Alzheimer's Disease in Mice Alleviated: Promising Therapeutic Approach for Humans

Pathological changes typical of Alzheimer's disease were significantly reduced in mice by blockade of an immune system transmitter. A research team from Charité -- Universitätsmedizin Berlin and the University of Zurich has just published a new therapeutic approach in fighting Alzheimer's disease in the current issue of Nature Medicine. This approach promises potential in prevention, as well as in cases where the disease has already set in.

Alzheimer's disease is one of the most common causes of dementia. In Germany and Switzerland alone, around 1.5 million people are affected, and forecasts predict a doubling of the number of patients worldwide within the next 20 years. The accumulation of particular abnormal proteins, including amyloid-ß (Aβ) among others, in patients' brains plays a central role in this disease. Prof. Frank Heppner from the Department of Neuropathology at Charité and his colleague Prof. Burkhard Becher from the Institute for Experimental Immunology at the University of Zurich were able to show that turning off particular cytokines (immune system signal transmitters) reduced the Alzheimer's typical amyloid-ß deposits in mice with the disease. As a result, the strongest effects were demonstrated after reducing amyloid-ß by approximately 65 percent, when the immune molecule p40 was affected, which is a component of the cytokines interleukin (IL)-12 and -23.

Relevant for human therapy

Follow-up experiments also relevant for humans showed that substantial improvements in behavioral testing resulted when mice were given the antibody blocking the immune molecule p40. This effect was also achieved when the mice were already showing symptoms of the disease. Based on the current study by Prof. Heppner's and Prof. Becher's team, the level of p40 molecules is higher in Alzheimer's patients' brain fluid, which is in agreement with a recently published study by American colleagues demonstrating increased p40 levels in blood plasma of subjects with Alzheimer's disease, thus showing obvious relevance for human therapy.

The significance of the immune system in Alzheimer's research is the focus of current efforts. Prof. Heppner and Prof. Becher suspect that cytokines IL-12 and IL-23 themselves are not causative in the pathology, and that the mechanism of the immune molecule p40 in Alzheimer's requires additional clarification. However, they are convinced that the results of their six-years of research work justify the step toward clinical studies in humans, for which they plan to collaborate with a suitable industrial partner.

IIn the context of other illnesses, such as psoriasis, a medication that suppresses p40 in humans has already been applied. "Based on the safety data in patients," comment Profs. Heppner and Becher, "clinical studies could now be implemented without delay. Now, the goal is to bring the new therapeutic approach to Alzheimer patients quickly."

Journal Reference:

1. Johannes vom Berg, Stefan Prokop, Kelly R Miller, Juliane Obst, Roland E Kälin, Ileana Lopategui-Cabezas, Anja Wegner, Florian Mair, Carola G Schipke, Oliver Peters, York Winter, Burkhard Becher, Frank L Heppner. Inhibition of IL-12/IL-23 signaling reduces Alzheimer's disease–like pathology and cognitive decline. Nature Medicine, 2012; DOI: 10.1038/nm.2965

Courtesy: ScienceDaily

Use of Stem Cells in Personalized Medicine

Johns Hopkins researchers report concrete steps in the use of human stem cells to test how diseased cells respond to drugs. Their success highlights a pathway toward faster, cheaper drug development for some genetic illnesses, as well as the ability to pre-test a therapy's safety and effectiveness on cultured clones of a patient's own cells.

he project, described in an article published November 25 on the website of the journal Nature Biotechnology, began several years ago, when Gabsang Lee, D.V.M., Ph.D., an assistant professor at the Johns Hopkins University School of Medicine's Institute for Cell Engineering, was a postdoctoral fellow at Sloan-Kettering Institute in New York. To see if induced pluripotent stem cells (iPSCs) could be used to make specialized disease cells for quick and easy drug testing, Lee and his colleagues extracted cells from the skin of a person with a rare genetic disease called Riley-Day syndrome, chosen because it affects only one type of nerve cell that is difficult if not impossible to extract directly from a traditional biopsy. These traits made Riley-Day an ideal candidate for alternative ways of generating cells for study.

In a so-called "proof of concept" experiment, the researchers biochemically reprogrammed the skin cells from the patient to form iPSCs, which can grow into any cell type in the body. The team then induced the iPSCs to grow into nerve cells. "Because we could study the nerve cells directly, we could for the first time see exactly what was going wrong in this disease," says Lee. Some symptoms of Riley-Day syndrome are insensitivity to pain, episodes of vomiting, poor coordination and seizures; only about half of affected patients reach age 30.

In the recent research at Johns Hopkins and Memorial Sloan-Kettering, Lee and his co-workers used these same lab-grown Riley-Day nerve cells to screen about 7,000 drugs for their effects on the diseased cells. With the aid of a robot programmed to analyze the effects, the researchers quickly identified eight compounds for further testing, of which one -- SKF-86466 -- ultimately showed promise for stopping or reversing the disease process at the cellular level.

Lee says a clinical trial with SKF-86466 might not be feasible because of the small number of Riley-Day patients worldwide, but suggests that a closely related version of the compound, one that has already been approved by the U.S. Food and Drug Administration for another use, could be employed for the patients after a few tests.

The implications of the experiment reach beyond Riley-Day syndrome, however. "There are many rare, 'orphan' genetic diseases that will never be addressed through the costly current model of drug development," Lee explains. "We've shown that there may be another way forward to treat these illnesses."

Another application of the new stem cell process could be treatments tailored not only to an illness, but also to an individual patient, Lee says. That is, iPSCs could be made for a patient, then used to create a laboratory culture of, for example, pancreatic cells, in the case of a patient with type 1 diabetes. The efficacy and safety of various drugs could then be tested on the cultured cells, and doctors could use the results to help determine the best treatment. "This approach could move much of the trial-and-error process of beginning a new treatment from the patient to the petri dish, and help people to get better faster," says Lee.

Other authors of the paper are Christina N. Ramirez, Ph.D., Nadja Zeltner, Ph.D., Becky Liu, Constantin Radu, M.S., Bhavneet Bhinder, Hakim Djaballah, Ph.D., and Lorenz Studer, Ph.D., of the Sloan-Kettering Institute; and Hyesoo Kim, Ph.D., Young Jun Kim, M.D., Ph.D., InYoung Choi, Ph.D., and Bipasha Mukherjee-Clavin of the Johns Hopkins University School of Medicine.

The work was supported by funds from New York State Stem Cell Science (NYSTEM), the New York Stem Cell Foundation (NYSCF), the state of Maryland (TEDCO, MSCRF), the Commonwealth Foundation for Cancer Research, the Experimental Therapeutics Center at Memorial Sloan-Kettering Cancer Center, the William Randolph Hearst Fund in Experimental Therapeutics, the L.S. Wells Foundation, and the National Cancer Institute (grant number 5 P30 CA008748-44).

Journal Reference:

1. Gabsang Lee, Christina N Ramirez, Hyesoo Kim, Nadja Zeltner, Becky Liu, Constantin Radu, Bhavneet Bhinder, Yong Jun Kim, In Young Choi, Bipasha Mukherjee-Clavin, Hakim Djaballah, Lorenz Studer. Large-scale screening using familial dysautonomia induced pluripotent stem cells identifies compounds that rescue IKBKAP expression. Nature Biotechnology, 2012; DOI: 10.1038/nbt.2435

Courtesy: ScienceDaily

Watermelon Genome Decoded: Scientists Find Clues to Disease Resistant Watermelons

Are juicier, sweeter, more disease-resistant watermelons on the way? An international consortium of more than 60 scientists from the United States, China, and Europe has published the genome sequence of watermelon (Citrullus lanatus) -- information that could dramatically accelerate watermelon breeding toward production of a more nutritious, tastier and more resistant fruit. The watermelon genome sequence was published in the Nov. 25 online version of the journal Nature Genetics.

The researchers discovered that a large portion of disease resistance genes were lost in the domestication of watermelon. With the high-quality watermelon sequence now complete, it is hoped that breeders can now use the information to recover some of these natural disease defenses.

The authors reported that the genome of the domesticated watermelon contained 23,440 genes, roughly the same number of genes as in humans. The group compared the genomes of 20 different watermelons and developed a first-generation genetic variation map for watermelon. This information allowed them to identify genomic regions that have been under human selection, including those associated with fruit color, taste and size.

"Watermelons are an important cash crop and among the top five most consumed fresh fruits; however, cultivated watermelons have a very narrow genetic base, which presents a major bottleneck to its breeding. Decoding the complete genome of the watermelon and resequencing watermelons from different subspecies provided a wealth of information and toolkits to facilitate research and breeding," said Zhangjun Fei, a scientist at the Boyce Thompson Institute for Plant Research at Cornell University, and one of the leaders of this project.

Fei worked with BTI scientists on different aspects of the research, including James Giovannoni, to generate the gene expression data through RNA-sequencing and Lukas Mueller to provide additional analysis to confirm the quality of the genome assembly. Fei also collaborated with Amnon Levi, a research geneticist at the USDA-ARS, U.S. Vegetable Laboratory, Charleston, S.C., on genetic mapping and identifying candidate genes that might be useful to enhance disease resistance in watermelon. The genome sequences of the watermelon are publicly available at the Cucurbit Genomics Database, which is created and maintained by Fei's group.

Believed to have originated in Africa, watermelons were cultivated by Egyptians more than 4,000 years ago, where the fruit was a source of water in dry, desert conditions. They are now consumed throughout the world -- with over 400 varieties in global commercial production. China leads in global production of the fruit, and the United States ranks fourth with more than 40 states involved in the industry. Despite being over 90 percent water, watermelons do contain important nutrients such as vitamins A and C, and lycopene, a compound that gives some fruits and vegetables their red color and appears to reduce the risk of certain types of cancer. Watermelon is also a natural source of citrulline, a non-essential amino acid with various health and athletic performance benefits.

Journal Reference:

1. Shaogui Guo, Jianguo Zhang, Honghe Sun, Jerome Salse, William J Lucas, Haiying Zhang, Yi Zheng, Linyong Mao, Yi Ren, Zhiwen Wang, Jiumeng Min, Xiaosen Guo, Florent Murat, Byung-Kook Ham, Zhaoliang Zhang, Shan Gao, Mingyun Huang, Yimin Xu, Silin Zhong, Aureliano Bombarely, Lukas A Mueller, Hong Zhao, Hongju He, Yan Zhang, Zhonghua Zhang, Sanwen Huang, Tao Tan, Erli Pang, Kui Lin, Qun Hu, Hanhui Kuang, Peixiang Ni, Bo Wang, Jingan Liu, Qinghe Kou, Wenju Hou, Xiaohua Zou, Jiao Jiang, Guoyi Gong, Kathrin Klee, Heiko Schoof, Ying Huang, Xuesong Hu, Shanshan Dong, Dequan Liang, Juan Wang, Kui Wu, Yang Xia, Xiang Zhao, Zequn Zheng, Miao Xing, Xinming Liang, Bangqing Huang, Tian Lv, Junyi Wang, Ye Yin, Hongping Yi, Ruiqiang Li, Mingzhu Wu, Amnon Levi, Xingping Zhang, James J Giovannoni, Jun Wang, Yunfu Li, Zhangjun Fei, Yong Xu. The draft genome of watermelon (Citrullus lanatus) and resequencing of 20 diverse accessions. Nature Genetics, 2012; DOI: 10.1038/ng.2470

Courtesy: ScienceDaily

Brain Imaging Alone Cannot Diagnose Autism

In a column appearing in the current issue of the journal Nature, McLean Hospital biostatistician Nicholas Lange, ScD, cautions against heralding the use of brain imaging scans to diagnose autism and urges greater focus on conducting large, long-term multicenter studies to identify the biological basis of the disorder.
"Several studies in the past two years have claimed that brain scans can diagnose autism, but this assertion is deeply flawed," said Lange, an associate professor of Psychiatry and Biostatistics at Harvard Medical School. "To diagnose autism reliably, we need to better understand what goes awry in people with the disorder. Until its solid biological basis is found, any attempt to use brain imaging to diagnose autism will be futile."
While cautioning against current use of brain imaging as a diagnostic tool, he is a strong proponent of using this technology to help scientists better understand autism. Through the use of various brain imaging techniques, including functional magnetic resonance imaging (MRI), positron emission tomography (PET), and volumetric MRI, Lange points out that researchers have made important discoveries related to early brain enlargement in the disorder, how those with autism focus during social interaction and the role of serotonin in someone with autism.
"Brain scans have led to these extremely valuable advances, and, with each discovery, we are getting closer to solving the autism pathology puzzle," said Lange. "What individuals with autism and their parents urgently need is for us to carry out large-scale studies that lead us to find reliable, sensitive and specific biological markers of autism with high predictive value that allow clinicians to identify interventions that will improve the lives of people with the disorder."
Autism and autism spectrum disorder (ASD) are terms regularly used to describe a group of complex disorders of brain development. This spectrum characterized, in varying degrees, by difficulties in social interaction, verbal and nonverbal communication, and repetitive behaviors, whose criteria have been revised in the newly proposed Diagnostic and Statistical Manual of Mental Disorders (DSM-5). The prevalence of ASD in the United States has increased 78 percent in the last decade, with the Centers for Disease Control estimating that one in 88 children has ASD.'

Journal Reference:

1. Nicholas Lange. Perspective: Imaging autism. Nature, 2012; DOI: 10.1038/491S17a

Courtesy: ScienceDaily

New Therapeutic Target for Alzheimer's Disease Identified

Research led by Chu Chen, PhD, Associate Professor of Neuroscience at LSU Health Sciences Center New Orleans, has identified an enzyme called Monoacylglycerol lipase (MAGL) as a new therapeutic target to treat or prevent Alzheimer's disease.

The study was published online November 1, 2012 in the Online Now section of the journal Cell Reports.

The research team found that inactivation of MAGL, best known for its role in degrading a cannabinoid produced in the brain, reduced the production and accumulation of beta amyloid plaques, a pathological hallmark of Alzheimer's disease. Inhibition of this enzyme also decreased neuroinflammation and neurodegeneration, and improved plasticity of the brain, learning and memory.

"Our results suggest that MAGL contributes to the cause and development of Alzheimer's disease and that blocking MAGL represents a promising therapeutic target," notes Dr. Chu Chen, who is also a member of the Department of Otolaryngology at LSU Health Sciences Center New Orleans.

The researchers blocked MAGL with a highly selective and potent inhibitor in mice using different dosing regimens and found that inactivation of MAGL for eight weeks was sufficient to decrease production and deposition of beta amyloid plaques and the function of a gene involved in making beta amyloid toxic to brain cells. They also measured indicators of neuroinflammation and neurodegeneration and found them suppressed when MAGL was inhibited. The team discovered that not only did the integrity of the structure and function of synapses associated with cognition remain intact in treated mice, but MAGL inactivation appeared to promote spatial learning and memory, measured with behavioral testing.

Alzheimer's disease is a neurodegenerative disorder characterized by accumulation and deposition of amyloid plaques and neurofibrillary tangles, neuroinflammation, synaptic dysfunction, progressive deterioration of cognitive function and loss of memory in association with widespread nerve cell death. The most common cause of dementia among older people, more than 5.4 million people in the United States and 36 million people worldwide suffer with Alzheimer's disease in its various stages. Unfortunately, the few drugs that are currently approved by the Food and Drug Administration have demonstrated only modest effects in modifying the clinical symptoms for relatively short periods, and none has shown a clear effect on disease progression or prevention.

"There is a great public health need to discover new therapies to prevent and treat this devastating disorder," Dr. Chen concludes. The research was supported by grants from the National Institutes of Health. In addition to scientists from LSU Health Sciences Center New Orleans, the research team also included investigators from the Massachusetts Institute of Technology.

Journal Reference:

1. Rongqing Chen, Jian Zhang, Yan Wu, Dongqing Wang, Guoping Feng, Ya-Ping Tang, Zhaoqian Teng, Chu Chen. Monoacylglycerol Lipase Is a Therapeutic Target for Alzheimer's Disease. Cell Reports, 01 November 2012 DOI: 10.1016/j.celrep.2012.09.030 .
2. Courtesy: ScienceDaily

New Finding Gives Clues for Overcoming Tamoxifen-Resistant Breast Cancer

A University of Cincinnati (UC) cancer biology team reports breakthrough findings about specific cellular mechanisms that may help overcome endocrine (hormone) therapy-resistance in patients with estrogen-positive breast cancers, combating a widespread problem in effective medical management of the disease.

Xiaoting Zhang, PhD, and his colleagues have identified a specific estrogen receptor co-activator -- known as MED1 -- as playing a central role in mediating tamoxifen resistance in human breast cancer. The team reports its findings in the Nov. 1, 2012, issue of Cancer Research, a scientific journal of the American Association for Cancer Research.

According to the National Cancer Institute, nearly 227,000 women are diagnosed with breast cancer annually in the United States. About 75 percent have estrogen-positive tumors and require adjuvant hormone therapy such as tamoxifen, a drug that works by interfering with estrogen's ability to stimulate breast cancer cell growth.

Despite advances in hormone therapy drugs, cancer surveillance research has shown that 50 percent of patients will develop resistance to the drug and experience a cancer relapse.

The hormones estrogen and progesterone can stimulate the growth of some breast cancers. Hormone therapy is used to stop or slow the growth of these tumors. Hormone-sensitive (i.e., positive) breast cancer cells contain specific proteins known as hormone receptors that become activated once hormones bind to them, leading to cancer growth.

Based on new findings, UC Cancer Institute scientists believe that tamoxifen resistance may be driven by a novel molecular "crosstalk" point between the estrogen and HER2 (human epidermal growth factor receptor 2) signaling pathways.

Testing in both pre-clinical models and human breast cancer tissue samples showed that MED1 co-amplifies and co-expresses with HER2, a gene that has an increased presence in 20-30 percent of invasive human breast cancer and plays a major role in tamoxifen resistance.

HER2 over-expression led to MED1 activation while reduction of MED1 caused breast cancer cells that were otherwise tamoxifen-resistant to respond and stop dividing. Further mechanistic studies showed that HER2 activation of MED1 resulted in the recruitment of co-activators instead of co-repressors by tamoxifen-bound estrogen receptor. This, explains Zhang, drives expression of not only traditional estrogen receptor-positive cancer target genes, but also HER2 and those estrogen receptor target genes abnormally activated by HER2.

"Together, these findings suggest this 'crosstalk' could play a central role in mediating tamoxifen resistance in human breast cancer, especially because recent published data also indicated that high MED1 expression levels correlate with poor treatment outcome and disease-free survival of patients who underwent endocrine therapy," explains Zhang, an assistant professor of cancer biology at the UC College of Medicine and breast cancer researcher with the UC Cancer Institute.

"We are currently utilizing RNA-based nanotechnology to target MED1 in an effort to simultaneously block both estrogen and HER2 pathways to overcome endocrine-resistant breast cancer."

UC study collaborators include cancer biologists Jiajun Cui, PhD, Katherine Germer, MD, Shao-chun Wang, PhD; environmental health researcher Tianying Wu, PhD; and pathologist Jiang Wang, MD. Qianben Wang, PhD of the Ohio State University College of Medicine, and Jia Luo, PhD, of the University of Kentucky, also contributed to this study.

The study was supported with start-up funding from the UC Cancer Institute, Ride Cincinnati/Marlene Harris Pilot Grant, Susan G. Komen for the Cure Foundation and the Center for Clinical and Translational Science and Training -- home to UC's institutional Clinical and Translational Science Award program grant from the National Institutes of Health.

Journal Reference:

1. J. Cui, K. Germer, T. Wu, J. Wang, J. Luo, S.-c. Wang, Q. Wang, X. Zhang. Cross-talk between HER2 and MED1 Regulates Tamoxifen Resistance of Human Breast Cancer Cells. Cancer Research, 2012; 72 (21): 5625 DOI: 10.1158/0008-5472.CAN-12-1305

 Courtesy: ScienceDaily