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May 4, 2018
Digest

Lack of Sleep May Be Linked to Risk Factor for Alzheimer’s Disease

The study is among the first to demonstrate that sleep may play an important role in human beta-amyloid clearance.
The study is among the first to demonstrate that sleep may play an important role in human beta-amyloid clearance.

IMAGE: DIANE39/ISTOCK

Losing just one night of sleep led to an immediate increase in beta-amyloid, a protein in the brain associated with Alzheimer’s disease, according to a small, new study by researchers at NIH. In Alzheimer’s disease, beta-amyloid proteins clump together to form amyloid plaques, a hallmark of the disease.

While acute sleep deprivation is known to elevate brain beta-amyloid levels in mice, less is known about the impact of sleep deprivation on beta-amyloid accumulation in the human brain. The study is among the first to demonstrate that sleep may play an important role in human beta-amyloid clearance.

“This research provides new insight about the potentially harmful effects of a lack of sleep on the brain and has implications for better characterizing the pathology of Alzheimer's disease,” said Dr. George Koob, director of the National Institute on Alcohol Abuse and Alcoholism, which funded the study. The work was reported Mar. 29 in the Proceedings of the National Academy of Sciences

Beta-amyloid is a metabolic waste product present in the fluid between brain cells. In Alzheimer’s disease, beta-amyloid clumps together to form amyloid plaques, negatively impacting communication between neurons.

In Alzheimer’s disease, beta-amyloid is estimated to increase about 43 percent in affected individuals relative to healthy older adults. It is unknown whether the increase in beta-amyloid in the study participants would subside after a night of rest.

The researchers also found that study participants with larger increases in beta-amyloid reported worse mood after sleep deprivation.

Genetically Altered Broadly Neutralizing Antibodies Protect Monkeys from HIV-like Virus

Two genetically modified broadly neutralizing antibodies (bNAbs) protected rhesus macaques from an HIV-like virus, report scientists at NIAID. After introducing genetic mutations into two potent HIV bNAbs, researchers prepared intravenous infusions of two bNAbs known as 3BNC117-LS and 10-1074-LS.Single infusions of each modified bNAb protected 2 groups of 6 monkeys each against weekly exposures to simian-human immunodeficiency virus (SHIV) for up to 37 weeks, compared with a median of 3 weeks in 12 monkeys receiving no antibody. SHIV is a manmade virus commonly used in HIV nonhuman primate studies.

The study, reported in Nature Medicine and led by Dr. Malcolm Martin, chief of NIAID’s Laboratory of Molecular Microbiology, also assessed the efficacy of injecting a combination of both modified bNAbs into 6 monkeys subcutaneously—a route of administration considered more feasible in resource-limited clinical settings. This bNAb mixture, administered at a three-fold lower concentration than the individual antibodies infused intravenously, protected this group of monkeys for a median of 20 weeks.

Martin’s team demonstrated that the genetic mutations introduced into the original bNAbs increased their durability following injection and led to the extended period of protection. The mutations did not affect the way the bNAbs bound to the virus but extended their activity following injection. This extended activity in the body could theoretically allow for longer periods between clinical visits to receive the prevention modality, if proven safe and effective in humans.

This approach joins other candidate drugs and biomedical technologies that aim to provide long-term protection against HIV in the absence of an HIV vaccine.  Among ongoing studies are two large phase 3 trials in Africa and the Americas known as the AMP Studies, for antibody-mediated prevention.

Given the success of the modified bNAbs in nonhuman primates, researchers will next test their safety and efficacy in people. A phase 1 clinical trial to evaluate 3BNC117-LS already has begun.

Epstein-Barr Virus Protein Can ‘Switch on’ Risk Genes for Autoimmune Diseases

When infection first occurs in adolescence or young adulthood, EBV can lead to a syndrome of infectious mononucleosis.
When infection first occurs in adolescence or young adulthood, EBV can lead to a syndrome of infectious mononucleosis.

IMAGE: DIGITAL VISION/THINKSTOCK

Infection with Epstein-Barr virus (EBV), the cause of infectious mononucleosis, has been associated with subsequent development of systemic lupus erythematosus and other chronic autoimmune illnesses, but the mechanisms behind this association have been unclear. Now, a novel computational method shows that a viral protein found in EBV-infected human cells may activate genes associated with increased risk for autoimmunity. Scientists supported by NIAID reported their findings Apr. 16 in Nature Genetics.

“Many cases of autoimmune illness are difficult to treat and can result in debilitating symptoms. Studies like this are allowing us to untangle environmental and genetic factors that may cause the body’s immune system to attack its own tissues,” said NIAID director Anthony Fauci.  “A better understanding of the complex causes of autoimmunity promises to lead to better treatment and prevention options.”

EBV infection is nearly ubiquitous in the human population worldwide. Most people acquire EBV in early childhood, experience no symptoms or only a brief, mild cold-like illness, and remain infected throughout their lives while remaining asymptomatic. When infection first occurs in adolescence or young adulthood, EBV can lead to a syndrome of infectious mononucleosis characterized by prolonged fever, sore throat, swollen lymph nodes and fatigue. This syndrome, also known as “mono” or the “kissing disease,” generally resolves with rest and only rarely causes serious complications.

When EBV infects human immune cells, a protein produced by the virus—EBNA2—recruits human proteins called transcription factors to bind to regions of both the EBV genome and the cell’s own genome. Together, EBNA2 and the human transcription factors change the expression of neighboring viral genes. 

In the current study, the researchers found that EBNA2 and its related transcription factors activate some of the human genes associated with the risk for lupus and several other autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, juvenile idiopathic arthritis and celiac disease.

“Because EBV is most often encountered in early childhood, avoiding infection is practically impossible,” said Dr. Daniel Rotrosen, director of NIAID’s Division of Allergy, Immunology and Transplantation. “However, now that we understand how EBV infection may contribute to autoimmune diseases in some people, researchers may be able to develop therapies that interrupt or reverse this process.”

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