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Archive - Jul 21, 2015

New Study Directly Links Beta-CTF Protein to Pathology of Alzheimer’s Disease Development; Protein Acts at Earliest Stage of the Disease

A recent study conducted at the Nathan S. Kline Institute for Psychiatric Research (NKI) and the NYU Langone Medical Center implicates a new culprit in Alzheimer's disease (AD) development. The research reveals that C-terminal fragment beta (beta-CTF) -- the precursor of the amyloid beta (Aß) peptide -- acts at the earliest stage of Alzheimer's to initiate a range of abnormalities leading to the loss of groups of neurons critical for memory formation. Results from the study were published online on July 21, 2015 in the journal, Molecular Psychiatry, and the article has been selected for an issue cover. The article is titled “De Novo Deleterious Genetic Variations Target a Biological Network Centered on Aβ Peptide in Early-Onset Alzheimer Disease.” The recent study findings involving beta-CTF have significant implications for treatment strategies and furthering the course of Alzheimer's drug development. Presently, the most common strategy for treating AD is targeting the amyloid beta peptide, which has had modest success in clinical trials. Findings from this new research suggest that drugs that may reduce beta-CTF levels as well as beta-amyloid, such as the class of BACE1 inhibitors currently under development, may help slow or stop the progression of AD. Beta-CTF is formed during endocytosis, the process by which cells absorb nutrients and sample various materials from the outside environment. It has been known for some time that abnormalities of endocytosis develop very early in AD, well before clinical symptoms, and that variant forms of genes controlling endocytosis are frequently implicated as risk factors promoting Alzheimer's.

Elevating cAMP Levels in Nucleus Accumbens Region of Brain Improves Stress Response; Signaling Molecule May Be Therapeutic Target for Depression Treatment

Increasing the levels of a signaling molecule found in the brain can positively alter response to stress, revealing a potential new therapeutic target for treatment of depression, University of Texas (UT) Southwestern Medical Center researchers said. The study, which appears in Nature Neuroscience, determined that elevating levels of the molecule cyclic adenosine monophosphate (cAMP) in brain cells had a positive impact on stress-induced behaviors in mice. Other studies have shown that patients with major depressive disorder often have impaired cAMP signaling and that chronic anti-depressant treatments often turn on this signaling system. The title of the current article is “The Role of Ventral Striatal cAMP Signaling in Stress-Induced Behaviors.” "This is the first step in the development of a treatment for patients with major depressive disorder using this new strategy," said senior author Dr. James Bibb, Professor of Psychiatry, and Neurology and Neurotherapeutics at UT Southwestern. Major depressive disorder (MDD) may be triggered or exacerbated by severe or chronic stress. Depression affects more than 120 million people worldwide. Between 20 percent to 40 percent of people with depression are not helped by existing therapies, highlighting the need for new treatments and approaches. The study was supported by the Center for Depression Research and Clinical Care at UT Southwestern. The Center, established with a $5 million lead gift from the Hersh Foundation earlier this year, combines basic research, translational clinical research in genetics, functional brain imaging, and treatment research across the entire age span, with a special focus on treatment of resistant, chronic, or recurrent depression.

Diabetes Drug Class (Glitazones) May Reduce Risk of Parkinson’s

A type of drug used to treat diabetes may reduce the risk of developing Parkinson's disease, according to a new study published online on July 21, 2015 in the open-acces journal PLOS Medicine. The article is titled “Glitazone Treatment and Incidence of Parkinson’s Disease among People with Diabetes: A Retrospective Cohort Study.” The research, led by the London School of Hygiene & Tropical Medicine, found that diabetes patients taking glitazone anti-diabetes drugs (either rosiglitazone or pioglitazone) had a 28% lower incidence of Parkinson's disease than people taking other treatments for diabetes who had never taken glitazones. Glitazones are a class of drug that activate the peroxisome proliferation-activated gamma (PPAR-gamma) receptor, which is found inside cells in many different body organs. PPAR-gamma receptor activation by glitazones leads to reduced insulin resistance, which has been useful for treating people with diabetes, but the receptor has many other functions that have not been studied as thoroughly in humans. Although the potential effect of glitazones on Parkinson's disease had previously been demonstrated in rodents and in vitro, the authors of the PLOS article believe this is the first study to show the relationship between glitazone use and incidence of Parkinson's disease in humans. The study, which was funded by The Michael J Fox Foundation for Parkinson's Research, looked at more than 160,000 diabetes patients in the UK. Researchers used electronic health records from the UK Clinical Practice Research Datalink to match 44,597 glitazone users with 120,373 people using other anti-diabetic drugs. Glitazone users were matched by age, sex, GP practice, and diabetes treatment stage with up to five users of other diabetic treatments.

Zone in with Zon: RNA Is Present in Normal Genomic DNA and May Play Functional Role; Human Genomic DNA “Misincorporates” Over 1 Million Ribonucleotides Per Replication Cycle

In a stunning discussion in his most recent blog, posted on July 20, 2015, eminent nucleic acid chemist Jerry Zon, Ph.D., describes recent findings that a significant amount of RNA is present in normal DNA. In fact, Dr. Zon said that ribonucleotide "misincorporation" represents the most common type of replication error and occurs quite frequently in normal cells. Even more surprising, Dr. Zon said, there seem to be some positive consequences to having “some Rs among the Ds,” so to speak. Replication fidelity is, of course, hugely important and a key facet of replication fidelity, Dr. Zon noted, is the discrimination of the sugar backbone of the nucleic acid strand [ribose nucleic acid triphosphates (rNTPs) versus deoxyribose dNTPs] so that the correct sugar NTP is chosen. The two classes have very similar structures, differing by the added presence of only a single oxygen in the ribo versus deoxy forms. Hence, polymerases are challenged, Dr. Zon said, with distinguishing between the two types of nucleotides. Otherwise they risk inserting the incorrect substrate into the newly replicated nucleic acid strand. Consequently, sugar discrimination is a very important trait for DNA polymerases in this environment enriched for rNTPs over dNTPs. Recent studies of human polymerase delta found that in reactions containing nucleotide concentrations similar to those estimated to be present in mammalian cells, there was one rNTP incorporated per ∼2000 dNTPs—a result which predicts that human polymerase delta may introduce >1,000,000 rNMPs into the genome per replication cycle. Earlier results in analogous studies using yeast, led investigators to state that “[t]he idea that rNMP incorporation into DNA may be more common than previously appreciated leads one to wonder about possible benefits of rNMP incorporation," Dr. Zon reported.

Successful Treatment of Eczema Using Rheumatoid Arthritis Drug Reported by Yale Physicians; Same Drug (Tofacitinib Citrate) Previously Also Found Useful in Vitiligo and Alopecia Areata

Researchers at Yale School of Medicine have successfully treated patients with moderate to severe eczema using a rheumatoid arthritis drug recently shown to reverse two other disfiguring skin conditions, vitiligo and alopecia areata. The study is evidence of a potential new era in eczema treatment, they report. The research findings were published online on July 17, 2015 in the Journal of the American Academy of Dermatology. The article is titled “Treatment of Recalcitrant Atopic Dermatitis with the Oral Janus Kinase Inhibitor Tofacitinib Citrate.” Eczema (atopic dermatitis) is a chronic condition that causes severe itching and leaves the skin red and thickened. It can adversely affect sleep and quality of life. Standard treatments, such as steroid creams and oral medicines, commonly fail to relieve symptoms in patients with moderate to severe eczema. Based on current scientific models of eczema biology, Yale Assistant Professor of Dermatology Brett King, M.D., Ph.D., hypothesized that a drug already approved for rheumatoid arthritis, tofacitinib citrate, would interrupt the immune response that causes eczema. The drug is an inhibitor of Janus kinase. In the new study, Dr. King and his colleagues report that treatment with the drug led to dramatic improvement in six patients with moderate to severe eczema who had previously tried conventional therapies without success. During treatment, all six patients reported significant reduction in itching, as well as improved sleep. The redness and thickening of the skin diminished, also. "These individuals were not only very happy with the results, they also expressed a tremendous sense of relief at being comfortable in their skin for the first time in many years," Dr. King said. Dr.