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Four months of multi-drug therapy that included rifapentine and moxifloxacin treated active tuberculosis (TB) as effectively as the standard six-month regimen in a multinational study, cutting treatment time by a third. Coauthors including Marc Weiner, MD, of The University of Texas Health Science Center at San Antonio, reported the findings May 6 in the New England Journal of Medicine.
“Shorter treatment would be easier for people to complete without missing doses, and ultimately may be cost-effective,” said Dr. Weiner, associate professor in the health science center’s Joe R. and Teresa Lozano Long School of Medicine and infectious diseases physician in the South Texas Veterans Health Care System. “These drugs have been around for more than 20 years and are widely available. This study demonstrates a new and feasible way to treat what is a global pandemic of tuberculosis.”
Risk of spread with active disease
According to the World Health Organization, a quarter of the world’s population has latent TB, which means the people are infected but don’t have signs and symptoms of illness. “However, with active disease, people become sicker and TB can more easily spread to other people,” Dr. Weiner said. Participants in the newly reported trial all had active TB disease.
The standard TB regimen consists of four drugs — rifampin, isoniazid, pyrazinamide and ethambutol. It is a successful therapy; approximately 95% of recipients are cured of TB disease with this treatment. The rifapentine-moxifloxacin regimen, while being meaningfully shorter in treatment duration, was non-inferior to and was safe and well tolerated compared to the standard therapy, Dr. Weiner said.
The study enrolled more than 2,500 participants in 13 countries, including nearly 200 people living with HIV (human immunodeficiency virus). HIV greatly increases the risk of patients with latent TB infection progressing to active TB disease. Other risk factors for progression to active disease include recent infection, diabetes and chronic renal disease. Participants were registered at 34 trial sites in Brazil, China (Hong Kong), Haiti, India, Kenya, Malawi, Peru, South Africa, Thailand, Uganda, the United States, Vietnam and Zimbabwe.
The study population was divided randomly into a group that received the standard regimen, and two experimental multidrug arms, one with rifapentine and another with rifapentine and moxifloxacin. Participants were followed for up to 18 months, and the primary outcome was survival free of tuberculosis at a year after study randomization.
Cost savings will be evaluated, Dr. Weiner said, as a generic version of rifapentine is being developed. “However, drug costs are just one component of the expenses of active TB treatment,” he said. “In general, TB drugs are taken daily, and five days a week, a health care provider observes the individual taking the medicine. In the U.S., there is substantial cost for personnel to administer this directly observed therapy to patients.”
COVID-19 pandemic complicates the TB problem
India, Indonesia, the Philippines and South Africa have high numbers of people with active TB. The Stop TB Partnership has suggested that because of a delay in diagnosis and treatment of TB in high-burden countries, the COVID-19 pandemic could cause an additional 6.3 million TB cases worldwide between 2020 and 2025.
TB is an infection of Mycobacterium tuberculosis (MTB). This bacterium usually first infects the lungs after airborne transmission. It is encased in a granuloma, a small area of inflammation, and for months or years, the body may be able to contain the infection. However, if the immune system weakens or something else affects the granuloma, MTB proliferates, and the patient usually develops signs and symptoms that can include fever, cough with or without sputum production, weight loss or fatigue.

Researchers have found that the inclusion of a third drug to commonly used dual-drug inhalers can reduce asthma exacerbations and improve control over the disease in children, adolescents, and adults with moderate-to-severe asthma.
A team from McMaster University and The Research Institute of St. Joe’s Hamilton announced their findings from a systematic review and meta-analysis. Data from 20 randomized controlled trials, which included a total of almost 12,000 patients, were analyzed in the study.
Dual-drug inhalers used to treat asthma typically contain an inhaled corticosteroid (ICS) to reduce inflammation, as well as a long-acting beta-adrenoceptor agonist (LABA) that acts as a bronchodilator. High-certainty evidence showed that the inclusion of a third drug to ICS-LABA combination therapy, known as a long-acting muscarinic antagonist (LAMA), reduced severe asthma exacerbations and slightly improved asthma control without an increase in adverse events. Previously, the benefits and harms of adding a LAMA to ICS-LABA therapy for asthma treatment were unclear and based off of only 1300 patients — mainly adults — leading to weak recommendations in treatment guidelines.
“Our findings provide clear, high-quality evidence on the benefits and harms of triple therapy that will inform asthma care and should prompt revision of current asthma guidelines,” said Dr. Derek Chu, lead author of the study.
Dr. Chu is a clinical scholar in the Departments of Medicine and Health Research Methods, Evidence, and Impact (HEI) at McMaster University and an affiliate of The Research Institute of St. Joe’s Hamilton.
“If we can reach optimal control of patients’ asthma and reduce asthma exacerbation rates through the LAMA add-on therapy, patients may be able to avoid other treatments that carry a higher risk of adverse events, such as oral corticosteroids, or therapies that are substantially more expensive, such as biologics,” said Lisa Kim, a clinical scholar in the Department of Medicine at McMaster and co-author of the study.
Inhaled LAMAs are currently available in separate inhalers or as three-in-one inhalers that also contain an ICS and LABA. According to the study, both approaches to administering the third drug work similarly.
More than 8 percent of Canadians over the age of 12 have been diagnosed with asthma, making it the most common chronic condition among children. The disease is characterized by constriction of the bronchial tubes, which impedes air flow to and from the lungs. Symptoms can include coughing or wheezing attacks, shortness of breath, chest tightness, and more. The exact causes of asthma may vary, adding to treatment complexity.
The study was published in the Journal of the American Medical Association (JAMA) in coordination with a presentation by the authors at the Advances in Asthma Therapies symposium. The symposium is part of the American Thoracic Society’s annual conference — ATS 2021 — which is being held virtually this year.
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By mapping its genetic underpinnings, researchers at University of California San Diego School of Medicine have identified a predictive causal role for specific cell types in type 1 diabetes, a condition that affects more than 1.6 million Americans.
The findings are published in the May 19, 2021 online issue of Nature.
Type 1 diabetes is a complex autoimmune disease characterized by the impairment and loss of insulin-producing pancreatic beta cells and subsequent hyperglycemia (high blood sugar), which is damaging to the body and can cause other serious health problems, such as heart disease and vision loss. Type 1 is less common than type 2 diabetes, but its prevalence is growing. The U.S. Centers for Disease Control and Prevention projects 5 million Americans will have type 1 diabetes by 2050. Currently, there is no cure, only disease management.
The mechanisms of type 1 diabetes, including how autoimmunity is triggered, are poorly understood. Because it has a strong genetic component, numerous genome-wide association studies (GWAS) have been conducted in recent years in which researchers compare whole genomes of persons with the same disease or condition, searching for differences in the genetic code that may be associated with that disease or condition.
In the case of type 1 diabetes, identified at-risk variants have largely been found in the non-coding regions of the genome. In the Nature study, senior author Kyle Gaulton, PhD, an assistant professor in the Department of Pediatrics at UC San Diego School of Medicine, and colleagues integrated GWAS data with epigenomic maps of cell types in peripheral blood and the pancreas. Epigenomic mapping details how and when genes are turned on and off in cells, thus determining the production of proteins vital to specific cellular functions.
Specifically, researchers performed the largest-to-date GWAS of type 1 diabetes, analyzing 520,580 genome samples to identify 69 novel association signals. They then mapped 448,142 cis-regulatory elements (non-coding DNA sequences in or near a gene) in pancreas and peripheral blood cell types.
“By combining these two methodologies, we were able to identify cell type-specific functions of disease variants and discover a predictive causal role for pancreatic exocrine cells in type 1 diabetes, which we were able to validate experimentally,” said Gaulton.
Pancreatic exocrine cells produce enzymes secreted into the small intestine, where they help digest food.
Co-author Maike Sander, MD, professor in the departments of Pediatrics and Cellular and Molecular Medicine at UC San Diego School of Medicine and director of the Pediatric Diabetes Research Center, said the findings represent a major leap in understanding the causes of type 1 diabetes. She described the work as “a landmark study.”
“The implication is that exocrine cell dysfunction might be a major contributor to disease. This study provides a genetic roadmap from which we can determine which exocrine genes may have a role in disease pathogenesis.”
First author Joshua Chiou, PhD, a recent graduate of the Biomedical Sciences graduate program at UC San Diego added: “Understanding how type 1 diabetes originates at the cellular level is a critical step in finding treatments for reversing its course and, ultimately, preventing the disease altogether.”
Co-authors include: Ryan J. Geusz, Mei-Lin Okino, Jee Yun Han, Michael Miller, Rebecca Melton, Elisha Beebe, Paola Benaglio, Serina Huang, Katha Korgaonkar, and Sebastian Preissl all at UC San Diego; David U. Gorkin, Emory University; and Sandra Heller and Alexander Kleger, Ulm University, Germany.

A new trial has been announced that will look at whether a booster vaccine will protect against new variants.All seven vaccines the UK has ordered will be tested on working-age people and over-75s as part of a randomised trial. The findings will help vaccine advisers decide if re-vaccinating some people in the autumn is necessary.The study, which costs £19.3 million, is being funded by the government and led by the University Hospital Southampton NHS Foundation Trust.Speaking at Downing Street, the Health Secretary, Matt Hancock, said the trial would help to ensure “vaccines stay ahead of the virus.”

He was a New York psychiatrist who went to Hollywood to help lay down guidelines for sex and violence in films. Not everyone was pleased.Dr. Aaron Stern, a psychiatrist who as head of Hollywood’s movie rating board in the early 1970s established himself as filmgoers’ sentry against carnal imagery and violence, died on April 13 in Manhattan. He was 96.His death, in a hospital, was confirmed by his stepdaughter Jennifer Klein.An author, professor and management consultant who had always been intrigued by corporate ladder-climbing, he jousted with egocentric studio executives, producers, directors and actors — providing ample grist for his 1979 book, “Me: The Narcissistic American.”From 1971 to 1974, Dr. Stern was the director of the self-policing Classification and Rating Administration of the Motion Picture Association of America, which had been founded only a few years earlier. It replaced the rigidly moralistic Production Code imposed in the early 1930s and censoriously administered by Will H. Hays, a Presbyterian deacon and former national Republican Party chairman.The new ratings board, which was struggling to gain credibility when it began, graded films by letter to let moviegoers know in advance how much violence, sexuality and foul language to expect on the screen.The board’s decision that a film merited a rating of R, or restricted, might lure more adults, but would immediately eliminate the pool of unchaperoned moviegoers under 17; an X rating would bar anyone under 17 altogether.Dr. Stern recast the PG (parental guidance) category to include a warning that “some material might not be suitable for pre-teenagers.” He also tried, but failed, to abolish the X rating — on the grounds, he told The Los Angeles Times in 1972, that it wasn’t the job of the Motion Picture Association to keep people out of theaters. (The X rating was changed to NC-17 in 1990, but its meaning remained unchanged.)Not until last year, with the release of “Three Christs,” a movie about hospitalized patients who believed they were Jesus, did Dr. Stern receive a screen credit (he was one of the film’s 17 producers). But the lack of onscreen recognition belied the power he wielded as director of the board, which privately screened films and then voted on which letter rating to impose.Even some critics gave the new letter-coded classification the benefit of the doubt in the early 1970s, agreeing that its decisions, in contrast to those of the old Production Code, were becoming more grounded in sociology than theology. Still, two young members of the rating board, appointed under a one-year fellowship, wrote a scathing critique of its methodology that was published in The New York Times in 1972.They accused Dr. Stern of megalomaniacal meddling, editing scripts before filming and cropping scenes afterward, and of tolerating gratuitous violence but being puritanical about sex. They claimed, among other things, that he had warned Ernest Lehman, the director of “Portnoy’s Complaint” (1972), that focusing on masturbation in the film version of Philip Roth’s novel risked an X rating.“You can have a love scene, but as soon as you start to unbutton or unzip you must cut,” Dr. Stern was quoted as saying in The Hollywood Reporter about sex in movies.The Times article prompted letters praising Dr. Stern from several directors, including Mr. Lehman, who said that Dr. Stern’s advice had actually improved his final cut of “Portnoy’s Complaint.” To which The Times film critic Vincent Canby sniffed, “If Mr. Lehman was really influenced by Dr. Stern’s advice two years ago, then he should sue the doctor for malpractice.”Dr. Stern argued that the rating system, while imperfect, served several goals. Among other things, he said, it fended off even more restrictive definitions of obscenity by Congress, the courts and localities; and it warned people away from what they might find intrusive as mores evolved and society became more accepting.“Social growth should make the rating system more and more obsolete,” he told The Los Angeles Times.Members of the movie rating board privately screened films and then voted on which letter rating to impose. An R rating might lure more adults, but would immediately eliminate the pool of unchaperoned moviegoers under 17.Motion Picture Association of AmericaAaron Stern was born on March 26, 1925, in Brooklyn to Jewish immigrants from Eastern Europe. His father, Benjamin Israel Stern, was a carpenter, and his mother, Anna (Fishader) Stern, was a homemaker. Raised in Bensonhurst and Sheepshead Bay, he was the youngest of three children and the only one born in the United States.After graduating from Brooklyn College in 1947, he earned a master’s degree in psychological services and a doctorate in child development from Columbia University, and a medical degree from the State University of New York’s Downstate Health Sciences University.In addition to his stepdaughter Ms. Klein, he is survived by his wife, Betty Lee (Baum) Stern; two children, Debra Marrone and Scott Stern, from his first marriage, which ended in divorce; two other stepchildren, Lauren Rosenkranz and Jonathan Otto; and 13 grandchildren.Dr. Stern was introduced to Jack Valenti, the president of the Motion Picture Association, by a neighbor in Great Neck, N.Y., Robert Benjamin, an executive at United Artists. He initially began reviewing films for the association and was recruited by Mr. Valenti to run the ratings administration in mid-1971.He left there early in 1974 to join Columbia Pictures Industries and eventually returned from Los Angeles to New York, where he revived his private practice. He also taught at Yale, Columbia, New York University and the University of California, Los Angeles, and he served as chief operating officer of Tiger Management, a hedge fund, and a trustee of the Robertson Foundation.A veteran educator at NewYork-Presbyterian/Columbia University Irving Medical Center, Dr. Stern, with his wife, donated $5 million in 2019 to endow a professorship and fellowship at Weill Cornell Medicine to treat patients with pathological personality disorders. The gift was in gratitude for the care he had received during a medical emergency.Dr. Stern had been interested in narcissism even before he went to Hollywood, but his experience there proved inspirational.In “Me: The Narcissistic American,” he wrote that babies are born narcissistic, unconcerned about whom they awaken in the middle of the night, and need to be disciplined as they mature to take others into account.“When narcissism is for survival, as with the infant and the founding of a country,” he wrote, “it is not as destructive as when one is established, successful and affluent.”In 1981, Mr. Valenti told The Times that he had “made a mistake of putting a psychiatrist in charge” of the ratings system. Dr. Stern replied, “I am at a loss to respond to that.”But he had acknowledged, when he still held the job, “There’s no way to sit in this chair and be loved.” He was constantly second-guessed.Why give “The Exorcist” (1973) an R rating? (“I think it’s a great film,” he told the director, Richard Friedkin. “I’m not going to ask you to cut a frame.”) Why originally give Stanley Kubrick’s “A Clockwork Orange” (1971) an X for a ménage à trois filmed in high speed? (“If we did that, any hard-core pornographer could speed up his scenes and legitimately ask for an R on the same basis.”) Later, as a private $1,000-a-day consultant, he helped edit Mr. Friedkin’s “Cruising” (1980), about a serial killer of gay men, to gain an R instead of an X.“You can only rate the explicit elements on the screen — never the morality or the thought issues behind it,” Dr. Stern said in 1972. “That is the province of religion, leaders, critics and each individual.”

The yeast Candida albicans can cause itchy, painful urinary tract and vaginal yeast infections. For women in low-resource settings who lack access to healthcare facilities, these infections create substantial social and economic burdens. Now, researchers reporting in ACS Omega have developed color-changing threads that turn bright pink in the presence of C. albicans. When embedded in tampons or sanitary napkins, they could allow women to quickly and discreetly self-diagnose vulvovaginal yeast infections, the researchers say.
According to the Mayo Clinic, about 75% of women will experience a yeast infection, or vulvovaginal candidiasis, at least once in their lifetime. Although women in high-resource areas can easily be diagnosed with a vaginal swab at their doctor’s office and then treated with an antifungal medication, many women throughout the world lack access to basic healthcare facilities. Moreover, in some resource-limited areas, societal taboos cause women to feel shame or embarrassment about the symptoms, which prevents them from seeking a doctor’s care. Therefore, Naresh Kumar Mani and colleagues wanted to develop an inexpensive method that could be integrated into menstrual hygiene products, allowing women to quickly, easily and discreetly self-diagnose yeast infections.
The researchers began with ordinary multifilament cotton threads purchased at a local craft store. To increase the wicking properties of the threads, the team treated them with a heptane solution that removed waxes and binders added during manufacturing. Then, the threads were coated with a molecule called L-proline ?-naphthylamide (PRO) — the substrate for an enzyme secreted by C. albicans — and embedded in the inner layers of sanitary napkins and pads. When the researchers added simulated vaginal fluid spiked with C. albicans and an indicator solution, the spots of the napkins or pads containing yeast changed to a bright pink color. The detection time was only 10 minutes, compared with 24-72 hours for conventional tests. In addition, the new test costs only 22 to 28 cents per napkin or tampon, and it could easily be adapted to simultaneously detect other pathogens, such as bacteria that also can cause urinary tract infections, the researchers say.
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Specialized immune cells that accumulate in the brain in the days and weeks after a stroke promote neural functions in mice, pointing to a potential immunotherapy that may boost recovery after the acute injury is over, University of Pittsburgh School of Medicine neurologists found.
The study, published today in the journal Immunity, demonstrated that a population of specialized immune cells, called regulatory T (Treg) cells, serve as tissue repair engineers to promote functional recovery after stroke. Boosting Treg cells using an antibody complex treatment, originally designed as a therapy after transplantation and for diabetes, improved behavioral and cognitive functions for weeks after a stroke in mice compared to those that did not receive the antibody complex.
“The beauty of this treatment is in its wide therapeutic window,” said senior author Xiaoming Hu, M.D., Ph.D., associate professor in the Department of Neurology at Pitt’s School of Medicine. “With most strokes, you have four and a half hours or less when you can give medication called tPA to reopen a blocked blood vessel and expect to rescue neurons. We’re excited to identify a mechanism that may promote brain recovery by targeting non-neuronal cells well after this window closes.”
Previous research in stroke has been focused on developing new drugs to reduce neuronal death. And whereas these acute stroke treatments quickly lose effectiveness after neurons die, Treg cells remain active for weeks after the injury.
True to their name, Treg cells are immune cells that regulate the immune response, including curtailing excessive inflammation that could harm more than help. Hu and her colleagues observed that the levels of Treg cells infiltrating the brain began to increase about a week after a stroke and continued increasing up to five weeks later. So, they did multiple tests in mice after they’d had strokes, paying particular attention to the brain’s white matter — which is the brain tissue through which neurons pass messages, turning thoughts into actions, like lifting food to your mouth or saying the name of an object you’re looking at.
Mice that were genetically unable to produce Treg cells fared worse than mice with a robust Treg cell response. Interestingly, it was only in the latter phases of stroke recovery that the Treg cell-depleted mice suffered impairments in white matter integrity and behavioral performance compared to mice with a normal Treg cell response.
Additionally, when normal mice were given an antibody complex called “IL-2:IL-2Ab” to boost their Treg cell levels after a stroke, their white matter integrity improved even more and neurological functions were rescued over the long term. The mice with more Treg cells had an easier time moving and had better memories, allowing them to navigate mazes faster after a stroke than their non-treated counterparts.
“This strongly suggests that, rather than working to preserve white matter structure and function immediately after a stroke, Treg cells influence long-term white matter repair and regeneration,” said Hu, also a member of the Pittsburgh Institute of Brain Disorders and Recovery and a U.S. Department of Veterans Affairs (VA) investigator. “Our findings pave the way for a therapeutic approach to stroke and other neurological disorders that involve excessive brain inflammation and damage to the white matter. Treg cells appear to hold neurorestorative potential for stroke recovery.”
Hu stressed that there are still many hurdles to cross before Treg cells could be used in humans for stroke recovery. Namely, research is needed to determine the best way to boost the number of Treg cells in stroke victims. This could be done by improving IL-2:IL-2Ab so that it better stimulates production of Treg cells with fewer side effects, or a personalized therapy could be developed where some cells are taken from an established Treg cell bank and used to grow custom Treg cells in the lab, which could then be infused back into the patient.
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The development of antibodies to the COVID-19 virus has been the great long-term hope of ending the pandemic. However, immune system turncoats are also major culprits in severe cases of COVID-19, Yale scientists report in the journal Nature.
These autoantibodies target and react with a person’s tissues or organs similar to ones that cause autoimmune diseases such as lupus or rheumatoid arthritis. In COVID-19 cases they can attack healthy tissue in brain, blood vessels, platelets, liver, and the gastrointestinal tract, researchers report. The more autoantibodies detected, the greater the disease severity experienced by patients.
And the autoantibodies paradoxically also target and interfere with many immune system proteins that are designed to fend off infections, the study found.
“It’s a two-edge sword,” said Aaron Ring, assistant professor of immunobiology at Yale and senior author of the paper. “Antibodies are crucial to fend off infection, but some COVID-19 patients also develop antibodies that damage their own cells and tissues.”
It is clear that in many cases the presence of coronavirus drove the creation of the damaging autoantibodies, Ring said. But it is also likely that some COVID-19 patients had pre-existing autoantibodies that made them more susceptible to infection, he said. Mice with these same autoantibodies were more susceptible to infection by the COVID-19 virus and more likely to die, the authors report.
The existence of these long-lived rogue autoantibodies could also help explain why some people infected with COVID-19 can later develop lasting medical symptoms, so-called long COVID cases. “This could be the unfortunate legacy of the virus,” Ring said.
“Our findings reinforce the importance of getting vaccinated,” added co-corresponding author Akiko Iwasaki, the Waldemar Von Zedtwitz Professor of Immunobiology at Yale. “The fact that even mild infections are associated with autoantibody production underscores the potential for long-term health consequences of COVID-19.”
For the study, Ring’s lab worked with Iwasaki’s lab and members of the Yale IMPACT team — a group of scientists, scholars, and physicians developing research and clinical efforts to combat COVID-19 — to screen blood samples from 194 patients who had contracted the virus, with varying degrees of severity, for the presence of autoantibodies. Specifically, they used a novel technology developed by Ring’s lab called Rapid Extracellular Antigen Profiling (REAP) to identify autoantibody interactions with nearly 3,000 human proteins.
Ring said the findings may lead to strategies to treat or prevent the damaging effects of autoantibodies in COVID-19 patients. In addition, the new REAP technology could be used to pinpoint important antibody responses for many other disease conditions beyond COVID-19. Ring’s lab has found a host of novel autoantibodies in patients with autoimmune disease and is now searching for autoantibodies in patients with cancer and neurological illnesses.
The work was led by co-first authors Eric Wang, a Yale College undergraduate, Jon Klein, a Yale M.D./Ph.D. student, and Yale immunobiology graduate students Tianyang Mao and Yile Dai. Funding for the project was provided by the Mathers Family Foundation and the Ludwig Family Foundation.
Ring, Wang, and Dai are inventors of a patent describing the REAP technology used in the study and Ring is the founder of Seranova Bio, which seeks to market the technology.
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In a major breakthrough, researchers at Massachusetts General Hospital (MGH) have discovered how amyloid beta — the neurotoxin believed to be at the root of Alzheimer’s disease (AD) — forms in axons and related structures that connect neurons in the brain, where it causes the most damage. Their findings, published in Cell Reports, could serve as a guidepost for developing new therapies to prevent the onset of this devastating neurological disease.
Among his many contributions to research on AD, Rudolph Tanzi, PhD, vice chair of Neurology and co-director of the McCance Center for Brain Health at MGH, led a team in 1986 that discovered the first Alzheimer’s disease gene, known as APP, which provides instructions for making amyloid protein precursor (APP). When this protein is cut (or cleaved) by enzymes — first, beta secretase, followed by gamma secretase — the byproduct is amyloid beta (sometimes shortened to Abeta). Large deposits of amyloid beta are believed to cause neurological destruction that results in AD. Amyloid beta formed in the brain’s axons and nerve endings causes the worst damage in AD by impairing communication between nerve cells (or neurons) in the brain. Researchers around the world have worked intensely to find ways to block the formation of amyloid beta by preventing cleavage by beta secretase and gamma secretase. However, these approaches have been hampered by safety issues.
Despite years of research, a major mystery has remained. “We knew that Abeta is made in the axons of the brain’s nerve cells, but we didn’t know how,” says Tanzi. He and his colleagues probed the question by studying the brains of mice, as well as with a research tool known as Alzheimer’s in a dish, a three-dimensional cell culture model of the disease created in 2014 by Tanzi and a colleague, Doo Yeon Kim, PhD. Earlier, in 2013, several other MGH researchers, including neurobiologist Dora Kovacs, PhD (who is married to Tanzi), and Raja Bhattacharyya, PhD, a member of Tanzi’s lab, showed that a form of APP that has undergone a process called palmitoylation (palAPP) gives rise to amyloid beta. That study indicated that, within the neuron, palAPP is transported in a fatty vesicle (or sac) known as a lipid raft. But there are many forms of lipid rafts. “So the question was, Which lipid rafts? And which ones are most relevant to the neuronal processes making up the neural networks of the brain?” says Tanzi.
The new investigation revealed that palAPP is stabilized and prepared for cleavage by beta secretase in special lipid rafts within the neuron known as mitochondria-associated endoplasmic reticulum membranes (MAMs). “We showed for the first time not only that the MAM is where palAPP is processed by beta secretase to make Abeta, but that this happens exclusively in axons and neuronal processes where Abeta does most of its damage,” says Bhattacharyya, lead author of the Cell Reports paper. This role for MAMs was previously unknown, though earlier research indicated that they are increased in number and activity in the brains of people with Alzheimer’s disease.
Next, the MGH team wanted to learn what happens when MAM levels and activity were intentionally altered. They showed for the first time that preventing assembly of MAMs, either with gene therapy or a drug that blocked a key protein called the sigma-1 receptor (S1R), dramatically decreased beta secretase cleavage of palAPP in axons and lowered Abeta production. Conversely, a drug that activated S1R triggered an increase in beta secretase cleavage of palAPP and increased production of amyloid beta in axons.
“Our results suggest that the sigma-1 receptor might be a viable therapeutic target for reducing Abeta production, specifically in axons,” says Tanzi. The study also lends support for a strategy already under investigation by Tanzi and his team, which is developing an experimental treatment that inhibits the palmitoylation of APP, the process that produces palAPP. It’s also known that another class of drugs that Kovacs is studying for preventing formation of amyloid beta, called ACAT inhibitors, works directly in MAMs. In the future, these and other interventions that thwart production of this most dangerous pool of axonal amyloid beta could be used in concert with early detection (through blood or imaging tests) to stop or slow the progression of AD.
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Though obesity in midlife is linked to an increased risk for Alzheimer’s disease, new research suggests that a high body mass index later in life doesn’t necessarily translate to greater chances of developing the brain disease.
In the study, researchers compared data from two groups of people who had been diagnosed with mild cognitive impairment — half whose disease progressed to Alzheimer’s in 24 months and half whose condition did not worsen.
The researchers zeroed in on two risk factors: body mass index (BMI) and a cluster of genetic variants associated with higher risk for Alzheimer’s disease.
Their analysis showed that a higher genetic risk combined with a lower BMI was associated with a higher likelihood for progression to Alzheimer’s, and that the association was strongest in men.
The finding does not suggest people should consider gaining weight in their later years as a preventive effort — instead, researchers speculate that lower BMI in these patients was likely a consequence of neurodegeneration, the progressive damage to the brain that is a hallmark of Alzheimer’s. Brain regions affected by Alzheimer’s are also involved in controlling eating behaviors and weight regulation.
“We don’t want people to think they can eat everything they want because of this lower BMI association,” said senior study author Jasmeet Hayes, assistant professor of psychology at The Ohio State University.