the worst at absorbing nutrients from their food lost the most weight.
Van der Burg et al. had a few ideas as to what mutant huntingtin might be doing to interfere with digestion. Since the protein is present in gut cells, it could interfere with cell function and nutrient absorption. They also thought that mutant huntingtin might affect transcription, the process by which DNA is converted into protein as described here. If mutant huntingtin affects transcription in gut cells, it could cause a decrease in levels of important proteins needed for cells to survive and function properly.
While findings in HD mice don’t always translate to humans, these results indicate that scientists might benefit from studying the way HD affects digestion in people. Van der Burg et al. suggest that such research might help doctors improve their understanding of nutritional supplements for HD, and might even change the way we think about how people with HD metabolize and react to medicine.
Weight loss in HD has long puzzled doctors, patients, and caretakers alike. Two popular explanations of the phenomenon – chorea and reduced food intake – have been debunked as major contributors to weight loss. However, scientists have made new in-roads in recent years. By discovering that mutant huntingtin might disrupt energy metabolism, digestion, and hormones in HD mice, scientists have enhanced our understanding of HD, which may pave the way to new treatments and therapies. For example, the hypothesis that weight loss is linked to abnormalities in energy metabolism suggests that energy-boosting drugs – namely creatine and Coenzyme Q10 – are strong candidates to fight HD, as described in these articles here. Each further discovery about HD leads to a greater understanding of the disease, and brings hope for patients and families.
1. Aziz NA, van der Burg JM, Landwehrmeyer GB, Brundin P, Stijnen T; EHDI Study Group, Roos RA. Weight loss in Huntington disease increases with higher CAG repeat number. Neurology. 2008 Nov 4;71(19):1506-13.
This medium-difficulty study describes how people with more CAG repeats lose more weight – and provides some theories as to why that might be the case.
2. Djoussé L, Knowlton B, Cupples LA, Marder K, Shoulson I, Myers RH. Weight loss in early stage of Huntington’s disease. Neurology. 2002 Nov 12;59(9):1325-30.
This medium-difficulty article describes weight loss in people with early-stage HD
3. Hamilton JM, Wolfson T, Peavy GM, Jacobson MW, Corey-Bloom J; Huntington Study Group. Rate and correlates of weight change in Huntington’s disease. J Neurol Neurosurg Psychiatry. 2004 Feb;75(2):209-12.
This medium-difficulty article describes weight loss in people with early-stage HD
4. Kremer HP, Roos RA. Weight loss in Huntington’s disease. Arch Neurol. 1992 Apr;49(4):349.
5. Petersén A, Björkqvist M. Hypothalamic-endocrine aspects in Huntington’s disease. Eur J Neurosci. 2006 Aug;24(4):961-7. Epub 2006 Aug 21. Review
This technical article describes how hormonal changes in people with HD might lead to weight loss
6. Pollard J, Best R, Imbrigilo S, Klasner E, Rublin A, Sanders G, Simpson W. A Caregiver’s Guide for Advanced-Stage Huntington’s Disease. Huntington’s Disease Society of America, 1999.
This easy-to-read handbook is a very helpful resource for caregivers taking care of people in late-stage HD
7. Pratley RE, Salbe AD, Ravussin E, Caviness JN. Higher sedentary energy expenditure in patients with Huntington’s disease. Ann Neurol. 2000 Jan;47(1):64-70
This study measured movements of people with HD, and found that their total energy expenditure was the same as that of people without the disease, and is somewhat technical
8. Seong IS, Ivanova E, Lee JM, Choo YS, Fossale E, Anderson M, Gusella JF, Laramie JM, Myers RH, Lesort M, MacDonald ME. HD CAG repeat implicates a dominant property of huntingtin in mitochondrial energy metabolism. Hum Mol Genet. 2005 Oct 1;14(19):2871-80. Epub 2005 Aug 22.
This technical article describes how huntingtin interferes with energy metabolism in a CAG-dependent fashion
9. Trejo A, Tarrats RM, Alonso ME, Boll MC, Ochoa A, Velásquez L. Assessment of the nutrition status of patients with Huntington’s disease. Nutrition. 2004 Feb;20(2):192-6.
This medium-difficulty paper discusses the result of the study on 25 HD patients that ate an average of 400 calories more than controls each day.
10. van der Burg JM, Winqvist A, Aziz NA, Maat-Schieman ML, Roos RA, Bates GP, Brundin P, Björkqvist M, Wierup N. Gastrointestinal dysfunction contributes to weight loss in Huntington’s disease mice. Neurobiol Dis. 2011 Oct;44(1):1-8. Epub 2011 May 23.
This technical article describes the impact of huntingtin on digestion in HD mice
M. Hedlin 11.16.11
A novel track of research has unearthed new meaning to the old adage “you are what you eat”. Research suggests that our diet plays a role in neurogenesis, the process by which we produce new neurons. Therefore, a diet rich in “brain food” may promote neurogenesis and thereby might repair some of the damage brought on by Huntington’s disease (HD).
The old myth that a person is born with as many neurons as he would ever have has recently been overturned. Though neurogenesis is most abundant before birth, scientists have shown that adults can make new neurons throughout life. This allows our brains to age gracefully, as these new neurons work to replace the neurons that inevitably die. Neurogenesis allows us to have flexible brains throughout life, which is critical for learning new skills (Greenwood and Parasuraman, 2010). For more information on neurogenesis, click here.
In particular, neurogenesis is important in the context of HD. Neurogenesis continues to occur in HD patients and, in fact, increases as the disease progresses. This increase is thought to be the brain’s attempt to repair itself in response to the widespread neuronal death caused by the disease. However, neurogenesis does not happen fast enough to counter the damage incurred (Taupin, 2008).
It is possible that a diet that promotes neurogenesis could help counter some of the deficits experienced by HD patients. Some scientists have explored how diet can impact neurogenesis, and have found a number of nutrients and dietary regimes that may play a role.
One major track of research on diet and neurogenesis focused on dietary restriction (DR). DR is a strategy wherein calories are limited to about 70% of the normal diet (Levenson and Rich, 2007). This calorie reduction has been shown to lengthen lifespan; the lives of rats and mice can be extended by as much as 50% if they are put on a restricted diet at a young age, and maintain that diet throughout life. In rats and monkeys, DR helps protect against age-related diseases, like cancer, diabetes, and cardiovascular disease (Mattson et al., 2004)
Scientists think DR brings about these beneficial effects by conditioning cells to be better at protecting themselves. DR is a mild stress that puts cells on the defensive, and causes them to start expressing protective genes and stockpiling useful proteins. Therefore, cells stressed by DR are better able to cope with further stressors. For more information on DR, click here.
One stressor that occurs in many neurodegenerative conditions, like Alzheimer’s, Parkinson’s, and HD, and can be ameliorated by DR, is oxidative stress. In HD, oxidative damage occurs when injured neurons release free radicals, which go on to damage neurons around them (Mattson et al., 2004). For more information on oxidative damage, click here. Therefore, DR may help patients with neurodegenerative diseases by causing neurons to fortify themselves, which could prepare them for the stress caused by HD.
Scientists also believe that DR can help patients with neurodegenerative conditions by promoting neurogenesis. DR increases adult neurogenesis in young adult rats, and reduces age-related declines in neurogenesis in older mice (Levenson and Rich, 2007). Furthermore, DR stimulates neurogenesis in the hippocampus, a brain region important for memory. DR also causes an increase in levels of BDNF, a protein shown to help newly born neurons survive (Mattson et al., 2004). For more information on BDNF, click here. Researchers have found that DR can improve the symptoms of HD and several other neurodegenerative conditions in mice. When rats were injected with a chemical that causes brain damage, the rats kept on a restricted diet were more resistant to the chemical’s neurodegenerative effects, and showed fewer learning and memory problems (Mattson et al., 2004). When HD mice were kept on a restricted diet, they showed less striatal neuron death, it took longer for movement problems to arise, and the mice lived longer (Mattson et al, 2004). So DR may protect against neurodegenerative conditions by stimulating neurogenesis and causing neurons to fortify themselves.
DR, however, is a drastic strategy: it takes tremendous willpower to limit calories to 70% of the normal diet. Furthermore, DR is difficult to implement properly; there is a risk of starvation if the diet is unbalanced, which can have wide-ranging consequences. Luckily, similar effects to DR have been found in mice by simply increasing the amount of time between meals (Stangl and Thuret, 2009).
Some scientists have attempted to harness the beneficial effects of DR through resveratrol, a chemical found in red wine. Resveratrol mimics many of the effects of DR, and is thought to work through the same biological pathways (Greenwood and Parasuraman, 2010). For more information, click here.
Conversely, researchers have also studied situations where cells have too many calories, and have found that neurogenesis is impaired. Mice on a high-fat diet have lower levels of BDNF in the hippocampus, and decreased neurogenesis in a particular area of the hippocampus called the dentate gyrus (Park et al., 2010). Furthermore, when injected with a chemical that injures the brain, mice fed a high-fat diet experienced much more damage than those fed a normal diet. Diets high in fat also decrease the learning and cognitive capabilities of rats (Greenwood and Prasuraman, 2010). Thus, experiments on rodents consistently show that a high-fat diet is unhealthy for the brain.
Another line of research on diet and neurogenesis has investigated the effect of dietary nutrients on the birth of new neurons. Several antioxidants, such as flavonoids, vitamin E, and curcumin, increase neurogenesis in rodent brains. Antioxidants are chemicals that prevent damage from free radicals, and thus might promote neurogenesis by protecting new neurons, among other things (Gómez-Pinilla, 2008). Flavonoids, found in cocoa and blueberries, are chemicals that increase neurogenesis in the hippocampus of stressed rats, possibly by increasing levels of BDNF (Stangl and Thuret, 2009), and/or by improving blood flow to the brain, which can increase hippocampal neurogenesis (Spencer, 2009). Vitamin E, abundant in vegetable oils, nuts, and green leafy vegetables, aids neurological performance in aging mice (Gómez-Pinilla, 2008). Curcumin, found in yellow curry spice, may increase neurogenesis in the hippocampus of rodents by activating certain cell signaling pathways known to increase neurogenesis and decrease stress responses (Stangl and Thuret, 2009). For more information on curcumin, click here.
Another antioxidant, found in green tea, goes one step further than the others. The chemical (-)-epigallocatechin-3-gallate (called EGCG) promotes neurogenesis in the hippocampus (Yoo et al., 2010), and has been shown to reduce the damage from oxidative stress in other neurodegenerative diseases (Ehrnhoefer et al., 2006). When flies with a form of HD were treated with EGCG, their control over their movements improved (Ehrnhoefer et al., 2006). EGCG might also directly fight the damage of HD, as it has been shown to slow the rate at which the mutant form of the huntingtin protein forms the plaques that are thought to hurt the brain (Ehrnhoefer et al., 2006).
In addition to antioxidants, other nutrients have also been shown to play a role in neurogenesis. Omega-3 fatty acids, present in fish and flaxseed, might also promote neurogenesis, and have been shown to decrease cognitive decline seen with aging and neurodegenerative diseases such as Alzheimer’s (Yurko-Mauro et al, 2010). For more information, click here. Vitamins might stimulate the birth of new neurons since, in some cases, vitamin deficiency can inhibit neurogenesis. For example, deficits in zinc inhibit neurogenesis in the hippocampus of rodents. Zinc, a vitamin essential for normal brain development, promotes the survival and proliferation of neural stem cells, which are the main cell type capable of generating neurons (Adamo and Oteiza, 2010). Therefore, zinc deficiency inhibits neurogenesis in the hippocampus of rodents. Similarly, a deficiency of retinoic acid, a metabolite of vitamin A found in animal foods such as milk, inhibits hippocampal neurogenesis (Stangl and Thuret, 2009).
Altogether, research on diet and neurogenesis is not conclusive. It is difficult to study nutrients effectively: studying a nutrient in isolation ignores many of the complex interactions the nutrient may have in the body. However, there are a few relatively consistent messages that emerge. A vitamin-rich, low-fat diet aids neurogenesis in experiments with rodents, and a low-calorie diet mitigates the effects of neurogenerative disease in mice. As for humans, this diet has not been shown to directly help neurogenesis or ameliorate the problems of HD (Huntington Study group, 2008; Block et al., 2011), but healthy diets have a vast number of other physical and mental benefits: longer life, elevated mood, and higher energy levels, to name a few. In conclusion, eating healthy might promote neurogenesis – but even if it does not, a healthy diet certainly will not hurt.
Adamo AM, Oteiza PI. Zinc deficiency and neurodevelopment: the case of neurons. Biofactors. 2010 Mar-Apr; 36 (2) :117-24
A technical paper that discusses the impact of zinc deficiency on the brain
A technical paper that discusses Omega-3 fatty acids and their effects on HD.
Curtis MA, Penney EB, Pearson AG, van Roon-Mom WM, Butterworth NJ, Dragunow M, Connor B, Faull RL. Increased cell proliferation and neurogenesis in the adult human Huntington’s disease brain. Proc Natl Acad Sci U S A. 2003 Jul 22; 100 (15) :9023-7.
A technical paper that discusses neurogenesis in an HD brain
Ehrnhoefer DE, Duennwald M, Markovic P, Wacker JL, Engemann S, Roark M, Legleiter J, Marsh JL, Thompson LM, Lindquist S, Muchowski PJ, Wanker EE. Green tea (-)-epigallocatechin-gallate modulates early events in huntingtin misfolding and reduces toxicity in Huntington’s disease models. Hum Mol Genet. 2006 Sep 15;15(18):2743-51. Epub 2006 Aug 7.
A technical paper that discusses strategies to counter the neuron damage that accompanies aging, such as education, exercise, dietary restriction, and a low-fat diet, and goes into research that has been performed on rodents.
Gómez-Pinilla, F. Brain foods: the effects of nutrients on brain function. Nature Reviews Neuroscience. 2008 Jul. Review; 9:568-578.
A technical paper that discusses how various nutrients affect brain function.
Levenson CW, Rich NJ. Eat less, live longer? New insights into the role of caloric restriction in the brain. Nutr Rev. 2007 Sep; 65 (9) :412-5.
A paper that discusses the impact of caloric restriction on the brain in rodents
Park HR, Park M, Choi J, Park KY, Chung HY, Lee J. A high-fat diet impairs neurogenesis: involvement of lipid peroxidation and brain-derived neurotrophic factor. Neurosci Lett. 2010 Oct 4; 482 (3) :235-9.
A technical paper that discusses the impact of a high-fat diet on rodents
A technical paper that discusses dietary restriction and its effect on the brain in rodents
A technical paper that discusses the impact of flavonoids on the brain
Stangl D, Thuret S. Impact of diet on adult hippocampal neurogenesis. Genes Nutr. 2009 Dec; 4 (4) :271-82.
Yurko-Mauro K, McCarthy D, Rom D, Nelson EB, Ryan AS, Blackwell A, Salem N Jr, Stedman M; MIDAS Investigators. Beneficial effects of docosahexaenoic acid on cognition in age-related cognitive decline. Alzheimers Dement. 2010 Nov;6(6):456-64.
A technical paper that discusses how Omega-3 fatty acids may aid patients with neurodegenerative conditions
Yoo KY, Choi JH, Hwang IK, Lee CH, Lee SO, Han SM, Shin HC, Kang IJ, Won MH. (-)-Epigallocatechin-3-gallate increases cell proliferation and neuroblasts in the subgranular zone of the dentate gyrus in adult mice. Phytother Res. 2010 Jul;24(7):1065-70.
A technical paper that discusses how EGCG enhances neurogenesis
M. Hedlin 6/17/2011More
People have been consuming red wine for thousands of years. Although most people drink wine because of its pleasurable sensory effects, recent studies suggest that drinking red wine may confer several health benefits. Many researchers believe that these health benefits come from a compound in red wine called resveratrol, which has been shown to exhibit neuroprotective effects in several experimental studies in test tubes as well as in various organisms including yeast, worms, and mice. A few studies also provide insight into how resveratrol may affect mice with neurodegenerative disorders and more specifically mice with the mutant huntingtin protein.
Preliminary research has suggested that resveratrol may help protect against common HD complications such as inflammation, oxidative stress, and possibly huntingtin protein aggregation. (For more information on inflammation, click here.) Further studies of resveratrol in the context of neurodegeneration and Huntington’s disease (HD) are required to understand the role of resveratrol and to assess its efficacy as a therapeutic agent. This chapter gives an overview of our current understanding of how resveratrol may combat disease, as well as how these mechanisms may have potential for HD treatment.
Scientists became interested in exploring the health benefits of resveratrol when its presence was first reported in red wine, leading to the possibility that it could explain a health phenomenon known as the “French Paradox.” Despite the fact that the French diet is high in saturated fats, the rate of heart disease is lower than that observed in other industrialized countries. This paradox led to the idea that regular consumption of red wine (and thus a higher consumption of resveratrol) may provide additional protection from cardiovascular disease. Recent studies have indicated that resveratrol is not the sole agent responsible for the cardioprotective effects associated with red wine consumption, and that other highly potent red wine constituents may have even greater effects.
Why not white wine or wine in general? The skins and seeds of grapes are used in the production of red wine, but not in the production of white wine. Because resveratrol is most highly concentrated in grape skins, the concentration of resveratrol is significantly higher in red wine than in white wine.
Resveratrol is one member of a class of compounds known as phytoalexins; “phyto” meaning “plant” and “alexin” meaning “to ward off or protect.” Phytoalexins are produced by some plants to respond to stressors such as injury, fungal infection, or ultraviolet radiation. Remarkably, resveratrol may be able to protect humans as well as plants. Studies suggest that a high resveratrol intake is associated with reduced incidence of heart disease, cancer, and age-related diseases such as Alzheimer’s disease. HD may also be a part of this list, but additional research is needed to test this notion.
Alcohol itself (better known in chemistry as ethanol) is toxic to the human body and has no redeeming qualities from a health perspective. After alcohol is consumed, a person’s blood alcohol level rises and the body begins to “detoxify” the alcohol. The first step in this process is the conversion of alcohol to another compound called acetaldehyde. Acetaldehyde stays in the body for several hours, producing a variety of undesirable toxic effects. Acetaldehyde binds readily to the walls of red blood cells. By attaching itself to the red blood cells, acetaldehyde reduces the oxygen supply to most of the cells of the body, including the brain. Acetaldehyde also combines with hemoglobin in the red blood cells and further reduces its ability to carry oxygen, which eventually leads to hypoxia (oxygen starvation at the cellular level).
Additionally, acetaldehyde interferes with the process of microtubule formation. Microtubules are essential to the brain because they provide structural support for nerve cells and their dendrites and they also transport chemicals manufactured in the nerve cells to the dendrites. Without microtubules, dendrites weaken and die. Deficiencies in various vitamins are also induced by acetaldehyde. Although individuals vary in vulnerability to acetaldehyde, it is clear that acetaldehyde is a dangerous and toxic chemical. In addition to the complications already mentioned, alcohol can also do significant damage to the liver and central nervous system. Thus, one must exercise caution when dealing with a powerful substance like alcohol and weighing its potential benefits and costs.
Oxidative stress (also known as oxidative damage) is believed to play a major role in the damage of nerve cells in HD. (For more information on oxidative stress, click here.) Studies indicate that resveratrol is an excellent antioxidant, which means that it is very good at combating oxidative stress. What makes resveratrol such a good antioxidant? Researchers believe that it works by inhibiting monoamine oxidase (MAO), an enzyme primarily found in the liver and nervous system that generates free radicals. Free radicals are dangerous because they are highly reactive. They tend to react with important structures in cells and accelerate cell injury. By reducing levels of MAO, resveratrol decreases the number of free radicals that degrade nerve cells. Decreasing the level of free radicals may slow the progression of neurodegenerative diseases such as HD.
In scientific studies, injecting resveratrol into rats led to decreased levels of certain free radicals in the brain. Additionally, the activities of several antioxidant enzymes increased. Not only can resveratrol help to prevent free radicals from forming, but it can also decrease the toxicity of free radicals by inhibiting a process called lipid peroxidation. Lipid peroxidation is the process whereby free radicals take away electrons from the lipids that make up our cell membranes and thereby cause damage to the cell. (For more information on lipid peroxidation, click here.) Rat studies indicate that resveratrol significantly inhibits lipid peroxidation in cells.
While resveratrol has been shown to be a powerful antioxidant in vitro and in rats, its role as an antioxidant has yet to be tested and confirmed in humans. Because circulating and intracellular levels of resveratrol in humans may be much lower than in vitro models, its true effects on the human body are controversial.
Long-term, or chronic inflammation in the brain is believed to play a significant role in neurodegeneration in HD. Studies indicate that resveratrol acts as an anti-inflammatory agent mainly by inhibiting the action of two key enzymes: cyclooxygenase and lipoxygenase. These enzymes lead to the production of leukotrienes and prostanoids, which are chemicals that significantly contribute to the inflammatory process. Resveratrol inhibits cyclooxygenase and lipoxygenase and their production of inflammatory substances, causing inflammation to decrease.
Resveratrol may also inhibit pro-inflammatory transcription factors, which increase inflammation. Transcription factors are proteins that bind to DNA and regulate gene expression by promoting transcription. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and activator protein-1 (AP-1) are examples of pro-inflammatory transcription factors. NF-kB is a transcription factor for genes that helps cells to survive, bind to a surface, specialize and grow. It is also involved in cell inflammation. AP-1, or activator protein-1, is also a transcription factor involved in cell proliferation and survival. Research has shown that most anti-inflammatory agents suppress NF-kB activation. Studies have indicated that resveratrol may inhibit NF-kB and AP-1 pathways, thus preventing inflammation. Resveratrol has been shown to decrease levels NF-kB directly and indirectly via inhibition of associated MAP kinases, which is discussed in the “MAP kinase” section of this article.
It is still unclear how resveratrol decreases inflammation. Some studies have shown that these anti-inflammatory effects may be partially due to resveratrol’s antioxidant capabilities, while others have shown that resveratrol’s anti-oxidant and anti-inflammatory capabilities are independent of one another. Further research is necessary to arrive at a scientific consensus.
Resveratrol has been shown to have neuroprotective effects in neurons, in rat brains and in cell culture. This suggests that the anti-inflammatory capabilities of resveratrol could potentially be beneficial in HD treatment. However, this hypothesis remains to be tested.
Resveratrol has a very simple chemical structure, which enables it to play a role in a wide range of biological processes. As a result, resveratrol is able to act upon many different systems within the body. The following sections discuss some potential mechanisms through which resveratrol may exert its effects. Please note that the mechanisms outlined in the sections “Heme oxygenase,” “MAP Kinase,” “Sirtuins,” and “Prevention of Neurodegeneration,” are interdependent and influence one another in ways that are not yet understood by the scientific community.
Similar to resveratrol, an enzyme called heme oxygenase (HO) also decreases oxidative stress and inflammation. Because of this similarity, researchers hypothesized that resveratrol might exert its function via a mechanism involving HO. This hypothesis was supported by a study that found that when resveratrol was administered to rats, the amount of HO in the rats’ neurons increased. The effect was dose-dependent, meaning that levels of HO increased as more resveratrol was administered. The connection between resveratrol and HO is important because HO is thought to have neuroprotective effects. In addition to being a powerful antioxidant, HO also produces several byproducts that may assist in cell survival.
HO is involved in regulating cellular uptake and storage of iron. Iron levels must be tightly regulated because adequate amounts of iron are essential for many cellular functions, but excessive amounts of iron can lead to the formation of reactive oxygen species (ROS). A ROS is a highly volatile compound, which is likely to damage cells. When resveratrol increases the amount of HO, higher levels of HO may in turn affect the level of iron in the cells. Thus, one way resveratrol may exert its neuroprotective effects is by stimulating HO to balance out iron levels and protect from iron-mediated toxicity.
Although the connection between resveratrol and HO is quite intriguing, further research is needed to determine the exact details of how they work together to protect nerve cells.
Numerous studies have demonstrated that resveratrol interacts with certain mitogen-activated protein (MAP) kinase family members. MAP kinases are proteins that respond to stimuli and regulate important cellular functions including gene expression cell survival and differentiation.
Earlier studies of MAP kinases indicated that resveratrol activated all three subfamilies of the enzymes, some of which have been linked to changes in brain cells changes that form the basis of memory and learning processes. However, the relationship between resveratrol and memory and learning processes has not been tested since the preliminary studies were published.
More recent studies have investigated how the effects of resveratrol on MAP kinases influence the expression of inflammatory mediators NF-kB and AP-1. See the “Anti-inflammatory Capabilities” section in the article to learn more about NF-kB and AP-1. In short, resveratrol inhibits NF-kB and AP-1 by acting on MAP kinases. MAP kinases reduce inflammation in part by encouraging cell death. Studies have also suggested that the inhibition of NF-kB combats beta-amyloid plaques in neurons, helping neurons survive. See the section on “Resveratrol and the Prevention of Neurodegeneration.”
The MAP kinase subfamilies are most likely related to a wide range of other processes, some of which are related HD. It is possible that some MAP kinases regulate heme oxidase, helping to combat oxidative stress and reduce chronic oxidative damage. (See “Heme Oxidase”)
Modulation of MAP kinases by resveratrol may inhibit or activate various pathways which in turn could reduce inflammation, promote cell death when need be, and protect against buildup of toxic protein fragments. However, such potential effects of resveratrol on MAP kinase related pathways and the potential relevance to HD still must be investigated.
Studies in yeast and fruit flies have demonstrated that resveratrol activates a group of enzymes called sirtuins, which promote longevity in a variety of organisms. Sirtuins are important for many cellular processes including gene silencing, regulation of the cell cycle, fatty acid metabolism, apoptosis and longevity. Research has also shown that resveratrol activates an enzyme called SIRT1, the human analog of the Sir2 protein, which is found in yeast. The function of SIRT1 in humans is similar to that of Sir2 in yeast; it mediates the cell cycle, protects the cell during stress, regulates transcription, prevents the destruction of axons, and is involved in extending the life span of cells. In mice, increased production of the SIRT1 gene shows both a protective and pro-aging role in neurons. Furthermore, researchers have demonstrated that both resveratrol and direct expression of the SIRT1 gene slow neurodegeneration and cognitive decline in mouse models of Alzheimer’s disease (AD).
The majority of research supports the hypothesis that resveratrol, by stimulating the activity of sirtuins, mimics the effects of calorie restriction. (For more information on dietary restriction, click here.) Calorie restriction has extended the life span in rodents and primates through a variety of mechanisms, one of which includes increasing levels of SIRT1. It has even been shown to slow disease progression and increase survival in huntingtin mutant mice. Both calorie restriction and resveratrol can decrease chronic oxidative damage, inhibit inflammatory pathways, and increase energy production in the cell. While a few studies suggest that sirtuins act independently of pathways mediated by calorie restriction, these studies do not propose an alternative mechanism for sirtuin action. Regardless of the relationship between resveratrol and calorie restriction, activation of SIRT1 proteins has had positive effects on a variety of organisms including mouse models for HD and AD. This suggests that resveratrol itself may have the potential to delay the onset and progression of HD symptoms.
Resveratrol has demonstrated neuroprotective effects through its anti-oxidant and anti-inflammatory capabilities, as well as its influence on sirtuins. Expanding upon these claims, numerous epidemiological studies (studies related to epidemiology) have determined that moderate red wine consumption is correlated with a lower incidence of dementia and a reduction in Alzheimer’s disease. (For a comparison of Alzheimer’s and HD, click here.) Nevertheless, it should be noted that the notion that red wine intake lowers AD risk is controversial. Based upon controlled studies, a dose of resveratrol much higher than the amount in red wine is needed for any positive effects. The correlation between reduced risk of dementia and moderate red wine consumption does not mean that red wine consumption or resveratrol are responsible for the reduced risk. Studies are ongoing to prove if correlation will translate to causation in this case.
Evidence suggests the possibility that resveratrol can prevent neurodegeneration in AD via protection against beta-amyloid plaques. Beta-amyloid (Aβ) plaques are an accumulation of small fibers called beta-amyloid fibrils and are present in the brains of people suffering from Alzheimer’s disease (AD). (For more on beta-amyloid plaques, click here.) These plaques are thought to greatly contribute to the neurodegenerative process of AD. Over the past decade, there has been compelling evidence that resveratrol has the ability to protect against the neurotoxic effects of amyloid-related proteins.
In one study, researchers treated mice injected with the AD gene with resveratrol, which reduced the number of Aβ plaques. Another study found that moderate consumption of red wine lowered Aβ levels and reduced its neurotoxic effect, implying that red wine intake may have a beneficial effect against AD pathology by promoting mechanisms that work against the accumulation of beta-amyloid plaques. Additional studies in mice and in cell cultures have supported these findings.
Because of the parallels between huntingtin protein aggregates and beta-amyloid fibrils, these results are promising developments in the search for treatments for neurodegenerative disorders like HD. It is possible that resveratrol may also have the ability to decrease huntingtin protein aggregates. However, this hypothesis remains to be tested and other substances that have decreased beta-amyloid fibrils have had no effect on huntingtin protein aggregates.
Future studies aimed at elucidating a more detailed understanding of the various cellular mechanisms involved in the neuroprotective effects of resveratrol have the potential to open new avenues for the treatment of neurodegenerative diseases such as HD. It is necessary to further study resveratrol in animals and most importantly, humans, before it can be proven as a safe, effective treatment for HD.
There are two measures that are used to determine the effectiveness of a drug: pharmacokinetics, how the body processes a drug, and bioavailability, the degree to which a drug or other substance becomes available to the target tissue after administration. Both the pharmacokinetics and bioavailability of resveratrol are still inconclusive. Studies in mice, rats and dogs have consistently shown that resveratrol can be absorbed and distributed in the blood stream at relatively high concentrations. However, due to its rapid metabolism and elimination from the human body, the potential impact of resveratrol on humans is debatable. There are a few major problems with resveratrol:
First, humans who receive an oral dose have plasma concentrations of resveratrol that peak after only 30 or 60 minutes. This shows that resveratrol is indeed metabolized quickly and may not be able to exert its positive effects before being metabolized.
Second, the dose of resveratrol needed to experience positive health effects remains unclear. Sirtris Pharmaceuticals Inc. is using very high doses in phase II clinical trials (2500 mg and 5000 mg per day) of this drug for diabetes. However, other scientists believe resveratrol supplements should be taken in lower doses. No other human clinical trials or studies have been conducted in order to determine the amount of resveratrol needed to exert its positive effects. The amount of resveratrol in a bottle of red wine can vary between types of grapes and growing seasons, and can vary between 0.2 and 5.8 milligrams per liter. While some research suggests that drinking a moderate amount of red wine (1 to 3 glasses a day) may provide enough of the active compound to exert protective effects, controlled scientific studies have not been undertaken to verify this hypothesis. Although resveratrol can be concentrated and obtained in capsule form, taking these supplements may not have the same effect as drinking red wine, primarily due to the reason explained below.
Third, resveratrol degrades quickly when it is exposed to oxygen. For example, resveratrol is no longer active in wine if the bottle has been opened for 24 hours. This directly applies to the manufacturing of resveratrol supplements, which are most likely exposed to air during the manufacturing process or storage. This presents an obstacle to supplement preparation and necessitates careful handling of the substance. It is very likely that the majority of marketed preparations of resveratrol do not contain the active form that is found in red wine.
While a few phase I clinical trials have shown that resveratrol is safe in certain doses for healthy participants and people with type II diabetes, many more clinical trials on humans are necessary before conclusions can be made regarding the effects of resveratrol in the context of neurodegenerative diseases such as Huntington’s disease.
Resveratrol has been shown to have wide-ranging positive effects on many diseases. Research has revealed resveratrol’s ability to protect against some of the common HD complications by decreasing inflammation, combating oxidative stress, increasing the energy production in cells, and potentially reducing huntingtin protein aggregates. However, it is important to note that nearly all of the research on resveratrol has been done in cell culture and in mice, and this data may not necessarily apply to humans. As more studies are conducted regarding the mechanism of resveratrol, the amount necessary in human body in order to have protective effects, and the effects of resveratrol supplements in humans, we will have a better idea about how resveratrol works and whether it will be an effective treatment for patients with neurodegenerative diseases such as HD.
-D. McGee, 01/11/05, and P. Bakhai, 6/19/10More
The Mediterranean diet, based on the dietary habits of the people of Crete, has become more popular to scientists and consumers, as studies continue to reveal its health benefits. For instance, studies show that the diet increases longevity and decreases the risk of Alzheimer’s disease. These promising results would suggest that studies investigating how the Mediterranean diet affects HD patients would be of interest the HD community. This chapter first discusses the history of the Mediterranean diet, what the diet consists of, and then explains in more detail the results of the diet’s studies.
Dr. Ancel Keys and his colleagues were the first to discover that the Mediterranean diet has health benefits for a wide range of diseases. During the early 1950s and late 1960s, while Keys was investigating his hypothesis, the Mediterranean region was recovering from the effects of World War II but was not yet influenced by the rising trend of fast food. Keys formed his hypothesis from his simple observation that the people of the island Crete were in especially good health, largely due to their dietary habits.
The ideal Mediterranean diet is based on the dietary patterns of the people of Crete in the early 1950s and late 1960s. The Mediterranean diet, as the name expresses, is characteristic of the foods that are commonly available in this region. For instance, the olive-rich Mediterranean makes it easy and common for the people to include olive oil abundantly in their diet.
The Mediterranean diet consists of 9 parts:
The Mediterranean Diet Food Pyramid
Remember to stay hydrated, and replace salt with herbs, such as oregano and basil (e.g. oregano, basil, thyme, etc.)
Figure Source: Trichopoulou A. Traditional Mediterranean diet and longevity in the elderly: a review. Public Health Nutrition. 2004 Oct;7(7):943-7. Review.
Dietary recommendations for our health often involve the increased consumption of certain nutrients, such as particular vitamins and minerals. However, the Mediterranean diet is different in that it is a dietary pattern, rather than the supplementation of a several nutrients. The benefit of the dietary pattern is that is more easily adaptable to one’s lifestyle, since people normally eat a range of different foods in different amounts, as opposed to the very high consumption of certain nutrients. Furthermore, the foods outlined in the Mediterranean diet are foods that many of us already typically include in our diets. Thus, adhering to the Mediterranean diet would not involve drastically changing from your current dietary habits. Rather, following the Mediterranean diet would translate into cutting down on some foods (such as refined cereals and meat) and changing the portion of foods that you already eat (such as increasing consumption of olive oil and fish). Additionally, studies have shown that the Mediterranean diet is also beneficial to ethnic populations different from those that reside in the Mediterranean area.
Since the Mediterranean diet is a dietary pattern, it is often difficult for scientists to determine exactly which parts of the diet are most beneficial, or which parts could even possibly be harmful. However, the scientific community generally believes that the benefits gained from the diet are not due to one single part of the diet. For example, Scarmeas et al reported that those who had high adherence to the Mediterranean diet were less likely to develop Alzheimer’s disease, with no isolated part of the diet significantly being associated with this health benefit. This finding supports Scarmeas’ hypothesis that “composite dietary patterns can capture dimensions of nutrition that may be missed by individual components.”
Although a direct benefit of the Mediterranean diet to HD has not yet been discovered, many studies report benefits of the Mediterranean diet that may be of interest to those with HD, as well as the general population.
Many studies on longevity have found that elderly individuals who follow the Mediterranean diet live longer. For instance, in studies that have taken place among elderly populations in locations such as Greece, Spain, Denmark, and Australia, all participants experienced longevity due to following the Mediterranean diet (see review, Trichopoulou et al). One study, conducted by Knoops et al, showed that elderly individuals, 70 to 90 years old who adhered to the Mediterranean diet and a healthy lifestyle had a lower rate of all-causes and cause-specific mortality by more than a 50% compared to those individuals who were not on the diet. Cause-specific mortality was defined here as mortality due to coronary heart disease, cardiovascular disease, and cancer. However, it must be noted that this mortality statistic is based on not only the Mediterranean diet but also on a healthy lifestyle. Healthy lifestyle was defined by moderate alcohol consumption, nonsmoking, and physical activity. A similar study by Trichopulou et al that measured only the Mediterranean diet’s effect on longevity, with no reference to healthy lifestyle, confirms the findings in the Knoops study.
Perhaps of more interest to those with HD is the finding that adherence to the Mediterranean diet reduces cognitive decline and the risk of Alzheimer’s disease. Panza et al discovered that the Mediterranean diet protected against cognitive decline associated with normal aging of healthy individuals as well as cognitive impairment that characterizes Alzheimer’s disease and vascular disease. One of their results was that those who drank moderate amounts of wine had a lower risk of dementia of Alzheimer’s or vascular origin than those who did not drink any. Similarly, Scarmeas et al found that the group of people that most closely adhered to the Mediterranean diet (highest tertile in scores) reduced their risk of getting Alzheimer’s disease by 40%, compared to those of the lowest tertile in adherence scores.
One of the hypotheses as to how the Mediterranean diet benefits those with Alzheimer’s disease is that the diet protects against inflammation and oxidative stress, which are also thought to be common complications of Huntington’s disease. (For information on inflammation in HD, please click here and for information on oxidative stress and HD please click here.) Consequently, the Mediterranean diet may be helpful in preventing the progression of HD. Studies investigating the specific effects of the Mediterranean diet on HD still need to be conducted.
-C. A. Chen 5-7-07More
In addition to the medications that we all get at a pharmacy, another large influence on human health can also be found in the marketplace… at the grocery store! One’s diet can have an immense influence on everything from energy level to the ability to fight diseases. Because of the immense importance of nutrition, HOPES has developed this chapter to discuss some of the various foods and eating practices that can have both a general health-promoting effect, and also special benefits for people coping with Huntington’s disease.
Many of the food and eating practices discussed in this section are still being researched, and so just as with HD treatments, please always consult a physician to see if a particular food or eating practice is right for you.More
Today in the U.S., we are commonly instructed to lower our fat intake because word is out that fats are bad. Low-fat, non-fat, and even “fake fat” food products dominate supermarket shelves. Consumers typically fear fat in any form. However, not all fats are bad. In fact, some types of fats are actually necessary for life and health and should not be eliminated from the diet. This chapter examines the different types of fats, as well as the effect that these fats can have on the brain. In addition, this chapter reveals how optimizing the amount and type of fat in the diet may help combat Huntington´s disease (HD).
The whole of issue of fat in the diet has become very confusing, mainly because there are so many different types of fat. Essentially, there are two broad categories of fat: saturated fat and unsaturated fat. These two types of fat differ in their chemical structure. Saturated fatty acids (the building blocks of saturated fat) have no double bonds (a particular kind of chemical link between adjoining molecules) and this lack of double bonds means that there are no gaps in the fatty acid chain: it is packed with CH2 molecules. Unsaturated fatty acids (the building blocks of unsaturated fat), on the other hand, have double bonds and these double bonds break up the string of CH2´s and create gaps within the fatty acid chain. See figure 1 for a depiction of the difference between saturated and unsaturated fatty acids. We will explore how this difference in chemical structure affects how different types of fat interact with the body below.
Saturated fats (meats, butter, dairy products) are solid at room temperature, whereas unsaturated fats (vegetable oils) are liquid at room temperature. Due to their difference in chemical structure, saturated fats and unsaturated fats exert different effects within the body. Because saturated fatty acid chains have no gaps, they are able to pack together very tightly. When these tightly packed saturated fatty acids enter the bloodstream, they increase levels of “bad” cholesterol known as low-density lipoprotein (LDL) cholesterol and clog arteries. In comparison, unsaturated fats do not increase “bad” cholesterol and, in fact, are able to increase levels of “good” cholesterol known as high-density lipoprotein (HDL) cholesterol. HDL is able to grab LDL and escort it to the liver where it is broken down and eventually removed from the body. Thus, by increasing levels of HDL, unsaturated fats are able to protect against the damage done by saturated fats. Since heart disease is a leading cause of death for people with HD, it is especially important to keep the heart healthy and limit intake of saturated fat. (For more information on the many complications of HD, including heart disease, click here.) And as we will see below, there are even more reasons than heart disease for people with HD to be conscientious about the types of fat that they consume.
Because saturated fats were shown to be so unhealthy, food manufacturers decided to start using more unsaturated fats. The problem is that unsaturated fats spoil quickly. Food manufacturers solved this problem by putting unsaturated fats through the process of hydrogenation, which essentially alters the chemical structure of unsaturated fats and makes them more solid and long-lasting. However, when unsaturated fat is hydrogenated, a new fat called trans fat is produced. Fried foods, doughnuts, cookies, and crackers all contain high levels of trans fat. Trans fat rarely exists in nature and has been shown to be toxic to the body. Not only does it increase levels of “bad” cholesterol, it also decreases levels of “good” cholesterol. Thus, it has no redeeming qualities within the body and, as will be discussed later, it can worsen HD symptoms.
Nutrition is an integral component of our daily life routine and it has the potential to modulate brain health and function. Although it may at first seem strange, fat is essential for brain development and maintenance. In fact, about two-thirds of the brain is composed of fat, which may come as a surprising statistic. Where is all that fat? It is found in two places associated with nerve cells themselves. First, the protective covering of nerve cells called myelin is 70% fat. More importantly, the membranes of nerve cells are made of a thin double-layer of fatty acid molecules. After the body breaks down fat from the diet into fatty acids, the brain then uses these fatty acids by incorporating them into its cell membranes. Nerve cell membranes are extremely important because their composition determines what is able to pass into and out of the cell. Oxygen, glucose, and the nutrients that the cell needs to survive all must pass through the membrane and into the cell´s interior. When saturated fatty acids are incorporated into normally very fluid cell membranes, they pack very tightly because saturated fatty acid chains have no gaps. Thus, essential nutrients are unable to get into the cell, making the cell less healthy and more prone to injury. In contrast, unsaturated fats can be beneficial to nerve cells because they prevent the tight packing of fatty acids in the membrane. Unsaturated fatty acids have gaps in their chains and these gaps allow for a certain amount of “fluidity.”
Membrane fluidity is absolutely essential for the optimal function of most cells in the body, but it is especially important for nerve cells. In addition to letting in essential nutrients and keeping out harmful substances, nerve cell membranes also contain proteins that act as receptors for some neurotransmitters. Neurotransmitters are the chemical messengers that nerve cells use to communicate with each other. (For more information on neurotransmitters and their role in HD, click here). In order for the receptors to be able to recognize neurotransmitters and send along the messages that they contain, the nerve cell membrane must be fluid. If the nerve cell membrane is too rigid, the receptors on the membrane become less capable of recognizing neurotransmitters and passing along messages to the nerve cell. Often, the messages contained in neurotransmitters are critical to the survival of the nerve cell. Thus, membrane composition is extremely important because it influences nerve cells´ ability to communicate with each other and, ultimately, survive.
Studies reveal that optimal membrane composition is obtained when one consumes equal amounts of saturated and unsaturated fat. However, nutritional studies show that the average North American eats three times as much saturated fat as unsaturated fat! The addition of trans fat to the diet has made the situation even worse. Let us consider each fat in the context of our cells. Although too much saturated fat is bad, a certain amount is necessary for the optimal functioning of the membrane. On the other hand, the cell membrane has absolutely no use for trans fat. When trans fat gets incorporated into nerve cell membranes, the membranes become less capable of performing many essential functions, making the nerve cells more prone to a variety of insults.
Excessive consumption of saturated fat and trans fat can be particularly hazardous for people with HD. Even without any dietary influences, the HD disease process causes some nerve cells in the brain to become less able to communicate with each other, which contributes to these nerve cells losing function and eventually dying. Consuming excessive amounts of saturated fat can worsen this situation by making it even harder for nerve cells to communicate with each other via neurotransmitters. If the nerve cell membrane consists of too much saturated fat or trans fat, the nerve cell may be unable to receive messages from neurotransmitters. Often, these messages are essential for the survival of the cell. (For more information on the neurobiology of HD, click here.) Thus, it is clear that the amount and type of fat in the diet may influence the ability of nerve cells to survive. Replacing saturated fat and trans fat with unsaturated fat in the diet can enhance the ability of the nerve cell membrane to pass along necessary messages. It can also increase the fluidity of the nerve cell membrane, which makes it easier for the nerve cell to receive an adequate supply of oxygen and other essential nutrients. With the nerve cell membrane functioning as efficiently as possible, the nerve cell may be better able to deal with the harmful effects of HD. Thus, it may be possible for a person with HD to delay the onset and progression of HD symptoms simply by altering his or her fat consumption.
In addition to negatively affecting membrane function, a diet high in saturated fat may also induce oxidative stress and decrease levels of a protein known to assist in nerve cell survival called brain-derived neurotrophic factor (BDNF). Increased oxidative stress and decreased BDNF would be highly damaging to a person with HD. When trying to combat a neurodegenerative disease such as HD, maximizing levels of BDNF is ideal because it may help combat the damage done by the disease. Thus, in the interest of maintaining levels of BDNF, one might consider limiting one´s consumption of saturated fat. In addition, keeping oxidative stress to a minimum is important for people with HD. Oxidative stress, a harmful process that injures cells and eventually causes them to die as a result of free radical damage, is thought to contribute significantly to the disease process of HD. (For more information about free radicals and HD, click here.) Although a certain amount of oxidative stress will inevitably occur due to aging, it is important for people with HD to be conscientious about not worsening oxidative stress from the food they eat. Since diet is a very controllable aspect of one´s lifestyle, limiting consumption of saturated fats is a great way for people with HD to ensure that they do not aggravate the damaging processes in their nerve cells any further. Although much more research needs to be done in this area, it seems likely that adjusting for less saturated fat in one´s diet could significantly slow down the progression of HD.
In general, it is true that any type of unsaturated fat is better for the brain and body than either saturated fat or trans fat. However, there are many different types of unsaturated fat and some types of unsaturated fat are better for you than others. Monounsaturated fatty acids have only one double bound and thus only one gap in the fatty acid chain. Polyunsaturated fatty acids have many double bonds and many gaps within the fatty acid chain. All saturated and monounsaturated fats can be made within the body and, therefore, they do not need to be supplied through the diet. However, the body is unable to make two types of polyunsaturated fat and these must be obtained through the diet. The first type of polyunsaturated fat is alpha-linolenic acid (ALA), which belongs to the omega-3 family of fatty acids. ALA is found abundantly in flax seed (a fiber derived from plants) and flax oil, and is found in small quantities in canola oil, wheat germ, and dark green leafy vegetables such as spinach and broccoli. The second type of polyunsaturated fat that the body cannot make is linoleic acid (LA) and it belongs to the omega-6 family of fatty acids. LA is found in soy oil, sesame seeds, corn oil, and in most nuts. Because the body is unable to make these two fatty acids, they are an essential part of the diet. Hence, they are called essential fatty acids (EFA´s).
Once the body is supplied with the essential fatty acid ALA, it can convert it into DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid). Both DHA and EPA are great at lowering one´s risk for heart disease. In addition, DHA is essential for nervous system maintenance and development. Infants who have low amounts of DHA in their diet have reduced brain development. Accordingly, human milk is extremely rich in DHA. DHA is the most abundant fatty acid in nerve cell membranes and is thought to contribute significantly to the fluidity of the cell membrane. DHA is also found in the synapses between nerve cells and is thought to greatly aid the nerve cells in sending signals to each other. The problem is that DHA levels naturally decline as one gets older. If DHA is not supplied through the diet (from consuming ALA), then the nerve cell membranes begin to function sub-optimally. Perhaps this may explain why societies whose diets are high in DHA (such as the Inuit of the arctic who eat a lot of fish, a great source of DHA) have a lower incidence of neurodegenerative disorders.
The other essential fatty acid, LA, is converted to GLA (gamma linoleic acid) within the body. GLA eventually leads to the production of prostaglandins, which are molecules that help regulate inflammation and blood pressure. (For more information on essential fatty acids and inflammation, click here.) While LA is termed “essential,” it is not entirely good for the body. In fact, Americans tend to consume way too much of it. This overconsumption is a problem because it turns out that both ALA and LA compete for the same enzymes to produce their final product. In other words, if there is too much LA, then the enzymes will be busy converting LA into GLA and there will be no enzymes left to convert ALA into DHA. (For more information on how ALA and LA compete for enzymes, click here.)Thus, a balance of ALA and LA is essential for proper health. Studies show that the optimal ratio of LA to ALA is somewhere between 2:1 and 1:1. It is estimated that the ratio of LA to ALA for most Americans is around 20:1. This imbalance makes sense because typical foods such as cereal, eggs, poultry, bread, and baked goods are made from oils rich in LA. Foods rich in ALA are much harder to find. Often, dietary supplementation may be needed in order to get enough ALA.
In addition to consuming enough ALA, humans must be able to absorb it. Findings suggest that an inadequate intake of vitamin E results in decreased absorption of ALA. Thus, some experts suggest that vitamin E supplementation may be useful in conjunction with ALA supplementation.
As mentioned earlier, nerve cell membranes are critical in terms of maintaining the safety of the nerve cell. Not only are they responsible for letting in essential nutrients and expelling harmful substances, but they also help nerve cells communicate with each other. Thus, in a person with HD, it is especially important for the nerve cell membranes to be operating optimally because it can greatly aid in the survival of the nerve cells. DHA, a product of ALA, has been shown to keep nerve cell membranes operating at an optimal level. It stands to reason that if a person with HD obtains adequate amounts of ALA and fixes the skewed imbalance of LA to ALA, he or she may be able to prolong the life of his or her nerve cells, and this too would likely delay the progression of the disease.
Fats play a significant role in the brain. Specifically, the amount and type of fat one consumes directly affects the composition of nerve cell membranes. The composition of nerve cell membranes is especially important for people with HD because it has the potential to protect the nerve cell from damage. Too much saturated fat or trans fat in the diet leads to stiff, rigid membranes and a loss of membrane fluidity. In addition, too much saturated fat and trans fat alters the shape and size of the nerve cell membrane, which ultimately makes it so that the nerve cells are less able to communicate with each other. By replacing saturated fat with unsaturated fat in the diet, a person with HD can help his or her nerve cell membranes to function as efficiently as possible. Furthermore, certain types of unsaturated fat are more beneficial than others. In particular, the essential fatty acid (EFA) called ALA, which leads to DHA as described above, is the most abundant and perhaps most important in the brain. Because ALA competes with LA, one must limit one´s consumption of LA in order to ensure adequate amounts of ALA.
In short, the research reviewed in this chapter indicates that a person with HD should strive to reduce the amount of saturated fat and trans fat in his or her diet and to increase the ratio of ALA to LA in his or her diet in order to ensure the optimal functioning of the nerve cell membranes. Better functioning membranes means healthier nerve cells and having healthier nerve cells may well postpone the onset of HD symptoms.
Vaddadi, et al. (1999) examined the effect that essential fatty acid (EFA) supplementation can have on the symptoms in people with HD. In the study, there were 17 HD patients who all showed clinical signs of HD, such as chorea. Genetic testing confirmed that these 17 patients did indeed have HD. During the study, the patients were told to stick to the same routine and continue taking the same amounts and types of medication. Randomly, nine of the subjects were assigned to the treatment group and they were given capsules that contained essential fatty acids. The other eight subjects were assigned to the control group and they received placebo capsules that did not contain essential fatty acids (this group was used to compare to the group receiving treatment). The study was designed to last two years and the patients´ symptoms were assessed at the beginning of the study and at six-month intervals. Their symptoms were assessed using two Huntington´s disease rating scales.
After twenty months, the study had to be stopped on ethical grounds because it was clear that the treatment group was receiving a significant benefit from the essential fatty acid capsules. The subjects in the treatment group improved in motor skills and functional performance while the subjects in the control group deteriorated. The results indicated an actual improvement over the starting measurements for the treatment group and not merely a slowing of deterioration. Of the nine subjects in the treatment group, only one subject did not improve over baseline. Much of the separation in results between the two groups occurred during the first six months of the study, indicating that it does not take long for the effects of essential fatty acid supplementation to be seen. However, the study did have a few shortcomings. The sample size was small and the effect of any earlier treatments that the subjects may have tried is unknown. Also, the study was terminated early so the long-term benefits of essential fatty supplementation are unclear. The study also does not indicate how high a dose is required to produce an effect. Clearly, much more research needs to be done in this area.
Clifford, et al. (2002) looked at how essential fatty acid (EFA) supplementation affected a mouse model of HD. These specific mice have an HD-like allele and they develop late-onset nervous system deficits in a manner similar to the motor abnormalities of HD. The mice were randomly divided into two groups: a treatment group receiving a mixture of fatty acids and a control group receiving a placebo. Through mid-adulthood, mice in the control group experienced progressive shortening of stride length and complications in movement ability. These deficits were either not evident in the mice in the treatment group or were significantly decreased. The findings of the study indicate that early and sustained treatment with essential fatty acids may be able to protect against motor deficits in mice that have an HD-like allele, and thus may also be able to protect against motor deficits in people with HD.
-D. McGee, 04/27/05More
For many years, people around the world have been preparing their meals with an Indian spice called curry. Although most people who eat curry probably do so simply because of its pleasant taste, some current research suggests that the spice may actually have another important characteristic: it may be helpful in combating the effects of some neurodegenerative diseases. According to research on Alzheimer’s disease (AD), the disease-fighting effects of curry come from a compound called curcumin, which is a component of turmeric, the yellow spice that is used in most traditional curries. This chapter gives an overview of curcumin’s beneficial effects on AD and suggests possibilities for how curcumin may affect Huntington’s disease.
Scientists first became interested in studying curcumin when they looked into some statistics about the prevalence of AD in India, where curry is eaten in large quantities. In India, a relatively small proportion (1%) of people age 65 and older have AD. Additionally, in comparison to their American counterparts (who eat significantly less curry), Indians aged 70-79 develop AD one-fourth as often.
Although these data indicate that there is something special about Indian people with regard to AD, the many factors involved in the disease (which may involve a variety of things like genetics, exposure to certain toxins, eating things besides curry, etc.) make it inaccurate to state that curcumin is definitely the cause of India’s low prevalence of AD. However, the fact that curry (and thus, curcumin) is much more common in the Indian diet than the American diet does demonstrate what is called an inverse correlation between the use of curry and the prevalence of AD; that is to say, higher average amounts of curry intake are associated with lower prevalences of AD.
Having recognized this inverse correlation between curry and AD, scientists were able to take the research one step further. Interested in finding out whether or not curcumin might have a causal effect on combating AD, researchers turned to rodents (mice) as experimental animals in which to study the effect of curcumin on nerve cells. What they found in this research is discussed in the next section.
The process through which Alzheimer’s disease degrades nerve cells is believed to involve three things: inflammation, oxidative damage, and most notably, the formation of beta-amyloid plaques. In order to understand how curcumin combats AD, we will look at its effects on each of these three phenomena.
On a short-term scale, inflammation is a very helpful event: it is the body’s way of protecting itself from foreign invaders. However, over an extended period of time, inflammation can actually be quite harmful. (For more info about inflammation, click here.) One of the ways that AD degrades nerve cells (and thus results in the manifestation of the disease’s symptoms) is by causing chronic inflammation in the central nervous system. For this reason, populations that exhibit prolonged use of certain nonsteroidal anti-inflammatory (NSAID) drugs like ibuprofen have been shown to have a reduced risk of developing the symptoms of AD. However, while ibuprofen significantly reduces the amount of inflammation in the central nervous system, its prolonged use has dangerous side effects like gastrointestinal, liver, and kidney damage.
Curcumin is a natural NSAID. For this reason, in mice models of AD, it was shown to reduce the levels of inflammation in the brain by about 60% (as measured by the reduced presence of a certain indicator of inflammation). An added benefit of curcumin is that it appears to be far less toxic than most drug NSAIDs. If further research confirms the safety of the substance, its use may become an alternative to drug NSAIDs for combating AD.
Like Huntington’s disease, AD can also increase the number of free radicals that nerve cells produce. Over time, this increased number of free radicals leads to oxidative damage, which can degrade nerve cells. In comparison to untreated mice with AD, mice with AD that were treated with curcumin had significantly reduced levels of free radicals. Thus, the oxidative damage that AD caused to the nerve cells of the curcumin mice was far less than the damage to the untreated mice.
The most prominent characteristic in the brains of people with Alzheimer’s disease is the presence of beta-amyloid plaques. These plaques are basically an accumulation of small fibers called beta-amyloid fibrils. The plaques can be found in the spaces between nerve cells, and in addition to being a tell-tale sign of the disease, their presence is believed to contribute greatly to the neurodegenerative process of AD.
The levels of beta-amyloid in AD mice that were given low doses of curcumin were decreased by around 40% in comparison to those AD mice that were not treated with curcumin. In addition, low doses of curcumin also caused a 43% decrease in the so-called “plaque burden” that these beta-amyloids have on the brains of AD mice. Surprisingly, those AD mice that received high doses of curcumin did not show any decreases in beta-amyloid levels or plaque burden in comparison with untreated mice. While the exact reason for this finding is not yet clear, the results of it are intriguing: low doses of curcumin were actually more effective than high doses in combating the neurodegenerative process of AD.
Although research to confirm such a notion is just now getting underway, the results of the Alzheimer’s study suggest that curcumin might well be helpful in combating other neurodegenerative diseases like HD. Despite the differences in the fundamental “cause” of each disease – HD is believed to be a purely genetic disorder, while AD is believed to have both genetic and environmental components – the damage to nerve cells in each disorder is strikingly similar. Thus, because curcumin combats the phenomena that contribute to neurodegeneration in AD, it is fair to suggest that the substance may possibly be capable of combating similar phenomena in HD.
Just as in Alzheimer’s, inflammation and oxidative damage play a strong role in the neurodegenerative process of HD: oxidative damage (also known as “oxidative stress”) helps to degrade nerve cells in the basal ganglia and cerebral cortex; chronic inflammation in the brains of people with HD is believed to play a significant role in the progression of the disease. ( For more info about inflammation, click here.) As shown previously, curcumin was able to reduce inflammation and oxidative damage in mouse models of AD. Although it is possible that the pattern of inflammation in the brain and the severity of oxidative damage may be different between AD and HD, if they are even slightly similar in the two disorders, then one would expect curcumin to also have a positive effect on combating HD.
Despite the harmful effects of inflammation and oxidative damage, beta-amyloid fibrils (which make up beta-amyloid plaques) have won the most attention among researchers and the general public with regard to AD. Similarly, despite the harmful effects of other phenomena that contribute to neurodegeneration, the most attention among researchers and the general public with regard to Huntington’s disease is devoted to huntingtin protein aggregation. The attention paid to beta-amyloid fibrils and huntingtin protein aggregation is not unjustified: in addition to being telltale signs of their respective disorders, these two phenomena may be key players in the neurodegenerative process. For instance, some researchers believe that substances which inhibit huntingtin protein aggregation will also be found to inhibit the initial structural alteration of the huntingtin protein, an alteration that is believed to start the entire disease process in HD. But there is another discovery that could have potentially profound effects on the research underway for both of these diseases: based on their ribbon-like structure and the mechanism by which they are created, huntingtin protein aggregates are quite similar to beta-amyloid fibrils. Given this discovery, it is possible that substances that decrease the presence of beta-amyloid fibrils may do the same with huntingtin protein aggregates, and vice-versa.
As of this writing (June 2004), research on the effectiveness of curcumin in combating huntingtin protein aggregation has just gotten underway. Should curcumin prove to decrease huntingtin protein aggregates as well as it did beta-amyloid plaques, this would be a true triumph in HD research. However, while this possibility is certainly a source of intrigue, it is important to note that not all substances that are proven to decrease beta-amyloid levels have shown the same effectiveness with huntingtin protein aggregation. For instance, the compounds thioflavine T, gossypol, melatonin, and rifampicin, all of which are believed to decrease the presence of beta-amyloid, had little or no success in inhibiting huntingtin protein aggregation. On the other hand, Congo Red and thioflavine S, which are also believed to decrease beta-amyloid, did effectively decrease huntingtin protein aggregation. Thus, while the similarities between beta-amyloid fibrils and huntingtin protein aggregates make us hopeful that curcumin can decrease the aggregates, current research on curcumin and HD will have the final say.
A closing remark: This section lacks definitive answers about how curcumin affects HD for one reason: the research simply has not yet been done. As the studies that are currently underway produce results, and as potentially more studies are begun, we will learn a great deal about how curcumin affects HD.
The AD mice study mentioned in the above sections prompts us to offer some cautionary notes about directly applying results from mice to humans:
First, the AD study tested curcumin by splitting the mice into three groups: one group received a low dose of curcumin, another group received a high dose, and the third group received no curcumin at all. Curiously, comparing the low-dose group and high-dose group, low doses of curcumin actually appeared to combat neurodegeneration in AD better than high doses. While the reason for this finding is not yet fully understood, the results do tell us something important: just because a substance is helpful does not mean its helpfulness is increased with every increase in dosage. In fact, increased or prolonged dosages of an initially helpful substance can actually be harmful. In the ibuprofen study mentioned above, for example, gastrointestinal, liver, and kidney damage resulted from the prolonged use of otherwise helpful ibuprofen.
Second, it is also important to keep in mind that mice, of course, have significantly smaller bodies than humans and may metabolize substances differently than we do. Thus, despite its apparent safety in animal studies (for example, one study on mice used 83 times the normal amount of curcumin, and still produced no mortalities), one should always exercise caution when using a new substance (medicinal or natural) to treat a disorder. And as always, for advice about treating disease, it is important to consult a physician.
Clinical trials should soon be underway in order to establish the safety of using curcumin to combat AD in humans. If future laboratory and animal studies suggest that curcumin holds promise for combating Huntington’s disease as well, then clinical trials to test its safety and effectiveness in HD would also be needed.
-M. Stenerson, 6-28-04More
This chapter will investigate how cholesterol relates to HD. The chapter begins with a general overview of cholesterol and its role in the body. Following this, the chapter will focus on the cholesterol that originates in the brain, and on new research that looks at the relationship between cholesterol in the brain and HD.
Cholesterol is a lipid molecule present in all animals. It is largely found in cell membranes, and there is a smaller amount circulating in the blood stream and stored inside cells. Cholesterol has a number of important functions. It is a key structural component of cell membranes, maintaining their fluidity and stability, and enabling important processes such as endocytosis. It is also important for the metabolism of fat-soluble vitamins, the manufacture of bile salts and the synthesis of vitamin D and steroid hormones. The synthesis of vitamins and hormones takes place in endocrine cells, while bile salts are generated in the liver.
Recently a small number of papers have shown that HD patients have altered levels of cholesterol in nerve cells. Since cholesterol plays a key role in the maintenance of healthy neurons, the disruption of normal cholesterol levels in HD patients may be a significant cause of neuron death and dysfunction.
There are two major ways for our bodies to get cholesterol; it can be synthesized in the body, or obtained from the diet. Normally, our bodies take advantage of both methods of getting cholesterol. On average, a 150 pound person will synthesize about 1 gram of cholesterol per day and intake 200-300 milligrams through their diet.
The highest rate of cholesterol synthesis by the body occurs in the liver, although cholesterol is also made in the intestines, adrenal glands, CNS, and reproductive organs. Other cells can produce cholesterol, but typically in much lower amounts.
Cholesterol is found in all animal foods including meat, poultry, fish, seafood, eggs, and dairy. Cholesterol is not found in plants, so foods like fruits, vegetables, grains, nuts and seeds do not raise cholesterol levels. It is partly because we synthesize so much of our own cholesterol that excess dietary cholesterol is not necessary and can be harmful in a variety of ways.
In this chapter, our goal is to first provide a general review on cholesterol and its activity in the human body, and then look at its relationship to Huntington’s disease.
Most people have heard of a distinction between two types of cholesterol: HDL and LDL. HDL stands for high-density lipoprotein, while LDL stands for low-density lipoprotein. HDL is commonly referred to as “good” cholesterol, while LDL is called “bad” cholesterol. More precisely, HDL and LDL are not simply different types of cholesterol, but rather alternative groups of lipids and proteins that transport the cholesterol throughout the body in the bloodstream. Molecules such as HDL and LDL are needed to carry cholesterol because it is a hydrophobic molecule and therefore cannot dissolve in blood and travel through the bloodstream on its own.
But if HDL and LDL are just alternative cholesterol carrier molecules, why is one considered good and the other bad? Medical studies have noted that high levels of LDL are associated with an increased risk of cardiovascular disease, whereas high levels of HDL are associated with decreased risk of cardiovascular disease.
How exactly does HDL produce beneficial effects and LDL produce harmful effects? LDL is the major cholesterol carrier in the blood and is responsible for delivering cholesterol to cells in the body. High levels of LDL cholesterol in the blood contribute to the formation of plaque. Plaque is a thick, hard deposit of fat, cholesterol and other substances that clogs arteries and causes atherosclerosis. If arteries become severely clogged with plaque, oxygen-carrying blood may not reach be able circulate around the body- which can lead to heart attack or stroke. Approximately one fourth of blood cholesterol is carried by HDL. HDL is believed to protect against atherosclerosis by carrying cholesterol away from the blood (so it cannot contribute to plaque formation) or even removing excess cholesterol from plaque already built-up in the arteries. HDL usually delivers cholesterol to the liver or endocrine cells, where it will be used in the synthesis of steroids or bile salts, and ultimately removed from the tissue and bloodstream.
When our cholesterol levels are tested, they are shown in milligrams per deciliter of blood (mg/dL). The American Heart Association classifies anyone with total cholesterol greater than or equal to 240 mg/dL as belonging to a high risk category. They recommend that those with a total cholesterol level in this high range get a complete fasting lipoprotein profile done. This test measures LDL, HDL, and triglyceride levels. Triglycerides are another contributor to atherosclerosis. The target HDL level is greater than 40 mg/dL, the target triglyceride level is less than 150 mg/dL, and the target total cholesterol level is less than 240 mg/dL.
|Optimal||Near Optimal||Borderline High||High||Very High|
|Total Blood Cholesterol||<200||—-||200-239||=240||—-|
*Information from the American Heart Association
There are several ways to lower cholesterol levels that are too high. The best methods are usually lifestyle changes. These can include dietary changes such as eliminating foods that are high in saturated fat, trans fat, and cholesterol and increasing the consumption of fruits, vegetables and grains. Exercise is also an important way to reducing the amount of cholesterol in our bodies. By exercising for 20-30 minutes each day we use up greater amounts of fats and other energy molecules that are stored in our bodies. Additionally, there are medications that help lower cholesterol. These medications usually employ one of two general strategies. They either block the synthesis of cholesterol within the bodies’ cells or they prevent cholesterol uptake in the intestine, forcing ingested cholesterol to pass through the body and never be absorbed. The best way to stay healthy is to make sure you have had your cholesterol tested and, if it is too high, to follow your doctor’s instructions for lowering it.
The CNS contains a large amount of cholesterol, as cholesterol is needed for the growth and maintenance of myelin, as well as neuron and glial cell membranes and for the formation of new connections between cells. However, the CNS is unique in that there is no evidence that it obtains any of its cholesterol from the blood. Instead, cells in the CNS synthesize all of their own cholesterol. In fact, the rate of cholesterol synthesis in the CNS exceeds the need for new cholesterol, so that some cholesterol must move out of the CNS through excretory pathways.
It is not easy for molecules to enter the CNS. Tightly joined endothelial cells found in the capillary network within the brain prevent many molecules from moving from the blood to the CNS. This blood-brain barrier makes it unlikely that cholesterol carried in lipoproteins could reach the CNS unless there were specific transporters in the endothelial cells of the vessel walls. Currently there is no evidence that existing transporters in those endothelial cells actively uptake lipoprotein-transported cholesterol.
A few studies have recently investigated the role of cholesterol in HD and have suggested that HD may disrupt the normal cholesterol homeostasis in the brain. These research articles propose that the altered huntingtin protein may cause a change in intracellular levels of cholesterol in neurons by disrupting at least two cellular mechanisms: endocytosis and cholesterol biosynthesis. Ultimately, these cellular changes may lead to dysfunction or death of the striatal neurons and reflect another pathway or mechanism by which the mutated huntingtin protein affects the cell and causes neurodegeneration.
A study by Trushina et al. has reported that the mutant huntingtin protein inhibits a specific type of endocytosis in striatal neurons. These neurons are also shown to have strikingly high intracellular levels of cholesterol.
Mutant huntingtin has been previously shown to interact with clathrin, which is a major protein involved in endocytosis. In this study however, a different protein has been implicated in the disruption of endocytosis in HD. It has been demonstrated that the mutant huntingtin protein interacts with the protein caveolin-1 (cav1), a key molecule in a different endocytotic pathway (called caveolar-related endocytosis). The interaction of mutant huntingtin protein and cav1 inhibits caveolar-related endocytosis and also causes an accumulation of cholesterol within neurons.
Examination of mouse tissue and HD striatal cell cultures revealed the accumulation of intracellular cholesterol. Researchers found that using siRNA to knockdown cav1 translation prevents cholesterol accumulation. For more on siRNA techniques, click here. This occurred only in the continued presence of mutant huntingtin protein, suggesting that it is something specifically about the nature of the interaction between altered huntingtin and cav1 that disrupts normal cholesterol homeostasis, and not simply the lack of cav1 altogether. It was also observed that in all cases clathrin-dependent endocytosis was normal, indicating that the mechanism of cholesterol accumulation was specific to the disruption of the caveolar-related pathway.
In another recent paper, by Valenza et al., Huntington’s disease has been shown to decrease cholesterol biosynthesis in nerve cells. The presence of altered huntingtin in these cells is correlated with significantly lower total cholesterol mass. This was observed in mouse tissue and in cultured striatal neurons expressing a fragment of the mutant huntingtin protein.
Mutant huntingtin affects the transcription of genes crucial to cholesterol synthesis. The altered huntingtin protein interacts with binding proteins called sterol regulatory element -binding proteins (SREBPs) and prevents these proteins from entering the nucleus. These proteins usually bind to DNA and promote transcription of many different genes important for synthesizing cholesterol. Mutant huntingtin has a strong effect on SREBPs; the proteins are reduced by 50% in the nucleus of HD cells. Reduction of the SREBPs results in significantly less transcription of the genes involved in cholesterol biosynthesis, which ultimately reduces total cholesterol.
Large changes in the levels of intracellular cholesterol will eventually lead to disruption of cellular homeostasis. Research with HD cell line models has shown that the addition of exogenous cholesterol to cultured striatal neurons expressing mutant huntingtin joined to a green fluorescent protein will prevent these neurons from dying.
Cholesterol is essential for promoting synapse formation and maintaining membrane integrity in CNS neurons. It is also a major component of myelin and important for optimal neurotransmitter release. Because cholesterol plays such a major role in CNS growth, development, and maintenance, disruptions of cholesterol homeostasis can have negative consequences. Accumulation and depletion of intracellular cholesterol in neurons are both possible mechanisms contributing to neuron dysfunction in these HD models. However, the findings are limited to HD cell models and postmortem HD tissue. This work now needs to be followed up by investigating these changes in HD patients to see whether similar dysfunction occurs.
If studies in human subjects found a similar dysfunction in cholesterol homeostasis, it might suggest that adjusting the cholesterol levels in neuronal cells could be a potential treatment for HD. Future research may aim to discover how to transport cholesterol across the blood brain barrier and whether cholesterol therapy could be one way of slowing or halting neuronal cell death in HD.
It is interesting to note that similar defects in caveolar-related endocytotic pathways and perturbations of cholesterol homeostasis have been implicated in other neurodegenerative diseases related to HD like Alzheimer’s disease and Parkinson’s disease.
Recent research has suggested that disruptions in cholesterol homeostasis could be important in explaining how the HD mutation causes neurodegeneration. However, cholesterol’s role in the disease is still not fully understood. It might seem strange that HD has been linked to both intracellular cholesterol accumulation and depletion. One current hypothesis is that different stages of the disease are characterized by different disruptions to cholesterol homeostasis. Future research should shed light on the connections between these different disruptions and normal cholesterol activity.
-A. Hepworth, 5/13/2007More