Theories about Alzheimer's Disease

Growing public awareness and the number and quality of Association grant applications reflect the increasing importance of Alzheimer's disease and the growing stature of Alzheimer research. The sense of urgency arising from the impending public health crisis has attracted some of the best minds in science to the effort to unravel Alzheimer's mysteries.

Expanding interest in dementia has nurtured a worldwide initiative exploring a wide array of disease mechanisms and approaches to treatment. Following is a summary of current developments in Alzheimer's research, written for nonspecialists.



Most scientists agree that the critical biological events leading to the behavioral and clinical problems of Alzheimer's center around loss of communication among certain nerve cells and eventual destruction of these cells. Divergent perspectives on the exact cause of this destruction have fostered different theories about what initiates the process and how best to intervene.


Amyloid hypothesis


The theory with the largest following remains the "amyloid hypothesis," which assigns a central role to abnormal processing of amyloid precursor protein (APP), a protein found widely throughout the body but whose normal function remains unknown.

This abnormal processing yields a fragment called beta-amyloid (A?), which aggregates by stages into the amyloid plaques that are one hallmark Alzheimer pathology. Proponents of the amyloid hypothesis see production and aggregation of A? as the key event in nerve cell disruption and destruction.

About half of the applicants to the Alzheimer's Association grants program propose investigations into various aspects of amyloid.


Insights into the steps involved in amyloid processing have already led to identification of two potential therapeutic approaches. One tactic relies on various strategies for stimulating an immune system response that destroys A?.

The first immunotherapeutic compound to reach clinical trials-the "Alzheimer vaccine"-failed to fulfill its early promise. Even though that trial failed, the effort may still yield valuable insights into amyloid and its role as well as point the way to refinements of the immunotherapeutic approach that may yet bear fruit.


The second amyloid-targeting strategy inhibits enzymes called secretases that cut APP into successively smaller pieces, ultimately producing A?. Secretases are classified as proteases, the same category of enzymes targeted by the protease inhibitors that have revolutionized AIDS therapy. A number of pharmaceutical companies are developing secretases, and the first such drug has reached clinical trials.

Nerve growth factors


Another promising drug that reached human clinical testing stimulated production of nerve growth factors, proteins that regulate nerve cell maturation, survival, and repair. Nerve growth factors are an active area of research in stroke, spinal cord injury, and other nerve-damaging conditions as well as in Alzheimer's disease.


Memantine, an Alzheimer drug already approved in Germany that recently won preliminary approval in the rest of the European Union, is now under development in the United States where it has reached Phase III trials. Because memantine treats Alzheimer symptoms in a different way than the four currently approved drugs, some of the Phase III trials are exploring whether individuals may be able to take both types of drugs simultaneously.


Tau theory


The second most prominent Alzheimer theory assigns a causative role to tau, a protein that normally helps organize and stabilize a cell's internal "skeleton." In Alzheimer's, tau deforms and loses its ability to support the cell, eventually aggregating into neurofibrillary tangles-the other hallmark Alzheimer brain lesion.

Although no therapies targeting tau have reached clinical trials, many experts remain convinced that understanding tau will reveal crucial clues about Alzheimer's devastating effects on nerve cells as well as chemical steps vulnerable to intervention.


Inflammation and Alzheimer's pathology


Other projects focus on inflammation as a key part of Alzheimer pathology. Epidemiological studies have revealed that individuals taking anti-inflammatory drugs to treat such conditions as arthritis appear to have a lower-than-expected occurrence of Alzheimer's.

Scientists have launched several clinical trials to investigate specifically whether use of anti-inflammatory drugs may reduce Alzheimer risk. Meanwhile, basic research proceeds to investigate the molecular mechanisms that may underlie the protective effects of anti-inflammatories.

Maternal Low Cholesterol May Cause Preterm, Lower-Weight Infants

Mothers with low serum cholesterol levels are significantly more likely to deliver premature babies, or full-term babies with lower weight, according to the study, "Adverse Birth Outcomes Among Mothers With Low Serum Cholesterol." Researchers studied 118 women with low total cholesterol (less than the 10th percentile) and 940 women with mid-range cholesterol levels. The women - between the ages of 21 and 34; all nonsmokers without diabetes - were referred to South Carolina clinics for routine second-trimester prenatal care between 1996 and 2001.

Among white mothers, the prevalence of preterm delivery was 21 percent for the
low cholesterol mothers, compared to 5 percent for the mid-cholesterol mothers. There were no significant increases in preterm birth rates among African American mothers. However, a low maternal serum cholesterol level was associated with lower infant birth weights at term - 150 grams less, on average - in both racial groups. In addition, a trend was found towards small head size among babies born to mothers with very low cholesterol. Low serum cholesterol levels often reflect poor diet or nutritional deficiencies.

The study authors recommend that future investigations of preterm births include cholesterol and lipoprotein profiles.


In a related commentary, "The Changing Face of Preterm Birth," the impact of Dr. Muenke's research is addressed.


The American Academy of Pediatrics is an organization of 60,000 primary care pediatricians, pediatric medical subspecialists and pediatric surgical specialists dedicated to the health, safety and well being of infants, children, adolescents and young adults.


American Academy of Pediatrics

Insight In Mechanism For The In-Vivo Transport Of SiRNA Has Potential To Be Used In Gene Therapy

How small RNAs enter mammalian cells


It all started with flowers: in the nineties of the last century Norwegian researchers discovered that additional copies of a particular gene in petunias inhibited its activity instead of reinforcing it as had been assumed. A few years later it was found that the mechanism is based on the degradation of messenger RNA in the cells. Finally, in the late nineties the Nobel prizewinners Andrew Fire and Craig Mello established the technique of RNA interference, in which double-stranded RNA switches genes off efficiently and specifically. The scientists used the nematode (roundworm) Caenorhabditis elegans to study this. Subsequently, however, considerable problems arose in the attempt to transfer the strategy used by Mello and Fire to vertebrates. In particular the administration of small RNAs, known as siRNAs (small interfering RNAs), in animals proved difficult. Although it was possible to administer siRNAs successfully by using various methods such as high-pressure injections or in conjunction with cholesterol, the underlying mechanisms remained obscure. Markus Stoffel, ETH Zurich Professor at the Institute for Molecular Systems Biology, together with chemists from the Alnylam Company, has now succeeded in elucidating the mechanism for the uptake of siRNA in combination with fatty acids in mammals. The corresponding paper, which has just been published in the scientific journal Nature Biotechnology and will also adorn the title page of the printed version in October, represents the basis for possible siRNA therapies, among other things. This is because Stoffel showed that siRNA can be coupled effectively to various fatty acids.



Cholesterol transporters also play a part


Stoffel and his team turned to chemically modified siRNAs in combination with cholesterol, not because the method based on this compound was particularly efficient but because it had the least side-effects. First of all the researchers wanted to know whether siRNA was capable of being bonded to other lipophilic substances in addition to cholesterol, and caused a reduction in the activity of a target gene in the liver at the same time. It turned out that there are several such fatty acids. But what is it in the blood to which all these RNAs conjugated with so-called lipophilic substances bond" The ETH Zurich researchers discovered that, depending on the fatty acid used, the binding partners are the well-known cholesterol transporters High Density Lipoproteins (HDL) and Low Density Lipoproteins (LDL) as well as the albumin (protein) present everywhere in the blood. Without these lipoprotein particles there is no uptake of siRNAs into the tissues, as became apparent from further experiments. In an additional experiment the scientists demonstrated that the uptake can be made considerably more efficient if the siRNA-fatty acid molecules are already firmly bonded to HDL and LDL before being administered. Stoffel's team also discovered that there is preferential uptake into different tissues depending on whether an siRNA-fatty acid molecule is bonded to HDL or LDL: all LDL compounds trigger responses in the liver, but HDL compounds also do so in the intestine or kidneys.
















An irritating finding


The latter finding indicated that the uptake proceeds via HDL and LDL receptors. The researchers proved this assumption by inactivating the receptors, with the result that uptake no longer occurred. Despite the clarity of the finding, it irritated Stoffel slightly. He found it hard to imagine that the siRNAs were able to enter the cell via the normal absorption route like HDL, because this route leads into the cell's own digestive system with lysosomes that would degrade the siRNAs. So how would the siRNAs be able to avoid this degradation" Stoffel concluded that they simply use a different doorway into the cell. Thus the HDL and LDL receptors would only act as docking stations but not as an entry portal.



But what might the alternative doors be" The ETH Zurich researchers remembered that a gene product Sid1, which is necessary for the cellular uptake of siRNA, occurs in the worm Caenorhabditis elegans. The corresponding gene also has a homologue in mammals. By inactivating it, the scientists showed that it is also necessary in mammals. The overall result from all the discoveries is a mechanism for siRNA administration that starts with the bonding of siRNAs to particular fatty acids. This combination is linked to lipophilic proteins that bring about docking onto the tissue cells. The doors that allow the siRNA-fatty acid molecules to enter are then situated close to the docking station.



Prospects for new therapies and research


Stoffel thinks that through their work they were able to determine the elements that are most important for the uptake mechanism. However, he says it is very likely that yet more molecules play a part. But since an insight into the mechanism now exists for the first time, it will be possible to make specific improvements in the technique. For example Stoffel's group wants to find out whether HDL and LDL can be replaced by synthetic proteins or lipid-rich particles. He says that basically the technique has the potential to be used in gene therapy. However, the determination of the siRNA doors also opens up new approaches to fundamental research. Instead of siRNA it might also be possible to smuggle in miRNAs, another group of small RNAs, in the same way. The same mechanism ought to work for miRNA inhibitors as well. Since miRNA is increasingly "suspected" of occupying a decisive role in gene regulation in nature, its targeted administration or inhibition could yield completely new insights.

Low-Fat Diets More Likely To Reduce Risk Of Heart Disease Than Low-Carb Diets

Low-fat diets are more effective in preserving and promoting a healthy cardiovascular system than low-carbohydrate, Atkins'-like diets, according to a new study by researchers at the Medical College of Wisconsin in Milwaukee.



The study, published in the February edition of the scientific journal Hypertension, was led by David D. Gutterman, M.D., Northwestern Mutual Professor of Cardiology, professor of medicine and physiology, and senior associate dean of research at the Medical College. Shane Phillips, M.D., a former Cardiology faculty member at the Medical College, and now assistant professor in the department of physical therapy at the University of Illinois - Chicago, was the lead author.



Public awareness of the "obesity epidemic" has resulted in various dietary weight loss strategies. In America, it is estimated that 45 percent of women and 30 percent of men diet to lose weight.



"The nutrient-specific effects of these diets on cardiovascular health are largely unknown," says Dr. Gutterman.



"Low-carbohydrate diets are significantly higher in total grams of fat, protein, dietary cholesterol and saturated fats than are low-fat diets. While a low-carbohydrate diet may result in weight loss and improvement in blood pressure, similar to a low-fat diet, the higher fat content is ultimately more detrimental to heart health than is the low-fat diet suggested by the American Heart Association," points out Dr. Phillips.



"The higher fat content of a low-carbohydrate diet may put dieters at an increased risk of atherosclerosis (hardening of the arteries) because low-carbohydrate diets often reduce protection of the endothelium, the thin layer of cells that line the blood vessels of the circulatory system. The reduced production from the endothelium of nitric oxide, a specific chemical, puts the vessel at higher risk of abnormal thickening, greater clotting potential, and cholesterol deposition, all part of the atherosclerosis process," says Dr. Gutterman.



Over a six-week period, the researchers found reduced flow-mediated dilation in the arm artery in participants who were on the low-carbohydrate diet. Reduced flow-mediated dilation, as measured in this study, is an early indicator of cardiovascular disease. On the other hand, flow-mediated dilation improved significantly in participants on the low-fat diet suggesting a healthier artery which is less prone to developing atherosclerosis.



"We observed a reduction in brachial artery flow-mediated dilation after six weeks of weight loss on a low-carbohydrate, Atkins'-style diet," Dr. Gutterman says.



Low-carbohydrate diets were also found to have significantly less daily folic acid than low-fat diets. Folic acid is thought to be helpful in reducing the likeliness of heart disease. This protective effect results from the antioxidant property of folic acid and its ability to lower levels of homocysteine, a naturally occurring amino acid that can be dangerous at elevated levels.
















The low-carbohydrate diet provided 20 grams of carbohydrates daily and was supplemented with protein and fat content according to the Atkins' diet recommendations. The low-fat diet provided 30 percent of the calories as fat, and was modeled after the American Heart Association's recommendations.



"The composition of diet may be as important as the degree of weight loss in determining the effect of dietary interventions on vascular health," Dr. Gutterman notes.



Twenty participants between the ages of 18 to 50 with a body mass index ranging from 29 to 39 were monitored for the study, and the type of diet was randomly assigned to participants. Weight loss, flow-mediated dilation, blood pressure and insulin and glucose levels in the participants were measured every two weeks for the six-week study.







The study was funded by the support of the National Institutes of Health General Clinical Research Center and the Medical College of Wisconsin Cardiovascular Center. It was conducted at Froedtert Hospital, the College's major teaching affiliate.



Co-authors of the study included Jason Jurva, M.D., assistant professor of medicine; Amjad Syed, resident in surgery (University of Illinois - Chicago); Amina Syed, resident in family practice with the Medical College of Wisconsin Affiliated Hospitals; Jacquelyn Kulinski, senior medical student; Joan Pleuss, senior research dietician; and Raymond Hoffmann, Ph.D., professor of population health in the division of biostatistics.

Metabolic Syndrome More Predominant In East Germany Than West Germany

More people suffer from being overweight and have high blood pressure and metabolic disturbances in East Germany than in West Germany. This is the result of a study with almost 36 000 patients, published in the current edition of the Deutsches ?„rzteblatt International (Dtsch Arztebl Int 2008; 105[12]: 207-13).



The so-called metabolic syndrome describes a typical constellation of overweight, high blood pressure, and abnormal sugar and fat metabolism. This increases the risk of diabetes mellitus and of cardiovascular disease.



The study shows that patients with metabolic syndrome are more often treated in general practices in East than in West Germany. In Germany as a whole, 22.7% of men and 18% of women exhibit metabolic syndrome. The syndrome is most frequent in Saxony-Anhalt, where it affects 25% of patients in primary care. The risk of coronary heart disease is the same in all German states, although diabetes is more frequent in East Germany. The authors advocate specific prophylactic measures in accordance with regional needs and socioeconomic differences within the population.

Tallow Magic Ingredient in Promising Cholesterol Fighter

Imagine a cholesterol-lowering hot fudge sundae. Tim Carr, a University of Nebraska-Lincoln nutrition scientist, envisions all sorts of foods with cholesterol-fighting power. He's working on a potential food additive that could turn such dreams into reality.


He has developed a compound that packs more cholesterol-lowering power than similar commercially available plant-based food additives and should be easier to incorporate into foods. Carr's new compound outperformed plant-based additives in animal studies. Preliminary research also indicates it works at least as well as widely prescribed cholesterol-lowering statin drugs.


And raw materials come from two abundant Nebraska products -- soybeans and beef tallow. Scientists have long known that plant substances called sterols help reduce blood cholesterol. However, sterols don't dissolve in water.


Mixing sterols with oil or fat improves their solubility but has limited their use to higher fat foods such as margarine or salad dressings. That snag bothered Carr. "Here we have this nice ingredient for lowering cholesterol but we can only deliver it in high-fat foods," the university Institute of Agriculture and Natural Resources researcher said. "What's wrong with this picture?" Carr studies the role of various fats in heart disease. His earlier research revealed that stearic acid, a saturated fat found in beef tallow and some other fats, actually lowers cholesterol. "I've built on that earlier discovery of the good saturated fats," he said. He devised a way to blend specific amounts of stearic acid with plant sterols.


"The magic ingredient or what I'm calling beneficial saturated fat is stearic acid," he said. Combining stearic acid-rich beef tallow with soybean-derived sterols boosts the cholesterol-lowering power.



Commercially available plant sterol additives are gooey, sticky substances. They stick to food manufacturing equipment.



Carr's compound is easily made into a powder that theoretically could be added to diverse foods, from breakfast cereals and drinks to dairy products and even chocolate.



"We think this powder is going to be much easier to work with and have a much broader application," he said.



Carr is testing his compound's effectiveness in animal studies and exploring how best to commercialize it to benefit consumers. The university is patenting this technology.



So far, results are impressive.



Carr's College of Education and Human Sciences team compared his compound to a commercially available plant sterol product in hamster feeding trials. The compound lowered LDL, or bad, cholesterol about 70 percent, compared with 10 percent using the commercial sterol additive.



While hamsters are a good model for humans, they aren't people. Carr hopes to get funding for human clinical studies.



Commercial plant sterol additives and the team's plant sterol/stearic acid compound both work by blocking cholesterol absorption in the small intestine. Typically, the body absorbs 50-60 percent of cholesterol in the gastrointestinal tract, he said. Excess cholesterol winds up in blood where it can contribute to heart disease.



"With our compound, absorption is in the 3 to 5 percent range," Carr said. "That's highly effective."



Carr is in the midst of a hamster study comparing the compound to a commercial statin drug.



"Our preliminary data indicates that it's as good or better than the statin drugs," he said. He'll have more definitive answers later this year.



Americans take about 2 million daily doses of statins, such as Lipitor, making them the nation's most widely prescribed drugs, Carr said. Statins help millions lower their cholesterol, but there is some concern about their potential for liver and muscle damage.



If the new compound proves effective in further studies, it might provide a new cholesterol management tool.



"The beauty of this is that our compound passes right through the GI tract and takes cholesterol with it. It's never absorbed into the body so there are no toxicity issues," he said.



This research is conducted in cooperation with the university's Agricultural Research Division.



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First 'Genetic Map' Of Han Chinese May Aid Search For Disease Susceptibility Genes

The first genetic historical map of the Han Chinese, the largest ethnic population in the world, as they migrated from south to north over evolutionary time was published online by the American Journal of Human Genetics by scientists at the Genome Institute of Singapore (GIS).



Based on genome-wide DNA variation information in over 6,000 Han Chinese samples from 10 provinces in China, this new map provides information about the population structure and evolutionary history of this group of people that can help scientists to identify subtle differences in the genetic diversity of Asian populations.



Understanding these differences may aid in the design and interpretation of studies to identify genes that confer susceptibility to such common diseases as diabetes in ethnic Chinese individuals. Understanding these differences also is crucial in exploring how genes and environment interact to cause diseases.



With the genetic map, the GIS scientists were able to show that the northern inhabitants of China were genetically distinguishable from those in the south, a finding that seems very consistent with the Han Chinese's historical migration pattern.



The genetic map also revealed that the genetic divergence was closely correlated with the geographic map of China. This finding suggests the persistence of local co-ancestry in the country.



"The genome-wide genetic variation study is a powerful tool which may be used to infer a person's ancestral origin and to study population relationships," said Liu Jianjun, Ph.D., GIS Human Genetics Group Leader.



"For example, an ethnic Chinese born and bred in Singapore can still be traced back to his or her ancestral roots in China," Dr. Liu said. "By investigating the genome-wide DNA variation, we can determine whether an anonymous person is a Chinese, what the ancestral origin of this person in China may be, and sometimes which dialect group of the Han Chinese this person may belong to.



"More importantly, our study provides information for a better design of genetic studies in the search for genes that confer susceptibility to various diseases," he added.



Of particular interest to people in Singapore are the findings that while the majority of Singaporean Chinese hail from Southern China as expected, some have a more northern ancestral origin.



GIS Executive Director Edison Liu, M.D., said, "Genome association studies have provided significant insights into the genes involved in common disorders such as diabetes, high cholesterol, allergies, and neurological disorders, but most of this work has been done on Caucasian populations.



"More recently, Dr. Liu Jianjun from our institute has been working with his Chinese colleagues to define the genetic causes of some of these diseases in Asian populations," the GIS Executive Director added. "This work refined those tools so that the results will not be obscured by subtle differences in the genetic diversity of Asian populations. In the process, Dr. Liu has reconstructed a genetic historical map of the Chinese people as they migrated from south to north over evolutionary time."
















"There are definite differences in genetic architecture between populations," noted Chia Kee Seng, M.D., Head, Department of Epidemiology & Public Health, National University of Singapore (NUS), and Director, NUS-GIS Centre for Molecular Epidemiology.



"We have seen this in the Singapore Genome Variation Project, a Joint NUH-GIS effort. Understanding these differences is crucial in exploring how genes and environment interact to cause diseases," he added.



The research results published in American Journal of Human Genetics is part of a larger ongoing project on the genome-wide association study of diseases among the Chinese population. The project is a collaboration between GIS and several institutions and universities in China.



In Jan. 2009, Nature Genetics published the findings of researchers at the GIS and Anhui Medical University, China, on psoriasis, a common chronic skin disease. In that study, led by Dr. Liu Jianjun at the GIS and Dr. Zhang Xuejun at the Anhui Medical University, the scientists discovered a genetic variant that provides protection against the development of psoriasis. The collaboration's recent discovery of over a dozen genetic risk variants for systematic lupus erythematosus (SLE) in the Chinese population was published in Nature Genetics in Oct. 2009.



The American Journal of Human Genetics paper is titled, "Genetic Structure of the Han Chinese Population Revealed by Genome-wide SNP Variation."



Authors: Jieming Chen 1*, Houfeng Zheng 3,4,5*, Jin-Xin Bei 6,7, Liangdan Sun 3,4 5, Wei-hua Jia 6,7, Tao Li 8,9, Furen Zhang 10, Mark Seielstad 1,2,11, Yi-Xin Zeng 6,7, Xuejun Zhang 3,4 5, Jianjun Liu 1,2,3,4
Human Genetics, Genome Institute of Singapore, Singapore 138672, Singapore


Centre for Molecular Epidemiology, (Yong Loo Lin) School of Medicine, the National University of Singapore 117597, Singapore


Institute of Dermatology and Department of Dermatology at No.1 Hospital, Anhui Medical University


The Key Laboratory of Gene Resource Utilization for Severe Diseases, Ministry of Education and Anhui Province


Department of Dermatology and Venereology, Anhui Medical University, Hefei, Anhui 230032, China


State Key Laboratory of Oncology in Southern China, Guangzhou, China


Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, China


The Department of Psychiatry & Psychiatric laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China


The Department of Psychological Medicine and Psychiatry, Institute of Psychiatry, King's College London, London SE5 8AF, UK


Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Science, Jinan, Shandong, China


Dept. of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA

* These authors contributed equally to this manuscript.