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Archive - Oct 5, 2015

Depletion of Microglia and Inhibition of Exosome Synthesis Halt Tau Propagation, a Hallmark of Alzheimer’s Disease; Scientists Believe Microglia Take Up Tau-Containing Fibrils and Spread Tau to Other Cells via Exosomes

For the first time, researchers have determined how toxic tau fibrils spread by the help of brain immune cells called microglia (image) during the early stages of Alzheimer's disease (AD). The discovery of this new pathway may lead to a therapeutic target for AD, one that has not been previously identified. In patients with AD, the gradual decline in cognitive function and loss of neurons is preceded by the harmful build-up of the protein tau in the brain. Tau accumulates as tiny fibers called fibrils in brain regions that are critical for learning and memory. But how they spread during the early stage of AD was previously unknown. "This study found that tau can be carried from one neuron to another by the brain's own immune cells in a process that may contribute to the progression of AD," explained corresponding author Tsuneya Ikezu, M.D., Ph.D., Professor of Pharmacology & Experimental Therapeutics and Neurology at Boston University School of Medicine. The findings were published online on October 5, 2015 in the journal Nature Neuroscience. The article is titled “Depletion of Microglia and Inhibition of Exosome Synthesis Halt tau Propagation.” One important function of microglia is to constantly survey the brain environment for sensing and clearing damage and infection. For this purpose, microglia actively engulf dead cells, debris, inactive synapses, or even unhealthy neurons. Then, to transfer signaling molecules and present antigen to activate an immune response, microglia release nano-scale particles called exosomes, which can be taken up by other cells. The researchers hypothesize that in an early stage of AD brain, microglia may spread the harmful protein tau by taking up tau-containing fibrils and then releasing them via the exosomes, which can be absorbed by nearby neurons.

Exosomes Mediate Acquisition of Disease Phenotypes by Normal WT Cells in Tuberous Sclerosis

Dr. Magdalena Karbowiscek, of Texas Tech University Health Science Center, and colleagues from Brigham and Women’s Hospital and Harvard Medical School, and the Fox Chase Cancer Center, report that extracellular vesicles such as exosomes derived from tuberous sclerosis 1 (Tsc1)-null cells (i.e., cells lacking the Tsc1 gene) transform the phenotypes of neighboring wild-type cells in vivo in such a way that these cells become functionally similar to Tsc1-null cells. The researchers noted that loss of Tsc1 in the mouse neural tube increases the number of the wild-type neuronal progenitors, which is followed by the precocious and transient acceleration of neuronal differentiation of these cells. The group’s experiments indicated that the mechanisms regulating these changes involve the exosomal delivery of exosomal shuttle Notch1 and Rheb esRNA and component of γ-secretase complex presenilin 1 from Tsc1-null cells to wild-type cells leading to the activation of Notch and Rheb signaling in the recipient cells. The scientists expressed their belief that these exosome-mediated mechanisms may also operate in the cells of angiomyolipoma (AML), which develops as a result of mutations in TSC1/TSC2 genes in TSC patients. They reached this conclusion because they observed the reactivation of mammalian target of rapamycin and Notch pathways, driven by the delivery of Rheb and Notch1 esRNA, in AML cells depleted of Rheb that were treated with the exosomes purified from AML cells with the constitutively high Rheb levels. The scientist pointed out that functions of extracellular vesicles including exosomes in the pathogenesis of tuberous sclerosis complex (TSC) had not previously been studied. This new report was published online on October 5, 2015 in the journal Oncogene.

Experimental Gene-Based Biologic (VB-111) Almost Doubles Survival Time for Those with Recurrent Glioblastoma (8 Months to 15 Months) in Phase 2 Study

Intravenous administration of a novel, gene-based, anti-angiogenic biologic (VB-111) essentially doubled the overall survival of patients with recurrent glioblastoma compared to the current standard of care, a researcher, at the Cancer Therapy & Research Center (CTRC) at The University of Texas Health Science Center (UTHSC) at San Antonio said in an October 1, 2015 press release from the UTHSC at San Antonio. Glioblastoma is an aggressive brain cancer that kills two-thirds of patients within five years. A patient's outlook with recurrence of the disease is considered to be weeks or months. CTRC Medical Oncologist Andrew J. Brenner, M.D., Ph.D., Associate Professor in Medicine, Neurology, and Neurosurgery at the UT Health Science Center School of Medicine, presented final results of a Phase 2 clinical research study that evaluated VB-111, in continuous and intermittent doses and in comparison to the treatment standard, the chemotherapy Avastin™. Patients receiving VB-111 survived 15 months on average, compared to 8 months on average for patients receiving Avastin alone. The CTRC and three other centers enrolled 62 patients with recurrent glioblastoma for the studies. "These are the patients with the most serious cases, whose glioblastoma has recurred after surgery and who, as a result, have a very short life expectancy," Dr. Brenner said. Dr. Brenner, principal investigator for the studies, presented the results this week at the European Cancer Congress 2015 meeting in Vienna, Austria (September 25-29). "In addition to the benefit in overall survival, VB-111 was safe and well-tolerated in the patients, and proved to be effective both as a single therapy for recurrent glioblastoma, and in combination with Avastin," he said.

2015 Nobel Prize for Physiology or Medicine Awarded for Work to Treat Parasitic Diseaeses—Including River Blindness, Elephantiasis, and Malaria—Discoveries of Avermectin and Artemisinin Have Changed the World

The Nobel Assembly at Karolinska Institutet in Sweden has today (Monday, October 5) awarded the 2015 Nobel Prize in Physiology or Medicine, with one half going jointly to William C. Campbell, Ph.D., and Satoshi Ōmura, Ph.D., for their discoveries concerning a novel therapy against infections caused by roundworm parasites, and the other half going to Youyou Tu, for her discoveries concerning a novel therapy against malaria diseases caused by parasites that have plagued humankind for millennia and constitute a major global health problem. In particular, parasitic diseases affect the world’s poorest populations and represent a huge barrier to improving human health and wellbeing. This year’s Nobel Laureates have developed therapies that have revolutionized the treatment of some of the most devastating parasitic diseases. Dr. Campbell and Dr. Ōmura discovered a new drug, avermectin, the derivatives of which have radically lowered the incidence of river blindness and lymphatic filariasis (often called elephantiasis), as well as showing efficacy against an expanding number of other parasitic diseases. Dr. Tu discovered artemisinin, a drug that has significantly reduced the mortality rates for patients suffering from malaria. These two discoveries have provided humankind with powerful new means to combat these debilitating diseases that affect hundreds of millions of people annually. The consequences in terms of improved human health and reduced suffering are immeasurable. Parasites cause devastating diseases We live in a biologically complex world, which is populated not only by humans and other large animals, but also by a plethora of other organisms, some of which are harmful or deadly to us.