Reprogramming the brain's cleaning crew to mop up Alzheimer's disease

 The discovery of how to shift damaged brain cells from a diseased state into a healthy one presents a potential new path to treating Alzheimer's and other forms of dementia, according to a new study from researchers at UC San Francisco.

The research focuses on microglia, cells that stabilize the brain by clearing out damaged neurons and the protein plaques often associated with dementia and other brain diseases.

These cells are understudied, despite the fact that changes in them are known to play a significant role Alzheimer's and other brain diseases, said Martin Kampmann, Ph.D., senior author on the study, which appears Aug. 11 in Nature Neuroscience.

"Now, using a new CRISPR method we developed, we can uncover how to actually control these microglia, to get them to stop doing toxic things and go back to carrying out their vitally important cleaning jobs," he said. "This capability presents the opportunity for an entirely new type of therapeutic approach."

Leveraging the brain's immune system

Most of the genes known to increase the risk for Alzheimer's disease act through microglial cells. Thus, these cells have a significant impact on how such neurodegenerative diseases play out, said Kampmann.

Microglia act as the brain's immune system. Ordinary immune cells can't cross the blood-brain barrier, so it's the task of healthy microglia to clear out waste and toxins, keeping neurons functioning at their best. When microglia start losing their way, the result can be brain inflammation and damage to neurons and the networks they form.

Under some conditions, for example, microglia will start removing synapses between neurons. While this is a normal part of brain development in a person's childhood and adolescent years, it can have disastrous effects in the adult brain.

Over the past five years or so, many studies have observed and profiled these varying microglial states but haven't been able to characterize the genetics behind them.

Kampmann and his team wanted to identify exactly which genes are involved in specific states of microglial activity, and how each of those states are regulated. With that knowledge, they could then flip genes on and off, setting wayward cells back on the right track.

From advanced genomics to a holy grail

Accomplishing that task required surmount fundamental obstacles that have prevented researchers from controlling gene expression in these cells. For example, microglia are very resistant to the most common CRISPR technique, which involves getting the desired genetic material into the cell by using a virus to deliver it.

To overcome this, Kampmann's team coaxed stem cells donated by human volunteers to become microglia and confirmed that these cells function like their ordinary human counterparts. The team then developed a new platform that combines a form of CRISPR, which enables researchers to turn individual genes on and off—and which Kampmann had a significant hand in developing—with readouts of data that indicate functions and states of individual microglia cells.

Through this analysis, Kampmann and his team pinpointed genes that effect the cell's ability to survive and proliferate, how actively a cell produces inflammatory substances, and how aggressively a cell prunes synapses.

And because the scientists had determined which genes control those activities, they were able to reset the genes and flip the diseased cell to a healthy state.

Armed with this new technique, Kampmann plans to investigate how to control the relevant states of microglia, by targeting the cells with existing pharmaceutical molecules and testing them in preclinical models. He hopes to find specific molecules that act on the genes necessary to nudge diseased cells back to a healthy state.

Kampmann said that once the right genes are flipped, it's likely that the "repaired," microglia will resume their responsibilities, removing plaques associated with neurodegenerative disease and protecting synapses rather than taking them apart.

"Our study provides a blueprint for a new approach to treatment," he said. "It's a bit of a holy grail."

---

Explore further

Ally and enemy? Scientists explore immune cell suspect in Alzheimer's disease

---

More information: Li Gan, A CRISPRi/a platform in human iPSC-derived microglia uncovers regulators of disease states, Nature Neuroscience (2022). DOI: 10.1038/s41593-022-01131-4. www.nature.com/articles/s41593-022-01131-4

https://medicalxpress.com/news/2022-08-reprogramming-brain-crew-mop-alzheimer.html

New antibody neutralizes all known SARS-CoV-2 variants

 As SARS-CoV-2 has evolved and mutated, therapeutic antibodies that worked early in the pandemic have become less effective, and newer variants, especially omicron, have developed ways to evade the antibodies we make in response to vaccines. A new, broadly neutralizing antibody developed at Boston Children's Hospital could potentially improve our ability to defend against future variants. In tests, it neutralized all currently known SARS-CoV-2 variants of concern, including all omicron variants.

"We hope that this humanized antibody will prove to be as effective at neutralizing SARS-CoV-2 in patients as it has proven to be thus far in preclinical evaluations," says Frederick Alt, Ph.D., of the Program in Cellular and Molecular Medicine at Boston Children's Hospital, who co-led the research.

As described in Science Immunology on August 11, Alt and Sai Luo, Ph.D., in his lab turned to a modified version of a humanized mouse model that the lab has used to search for broadly neutralizing antibodies to HIV, another virus that frequently mutates. The mice essentially have built-in human immune systems, and the model mimics the trial-and-error process our immune system uses to create increasingly effective antibodies.

The researchers first inserted two human gene segments into the mice, pushing their B cells to rapidly produce a diverse repertoire of humanized antibodies. They then exposed the mice to the SARS-CoV-2 spike protein, the main protein targeted by our antibodies and current vaccines, from the original Wuhan-Hu-1 strain of the virus. In response, the modified mice produced nine lineages or "families" of humanized antibodies that bound to the spike.

Alt and Luo then vetted these antibodies for efficacy in collaboration with the group of Barton Haynes, MD at Duke University. Antibodies in three of the nine lineages were potent neutralizers of the original Wuhan-Hu-1 virus. In particular, the SP1-77 antibody and other members of its lineage showed very broad activity, neutralizing alpha, beta, gamma, delta, and all previous and current omicron strains.

A novel approach to virus neutralization

What made the SP1-77 antibody so broadly neutralizing? Structural studies by a collaborating team led by Bing Chen, Ph.D. and Jun Zhang, Ph.D. at Boston Children's Hospital and the Haynes group at Duke, showed that SP1-77 works differently from current antibodies (either therapeutic antibodies or those we make in response to current vaccines).

Many of the existing antibodies function by binding to the spike's receptor-binding domain (RBD) in specific locations that prevent SARS-CoV-2 from binding to our cells' ACE2 receptors, the first step in initiating infection. The SP1-77 antibody also binds to the RBD, but in a totally different manner that does not block the virus from binding to ACE2 receptors.

Using a novel live-cell imaging platform described in a preprint, collaborators Alex Kreutzberger, Ph.D. and Tomas Kirchhausen, Ph.D., of Boston Children's Hospital showed that SP1-77 prevents the virus from fusing its outer membrane with the membrane of the target cell. This thwarts the final necessary step that throws the door open to infection.

These features may inform design of new SARS-CoV-2 vaccines. "SP1-77 binds the spike protein at a site that so far has not been mutated in any SARS-CoV-2 variant, broadly neutralizing current variants by a novel mechanism," says Kirchhausen.

---

Explore further

Scientists discover antibodies that induce broad immunity against SARS viruses, including emerging variants

---

More information: An Antibody from Single Human VH-rearranging Mouse Neutralizes All SARS-CoV-2 Variants Through BA.5 by Inhibiting Membrane Fusion, Science Immunology (2022). DOI: 10.1126/sciimmunol.add5446

https://medicalxpress.com/news/2022-08-powerful-antibody-neutralizes-sars-cov-variants.html

What happens inside artery plaque to trigger strokes

 Heart attacks and strokes are a leading cause of death in the United States, but scientists are still working to understand one of their primary triggers. What causes plaque buildup within arteries to become unstable, leading parts to suddenly burst or break away?

A key obstacle is that researchers haven't been able to study plaques during a stroke.

For the first time, researchers at Tulane University and Ochsner Health were able to genetically sequence carotid plaque tissue collected from patients within days after a stroke. When compared to stable plaque, researchers discovered the tissues from recent stroke victims contained messenger RNA that can cause inflammation and processes that degrade a key portion of the plaque that protects against rupture, according to results recently published in Scientific Reports.

The discovery could help researchers develop new tools to stop strokes from happening.

"The genes identified in our study could be used as targets to develop new drugs or diagnostics to help prevent strokes and heart attacks," said study senior author Cooper Woods, Ph.D., associate professor of physiology and medicine at Tulane University School of Medicine.

The study was co-authored by Dr. Hernan Bazan, the John Ochsner Endowed Professor for Cardiovascular Innovation at Ochsner Health.

Surprisingly, the researchers found that ruptured plaques had increased markers of B-cells, a white blood cell whose role in plaque rupture has not previously been appreciated.

Previous studies have relied on carotid artery samples obtained after the patient's death or months after the stroke or heart attack. This either limits the information that can be obtained or misses events that occur only at the time of rupture.

Carotid artery blockage is a common cause of some ischemic strokes, which happens when the blood supply to part of the brain is interrupted, preventing brain tissue from getting necessary oxygen and nutrients. Because the mechanisms that lead to some strokes and most heart attacks involve the same plaque rupture events, these findings also have implications for heart disease.

"Inflammation is a known risk factor in atherosclerosis, leading to stroke and heart attacks," Bazan said. "Carotid and coronary plaques develop a protective cap that, for unclear reasons, thins, making strokes and heart attacks more likely."

---

Explore further

New study makes case for expanding coverage for carotid artery stenting

---

More information: Hernan A. Bazan et al, A pro-inflammatory and fibrous cap thinning transcriptome profile accompanies carotid plaque rupture leading to stroke, Scientific Reports (2022). DOI: 10.1038/s41598-022-17546-9

https://medicalxpress.com/news/2022-08-uncovers-artery-plaque-trigger.html

Medicine for asthma and eczema helps COVID patients

 A medication used to treat asthma and eczema can improve survival rates for patients with moderate to severe COVID-19, a clinical trial conducted at UVA Health suggests.

UVA is the first to test this novel and promising approach to COVID-19 treatment. The study centered on a monoclonal antibody called dupilumab, most often prescribed for skin conditions, asthma, and sinus congestion and swelling. The treatment also proved safe in the small study, as expected, because dupilumab is already a safe and effective allergy medicine.

The small trial, designed and led by Dr. Jennifer Sasson, found that dupilumab improved patient survival at 60 days and reduced the number of patients who needed intensive care. Almost 90% of patients who received dupilumab in the randomized trial were alive at 60 days, compared with 76% of patients who did not.

"Our clinical trial suggests that treatment with the anti-allergy medicine dupilumab may decrease deaths due to COVID-19," said Sasson, of the University of Virginia School of Medicine's Division of Infectious Diseases and International Health. "A large multi-institution study to validate these preliminary results is being designed. If successful, this multi-site trial will open a new window to treatment of COVID-19 and potentially other viral pneumonias."

Treating COVID-19

Sasson and her collaborators were inspired to launch the trial after discovering that patients with COVID-19 were at significantly greater risk of needing a ventilator if their blood contained high levels of interleukin-13, a driver of inflammation in the body. Dupilumab, sold under the brand name Dupixent, works by blocking the effects of IL-13. The federal Food and Drug Administration approved dupilumab in 2017 for the treatment of moderate to severe eczema, an itchy skin condition also known as atopic dermatitis. Dupilumab is now also used to treat patients with asthma and chronic sinus inflammation.

To see if dupilumab could improve the body's immune response to COVID-19, Sasson and her collaborators enrolled 40 patients with moderate to severe cases in a clinical trial. The trial was double-blinded, meaning neither the patients nor the doctors knew whether the patient was receiving the antibody or a placebo. Both groups of trial participants otherwise received standard care.

After 28 days, the two groups saw no difference in ventilator-free survival or in adverse events. But by 60 days, there were only two deaths among the patients receiving dupilumab and five deaths among those receiving placebo.

Among the patients who were not already in the intensive care unit when they joined the trial, three receiving dupilumab were ultimately admitted to the ICU. That's compared with six of those receiving placebo.

"We are indebted to the patients at UVA who consented to participate in this study, without even knowing if they would receive the medicine or placebo, as they are the ones who have advanced our understanding of the pandemic," Sasson said.

The researchers have published their findings in the journal Open Forum Infectious Diseases.

---

Explore further

OCS-sparing effect of dupilumab for severe asthma maintained

---

More information: Jennifer Sasson et al, Safety and Efficacy of Dupilumab for the Treatment of Hospitalized Patients With Moderate to Severe Coronavirus Disease 2019: A Phase 2a Trial, Open Forum Infectious Diseases (2022). DOI: 10.1093/ofid/ofac343

https://medicalxpress.com/news/2022-08-medicine-asthma-eczema-covid-patients.html

Sound plus electrical body stimulation has potential to treat chronic pain

 A University of Minnesota Twin Cities-led team has found that electrical stimulation of the body combined with sound activates the brain's somatosensory or "tactile" cortex, increasing the potential for using the technique to treat chronic pain and other sensory disorders. The researchers tested the non-invasive technique on animals and are planning clinical trials on humans in the near future.

The paper is published in the Journal of Neural Engineering.

During the experiments, the researchers played broadband sound while electrically stimulating different parts of the body in guinea pigs. They found that the combination of the two activated neurons in the brain's somatosensory cortex, which is responsible for touch and pain sensations throughout the body.

While the researchers used needle stimulation in their experiments, one could achieve similar results using electrical stimulation devices, such as transcutaneous electrical nerve stimulation (TENS) units, which are widely available for anyone to buy at pharmacies and stores. The researchers hope that their findings will lead to a treatment for chronic pain that's safer and more accessible than drug approaches.

"Chronic pain is a huge issue for a lot of people, and for most, it's not sufficiently treatable," said Cory Gloeckner, lead author on the paper, a 2017 Ph.D. alumnus of the University of Minnesota Twin Cities Department of Biomedical Engineering, and an assistant professor at John Carroll University. "Right now, one of the ways that we try to treat pain is opioids, and we all know that doesn't work out well for many people. This, on the other hand, is a non-invasive, simple application. It's not some expensive medical device that you have to buy in order to treat your pain. It's something that we think would be available to pretty much anyone because of its low cost and simplicity."

The researchers plan to continue investigating this "multimodal" approach to treating different neurological conditions, potentially integrating music therapy in the future to see how they can further modify the somatosensory cortex.

"A lot of people have been using acupuncture or electrical stimulation -- non-invasive or invasive -- to try to alter brain activity for pain," said Hubert Lim, senior author on the paper and a professor in the University of Minnesota Twin Cities Department of Biomedical Engineering and Department of Otolaryngology. "Our research shows that when you combine this with sound, the brain lights up even more."

Lim said this opens up a whole new field of using this bimodal and multimodal stimulation for treating diseases.

"It's odd to think about using sound to treat pain, but if you think about what institutes like the University of Minnesota's Center for Spirituality and Healing or the NIH's National Center for Complementary and Integrative Health are doing, they're looking at music therapy and combining other modalities with the traditional methods to be able to enhance healing of these types of conditions," Lim said. "This research gives us a new, structured framework for doing that moving forward."

The research was funded by the National Science Foundation, the Lions Hearing Foundation, the University of Minnesota Interdisciplinary Fellowship, and University of Minnesota Lab Startup Funds.

In addition to Gloeckner and Lim, the research team included University of Minnesota Twin Cities Department of Biomedical Engineering alumnus Jian Nocon (B.S. BME '17).

---

Story Source:

Materials provided by University of Minnesota. Note: Content may be edited for style and length.

---

Journal Reference:

1. Cory D Gloeckner, Jian C Nocon, Hubert H Lim. Topographic and widespread auditory modulation of the somatosensory cortex: potential for bimodal sound and body stimulation for pain treatment. Journal of Neural Engineering, 2022; 19 (3): 036043 DOI: 10.1088/1741-2552/ac7665

https://www.sciencedaily.com/releases/2022/08/220811083335.htm

'Tranq' Making Street Drugs Even More Dangerous

 Approaching a van that distributes supplies for safer drug use in Greenfield, Massachusetts, a man named Kyle noticed an alert about xylazine.

"Xylazine?" he asked, sounding out the unfamiliar word. "Tell me more."

A street-outreach team from Tapestry Health Systems delivered what's becoming a routine warning. Xylazine is an animal tranquilizer. It's not approved for humans but is showing up in about half the drug samples that Tapestry Health tests in the rolling hills of western Massachusetts. It's appearing mostly in the illegal fentanyl supply but also in cocaine.

"The past week, we've all been just racking our brains — like, 'What is going on?'" Kyle said. "Because if we cook it up and we smoke it, we're falling asleep after."

(NPR and KHN are using only first names in this article for people who use illegal drugs.)

Kyle's deep sleep could also have been triggered by fentanyl, but Kyle said one of his buddies used a test strip to check for the opioid and none was detected.

Xylazine, which is also known as "tranq" or "tranq dope," surged first in some areas of Puerto Rico and then in Philadelphia, where it was found in 91% of opioid samples in the most recent reporting period. Data from January to mid-June shows that xylazine was in 28% of drug samples tested by the Massachusetts Drug Supply Data Stream, a state-funded network of community drug-checking and advisory groups that uses mass spectrometers to let people know what's in bags or pills purchased on the street.

Whatever its path into the drug supply, the presence of xylazine is triggering warnings in Massachusetts and beyond for many reasons.

As Xylazine Use Rises, So Do Overdoses

Perhaps the biggest question is whether xylazine has played a role in the recent increase in overdose deaths in the U.S. In a study of 10 cities and states, xylazine was detected in fewer than 1% of overdose deaths in 2015 but in 6.7% in 2020, a year the U.S. set a record for overdose deaths. The record was broken again in 2021, which had more than 107,000 deaths.

The study does not claim xylazine is behind the increase in fatalities, but study co-author Chelsea Shover said it may have contributed. Xylazine, a sedative, slows people's breathing and heart rate and lowers their blood pressure, which can compound some effects of an opioid like fentanyl or heroin.

"If you have an opioid and a sedative, those two things are going to have stronger effects together," said Shover, an epidemiologist at UCLA's David Geffen School of Medicine.

In Greenfield, Tapestry Health is responding to more overdoses as more tests show the presence of xylazine. "It correlates with the rise, and it correlates with Narcan not being effective to reverse xylazine," said Amy Davis, assistant director for rural harm-reduction operations at Tapestry. Narcan is a brand name of naloxone, an opioid overdose reversal medication.

"It's scary to hear that there's something new going around that could be stronger maybe than what I've had," said May, a woman who stopped by Tapestry Health's van. May said that she has a strong tolerance for fentanyl but that a few months ago, she started getting something that didn't feel like fentanyl, something that "knocked me out before I could even put my stuff away."

A Shifting Overdose Response

Davis and her colleagues are ramping up the safety messages: Never use alone, always start with a small dose, and always carry Narcan.

Davis is also changing the way they talk about drug overdoses. They begin by explaining that xylazine is not an opioid. Squirting naloxone into someone's nose won't reverse a deep xylazine sedation — the rescuer won't see the dramatic awakening that is common when naloxone is administered to someone who has overdosed after using an opioid.

If someone has taken xylazine, the immediate goal is to make sure the person's brain is getting oxygen. So Davis and others advise people to start rescue breathing after the first dose of Narcan. It may help restart the lungs even if the person doesn't wake up.

"We don't want to be focused on consciousness — we want to be focused on breathing," Davis said.

Giving Narcan is still critical because xylazine is often mixed with fentanyl, and fentanyl is killing people.

"If you see anyone who you suspect has an overdose, please give Narcan," said Dr. Bill Soares, an emergency room physician and the director of harm reduction services at Baystate Medical Center in Springfield, Massachusetts.

Soares said calling 911 is also critical, especially when someone has taken xylazine, "because if the person does not wake up as expected, they're going to need more advanced care."

"Profound Sedation" Worries Health Providers

Some people who use drugs say xylazine knocks them out for six to eight hours, raising concerns about the potential for serious injury during this "profound sedation," said Dr. Laura Kehoe, medical director at Massachusetts General Hospital's Substance Use Disorders Bridge Clinic.

Kehoe and other clinicians worry about patients who have been sedated by xylazine and are lying in the sun or snow, perhaps in an isolated area. In addition to exposure to the elements, they could be vulnerable to compartment syndrome from lying in one position for too long, or they could be attacked.

"We're seeing people who've been sexually assaulted," Kehoe said. "They'll wake up and find that their pants are down or their clothes are missing, and they are completely unaware of what happened."

In Greenfield, nurse Katy Robbins pulled up a photo from a patient seen in April as xylazine contamination soared. "We did sort of go, 'Whoa, what is that?' " Robbins recalled, studying her phone. The image showed a wound like deep road rash, with an exposed tendon and a spreading infection.

Robbins and Tapestry Health, which runs behavioral and public health services in Western Massachusetts, have created networks so clients can get same-day appointments with a local doctor or hospital to treat this type of injury. But getting people to go get their wounds seen is hard. "There's so much stigma and shame around injection drug use," Robbins said. "Often, people wait until they have a life-threatening infection."

That may be one reason amputations are increasing for people who use drugs in Philadelphia. One theory is that decreased blood flow from xylazine keeps wounds from healing.

"We're certainly seeing a lot more wounds, and we're seeing some severe wounds," said Dr. Joe D'Orazio, director of medical toxicology and addiction medicine at Temple University Hospital in Philadelphia. "Almost everybody is linking this to xylazine."

https://www.medscape.com/viewarticle/979084

Dems' Inflation Reduction Act could mean lower wages for millions of Americans

 Democrats are pitching their newest health care and climate spending bill as a key way to reduce costs for U.S. households, but a new analysis shows the legislation could actually reduce take-home pay for millions of Americans, regardless of income level. 

Findings from the Tax Foundation, a nonpartisan group that advocates for lower taxes, show the initiative could trim 0.1% from workers' wages over the long term. It would also eliminate roughly 29,000 full-time positions from the U.S. economy. 

The Inflation Reduction Act of 2022, passed by Senate Democrats on Sunday, would raise an estimated $739 billion over the next decade by increasing IRS funding, establishing a 15% minimum corporate tax targeting companies' book income, allowing Medicare to negotiate prescription drug costs and imposing a 1% excise tax on corporate stock buybacks.

Revenue raised by the policies would go toward initiatives designed to combat climate change and curb pharmaceutical prices, as well as efforts to reduce the nation's $30 trillion debt. It includes about $433 billion in new spending, while roughly $300 billion of the new revenue raised would go toward paying down the nation's deficit.

"This is the action the American people have been waiting for. This addresses the problems of today — high health care costs and overall inflation — as well as investments in our energy security for the future," Biden said in a statement on July 27.

The Tax Foundation analysis showed the spending bill could generate about $676 billion over the next decade before accounting for the expanded tax credits for individuals and businesses. When factoring those in, the measure would add about $324 billion to the nation's coffers from 2022 to 2031.

Despite that, the legislation would have little impact on the broader economy, decreasing household income by less than 0.05% over the next decade. The measure would also reduce the capital stock by about 0.3%.

The "most damaging" tax provision included in the bill is the 15% minimum tax on book income, according to the Tax Foundation analysts: That levy would reduce GDP, the broadest measure of goods and services produced in the nation, by 0.3% and cause wages to decline by 0.1%. The tax increase on corporations would cost the economy roughly 23,000 jobs.

"Inflation is driven by expectations regarding the likelihood that the federal government will be able to repay its debt over the long term, which is a function of the expected performance of the economy, tax collections, and spending," the Tax Foundation analysis said. "By reducing long-run economic growth, the bill worsens inflation by constraining the productive capacity of the economy."

Democrats say the legislation will help to reduce inflation and provide relief to Americans in the form of lower health care costs, while Republicans argue the measure does little to tackle higher prices – and could actually exacerbate the crisis. 

The nonpartisan Congressional Budget Office said in an analysis last week that the spending bill will have a negligible impact on inflation.

https://www.foxbusiness.com/economy/democrats-inflation-reduction-act-could-mean-lower-wages-millions-americans