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Though well-known as a respiratory illness, COVID-19 can also affect the nervous system, bringing on headaches and fatigue and wiping out the sense of smell. But it’s unclear whether these symptoms are caused by an immune response or the virus itself invading the central nervous system (CNS). Now, researchers reporting in ACS Infectious Diseases have developed a new tool and possible vaccine candidate that could help scientists understand how SARS-CoV-2 could be invading these cells.
Over the past two years, researchers have been trying to get a better understanding of the virus and developing vaccines against it. To date, the U.S. Food and Drug Administration (FDA) has approved four COVID-19 vaccines. They offer a great deal of protection against the virus, but some people who have received the shots still catch COVID-19. To develop even better vaccines and treatments, many scientists must conduct experiments with the real virus, which can only be handled in very specialized laboratories. Working with live viruses can put personnel at risk, and the requirement for specially designed settings can limit the scope of research that some teams can perform.
Instead, a safer and easier strategy is to use virus-like particles (VLPs), which are molecular mimics that look and act like a certain virus without being infectious. The particles can even serve as a vaccine themselves, as is the case with two that are currently available against the human papillomavirus. Researchers have developed VLPs of SARS-CoV-2 previously but have yet to specifically study how they affect the CNS. So, Manidipa Banerjee and colleagues wanted to create SARS-CoV-2 VLPs and run them through tests to see whether they function like the real deal and could be used one day as vaccines.
The researchers made VLPs with the four major structural proteins of SARS-CoV-2 — the spike, membrane, envelope and nucleocapsid — and allowed them to self-assemble into small, spherical particles. The particles looked similar to SARS-CoV-2 and could bind ACE2, which the virus latches onto to enter human cells. In other experiments, the team showed that the VLPs could get into brain cells in petri dishes, and the process depended on both cholesterol and an enzyme called dynamin. In addition, the VLPs tricked the immune system into launching a counterattack in mice, just as it does against SARS-CoV-2. The researchers say that VLPs could, therefore, be used in future vaccine development research and to get a better handle on what makes this new virus tick.
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In yet another example of the prevalence of the hazardous chemicals known as PFAS (per- and polyfluoroalkyl substances) in consumer products, industrial products and textiles, researchers have found notably high levels in school uniforms sold in North America.
In a study published in Environmental Science and Technology Letters, scientists at the University of Notre Dame, Indiana University, the University of Toronto and the Green Science Policy Institute analyzed a variety of children’s textiles. Fluorine was detected in 65 percent of samples tested.
But concentrations were highest in school uniforms — and higher in those uniforms labeled as 100 percent cotton as opposed to synthetics.
“What was surprising about this group of samples was the high detection frequency of PFAS in the garments required for children to wear,” said Graham Peaslee, professor of physics at Notre Dame and a co-author of the study. “Children are a vulnerable population when it comes to chemicals of concern, and nobody knows these textiles are being treated with PFAS and other toxic chemicals.”
An estimated 20 percent of public schools in the United States require students to wear uniforms — meaning millions of children could be at risk of exposure to the toxic compounds.
Known as “forever chemicals,” PFAS are known to accumulate in the bloodstream and have been linked to an increased risk of several health problems including weakened immune systems, asthma, obesity, and neurodevelopmental and behavioral problems. The National Health and Nutrition Examination Surveys from the Centers for Disease Control and Prevention routinely find PFAS in blood samples of children between the ages of 3 and 11.

A mutation in a newly discovered small protein is connected to a significant increase in the risk for Alzheimer’s disease, expanding the known gene targets for the disease and presenting a new potential avenue for treatment, according to a new USC study.
The protein, called SHMOOSE, is a tiny “microprotein” encoded by a newly discovered gene within the cell’s energy-producing mitochondria. A mutation within this gene partially inactivates the SHMOOSE microprotein and is associated with a 20-50 % higher risk for Alzheimer’s disease across four different cohorts. Nearly a quarter of people of European ancestry have the mutated version of the protein, according to the researchers.
The research appears Wednesday, September 21 in the journal Molecular Psychiatry.
The researchers say that both the substantial risk and high prevalence of this previously unidentified mutation differentiate it from other proteins involved in Alzheimer’s disease. Apart from APOE4 — the most potent known genetic risk factor for the disease — only a limited number of other gene mutations have been identified and these only mildly increased risk by less than 10%. Also, because the microprotein is approximately the size of the insulin peptide, it can be easily administered, which increases its therapeutic potential.
“This discovery opens exciting new directions for developing precision medicine-based therapies for Alzheimer’s disease, focusing on SHMOOSE as a target area,” said Pinchas Cohen, professor of gerontology, medicine and biological sciences and senior author of the study. “Administration of SHMOOSE analogs in individuals who carry the mutation and produce the mutant protein may prove to have benefit in neurodegenerative and other diseases of aging.”
Brendan Miller, ’22 PhD in neuroscience graduate and first author of the study, used big data techniques to identify genetic variations in mitochondrial DNA associated with disease risk. After analyses revealed a gene mutation increased Alzheimer’s disease risk, brain atrophy, and energy metabolism, Miller and his colleagues discovered that the mutated gene coded for the SHMOOSE microprotein and began studying its mutated and default forms. The researchers stated SHMOOSE is the first mitochondrial-DNA-encoded microprotein to have been detected using both antibodies and mass spectrometry.

Researchers at Linköping University, Sweden, have discovered a biological mechanism that increases the strength with which fear memories are stored in the brain. The study, carried out in rats, is published in the scientific journal Molecular Psychiatry. It provides new knowledge on the mechanisms behind anxiety-related disorders, and identifies shared mechanisms behind anxiety and alcohol dependence.
The ability to experience fear is essential to escape life-threatening situations and to learn to avoid them in the future. In some conditions, however, such as post-traumatic stress disorder (PTSD) and other anxiety-related disorders, the fear reactions become excessive, and persist even when they are no longer appropriate. This triggers intense anxiety even though the danger is no longer present, and leads to disability for the person who is affected. Researchers suspect that certain individuals have a greater tendency to develop pathological fears, and that this is caused by disorders in the way that the brain processes fearful memories.
Some areas of the brain are particularly important for processing fear-related memories. The amygdala is activated when threats are experienced, and works together with parts of the frontal brain lobes, the “prefrontal cortex,” which are important for regulating emotions.
“We know that the network of nerve cells that connects the frontal lobes to the amygdala is involved in fear responses. The connections between these brain structures are altered in people with PTSD and other anxiety disorders,” says Estelle Barbier, assistant professor in the Center for Social and Affective Neuroscience (CSAN), and the Department of Biomedical and Clinical Sciences (BKV) at Linköping University, who led the study.
However, the molecular mechanisms involved have long remained unknown. The researchers in the current study have investigated a protein known as PRDM2, an epigenetic enzyme that suppresses the expression of many genes. The researchers have previously found that levels of PRDM2 are lower in alcohol dependence, and lead to exaggerated stress responses. In people, it is very common for alcohol dependence and anxiety-related conditions to be present at the same time, and the researchers suspect that this is caused by common mechanisms behind these conditions.
In order for new memories to last, they must be stabilised and preserved as long-term memories. This process is known as “consolidation.” The researchers in the current study have investigated the effects of reduced levels of PRDM2 on the way fear memories are processed.
“We have identified a mechanism in which increased activity in the network between the frontal lobes and the amygdala increases learned fear reactions. We show that down-regulation of PRDM2 increases the consolidation of fear-related memories,” says Estelle Barbier.
The researchers have also identified genes that are affected when the level of PRDM2 is reduced. It became clear that this resulted in an increase in the activity of nerve cells that connect the frontal lobes and the amygdala.
“Patients with anxiety disorders may benefit from treatments that weaken or erase fear memories. The biological mechanism that we have identified involves down-regulation of PRDM2, and we currently do not have any way of increasing it. But the mechanism may be part of the explanation of why some individuals have a greater vulnerability to developing anxiety-related conditions. It may also explain why these conditions and alcohol dependence so often are present together,” says Estelle Barbier.
This work was funded by the Swedish Research Council, Region Östergotland, Stiftelsen Psykiatriska Forskningsfonden, the Wallenberg Foundations and the Knut och Alice Wallenberg Foundation.
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Mount Sinai researchers have used novel artificial intelligence methods to examine structural and cellular features of human brain tissues to help determine the causes of Alzheimer’s disease and other related disorders. The research team found that studying the causes of cognitive impairment by using an unbiased AI-based method — as opposed to traditional markers such as amyloid plaques — revealed unexpected microscopic abnormalities that can predict the presence of cognitive impairment. These findings were published in the journal Acta Neuropathologica Communications on September 20.
“AI represents an entirely new paradigm for studying dementia and will have a transformative effect on research into complex brain diseases, especially Alzheimer’s disease,” said co-corresponding author John Crary, MD, PhD, Professor of Pathology, Molecular and Cell-Based Medicine, Neuroscience, and Artificial Intelligence and Human Health, at the Icahn School of Medicine at Mount Sinai. “The deep learning approach was applied to the prediction of cognitive impairment, a challenging problem for which no current human-performed histopathologic diagnostic tool exists.”
The Mount Sinai team identified and analyzed the underlying architecture and cellular features of two regions in the brain, the medial temporal lobe and frontal cortex. In an effort to improve the standard of postmortem brain assessment to identify signs of diseases, the researchers used a weakly supervised deep learning algorithm to examine slide images of human brain autopsy tissues from a group of more than 700 elderly donors to predict the presence or absence of cognitive impairment. The weakly supervised deep learning approach is able to handle noisy, limited, or imprecise sources to provide signals for labeling large amounts of training data in a supervised learning setting. This deep learning model was used to pinpoint a reduction in Luxol fast blue staining, which is used to quantify the amount of myelin, the protective layer around brain nerves. The machine learning models identified a signal for cognitive impairment that was associated with decreasing amounts of myelin staining; scattered in a non-uniform pattern across the tissue; and focused in the white matter, which affects learning and brain functions. The two sets of models trained and used by the researchers were able to predict the presence of cognitive impairment with an accuracy that was better than random guessing.
In their analysis, the researchers believe the diminished staining intensity in particular areas of the brain identified by AI may serve as a scalable platform to evaluate the presence of brain impairment in other associated diseases. The methodology lays the groundwork for future studies, which could include deploying larger scale artificial intelligence models as well as further dissection of the algorithms to increase their predictive accuracy and reliability. The team said, ultimately, the goal of this neuropathologic research program is to develop better tools for diagnosis and treatment of people suffering from Alzheimer’s disease and related disorders.
“Leveraging AI allows us to look at exponentially more disease relevant features, a powerful approach when applied to a complex system like the human brain,” said co-corresponding author Kurt W. Farrell, PhD, Assistant Professor of Pathology, Molecular and Cell-Based Medicine, Neuroscience, and Artificial Intelligence and Human Health, at Icahn Mount Sinai. “It is critical to perform further interpretability research in the areas of neuropathology and artificial intelligence, so that advances in deep learning can be translated to improve diagnostic and treatment approaches for Alzheimer’s disease and related disorders in a safe and effective manner.”
Lead author Andrew McKenzie, MD, PhD, Co-Chief Resident for Research in the Department of Psychiatry at Icahn Mount Sinai, added: “Interpretation analysis was able to identify some, but not all, of the signals that the artificial intelligence models used to make predictions about cognitive impairment. As a result, additional challenges remain for deploying and interpreting these powerful deep learning models in the neuropathology domain.”
Researchers from the University of Texas Health Science Center in San Antonio, Texas, Newcastle University in Tyne, United Kingdom, Boston University School of Medicine in Boston, and UT Southwestern Medical Center in Dallas also contributed to this research. The study was supported by funding from the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, and the Tau Consortium by the Rainwater Charitable Foundation.

Aggregates of the protein alpha-synuclein spread in the brains of people with Parkinson’s disease through a cellular waste-ejection process, suggests a new study led by Weill Cornell Medicine researchers.
During the process, called lysosomal exocytosis, neurons eject protein waste they cannot break down and recycle. The discovery, published Aug. 22 in Nature Communications, could resolve one of the mysteries of Parkinson’s disease and lead to new strategies for treating or preventing the neurological disorder.
“Our results also suggest that lysosomal exocytosis could be a general mechanism for the disposal of aggregated and degradation-resistant proteins from neurons — in normal, healthy circumstances and in neurodegenerative diseases,” said study senior author Dr. Manu Sharma, an assistant professor of neuroscience in the Feil Family Brain and Mind Research Institute and Appel Alzheimer’s Disease Research Institute at Weill Cornell Medicine.
Parkinson’s is a disorder that features the deaths of neurons in a characteristic pattern of spread through the brain, normally unfolding over decades. The disease is best known for causing hand tremors, muscle rigidity, slowed gait and other impairments of normal movement. But it affects a broad set of brain regions, resulting in many different symptoms, including dementia in late stages. Approximately 1 million people in the United States have Parkinson’s. Available treatments can alleviate some movement abnormalities but do not stop disease progression — essentially because researchers don’t yet have a full understanding of that process.
One important finding that has emerged from the past few decades of Parkinson’s research is that the deaths of neurons in the disease follow the spread, within the brain, of abnormal aggregates of alpha synuclein, a neuronal protein. This spread is an infection-like, chain-reaction process in which aggregates induce normal alpha synuclein to join them, and — as they grow larger — break into smaller aggregates that continue to propagate. Experiments in mice and non-human primates have shown that injecting these aggregates into the brain can initiate this spread as well as some Parkinson’s-like neurodegeneration. But the details of how neurons transmit them to other neurons, have never been well understood.
In the study, Dr. Sharma and his team, including co-first author Ying Xue Xie, a doctoral candidate in the Weill Cornell Graduate School of Medical Sciences, showed with detailed studies of Parkinson’s mouse models that alpha synuclein aggregates — capable of spreading and causing neurodegeneration — originated within neurons. These aggregates, they found, then accumulate within capsule-like waste bins in cells called lysosomes.
Lysosomes contain enzymes that can break down, or “lyse,” proteins and other molecular waste into their building blocks, essentially digesting and recycling them. But the researchers found evidence that alpha synuclein aggregates, which are knit together with tight bonds in a close-fitting/snugly layered structure called “amyloid,” are not broken down well within lysosomes; instead, they were often found to be simply dumped from their originating neurons. In this process, called exocytosis, the lysosome moves to the cell membrane and merges with it, so that the lysosome contents are discharged — as-is, without any encapsulation — into the fluid surrounding the cell. The finding helps resolve a hotly debated question in the field.
The researchers also showed in further experiments that by reducing the rate of lysosomal exocytosis, they could reduce the apparent concentration of spread-capable aggregates. That, Dr. Sharma said, suggests a future approach to treating Parkinson’s.
“We don’t know yet, but neurons might be better off, even in the long term, if they keep these aggregates inside their lysosomes,” he said. “We see a similar impairment of lysosomal function in some genetic disorders, but these don’t necessarily lead to a Parkinson’s level of disease.”
Dr. Sharma emphasized that prior studies, including genetic studies, have linked lysosomal abnormalities not only to Parkinson’s but to also many other neurodegenerative disorders. This hints that lysosomal exocytosis may be a general mechanism of protein-aggregate spread in these diseases — and potentially a general target for treatments and preventives.
He and his team are currently following up with studies of lysosomes’ roles in Alzheimer’s disease.

Scientists at UCLA have used a molecule found in green tea to identify additional molecules that could break up protein tangles in the brain thought to cause Alzheimer’s and similar diseases.
The green tea molecule, EGCG, is known to break up tau fibers — long, multilayered filaments that form tangles that attack neurons, causing them to die.
In a paper published in Nature Communications, UCLA biochemists describe how EGCG snaps tau fibers layer by layer. They also show how they discovered other molecules likely to work the same way that would make better potential candidates for drugs than EGCG, which can’t easily penetrate the brain. The finding opens up new possibilities for fighting Alzheimer’s, Parkinson’s and related diseases by developing drugs that target the structure of tau fibers and other amyloid fibrils.
Thousands of J-shaped layers of tau molecules bound together make up the type of amyloid fibrils known as tangles, first observed a century ago by Alois Alzheimer in the post-mortem brain of a patient with dementia. These fibers grow and spread throughout the brain, killing neurons and inducing brain atrophy. Many scientists think removing or destroying tau fibers can halt the progression of dementia.
“If we could break up these fibers we may be able to stop death of neurons,” said David Eisenberg, UCLA professor of chemistry and biochemistry whose lab led the new research. “Industry has generally failed at doing this because they mainly used large antibodies that have difficulty getting into the brain. For a couple of decades, scientists have known there’s a molecule in green tea called EGCG that can break up amyloid fibers, and that’s where our work departs from the rest.”
EGCG has been studied extensively but has never worked as a drug for Alzheimer’s because it’s ability to dismantle tau fibers works best in water, and it doesn’t enter cells or the brain easily. Also, as soon as EGCG enters the bloodstream it binds to many proteins besides tau fibers, weakening its efficacy.

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A Ludwig Cancer Research study has identified a combination of three existing drugs that significantly extends survival in mouse models of the lethal brain cancer glioblastoma multiforme (GBM). Researchers led by Ludwig Lausanne’s Douglas Hanahan report in the current issue of Cancer Cell how the drugs used in the combination — an antidepressant, an immune checkpoint blockade antibody and a mouse analog of a cancer therapy that by themselves provide no survival benefit against GBM — synergize to unleash potently therapeutic immune responses against the tumor.
“Our investigation illustrates the great potential of drug repurposing for cancer therapy,” said Hanahan, distinguished scholar at the Ludwig Institute for Cancer Research Lausanne Branch. “We’ve shown here that three extensively characterized drugs already in use in the clinic can be newly combined to lift the tumor’s immunosuppressive barrier and induce a therapeutic immune response that significantly extends survival in mouse models of GBM, a cancer that has so far evaded every therapy used to treat it.”
Hanahan and his colleagues have been exploring in preclinical studies whether drug combinations that target distinct growth-promoting properties of tumors might work synergistically to stall or reverse disease progression. Previous studies in Hanahan’s lab had shown that a generic “tricyclic” antidepressant, imipramine, could be used in combination with an anticoagulant drug to hyperactivate a process known as autophagy, in which cells cannibalize their own proteins and organelles for the nutrients required to sustain their growth. Hyperactivation of autophagy by these drugs modestly extended survival of mice with GBM.
In this study, the researchers tested whether a drug aimed at an unrelated phenomenon, the abnormal blood vessels of tumors, used in combination with imipramine might further improve outcomes. They used a mouse analog of the human anti-VEGF antibody bevacizumab, which has been approved as a second line treatment for GBM, though not so much to extend survival as to provide relief to patients by alleviating the edema caused by the aberrant vasculature. Bevacizumab is known to quasi-normalize leaky tumor blood vessels, whose abnormalities also compromise both chemotherapy and immunotherapy.
The researchers found that combining imipramine and the VEGF-blocking antibody significantly delayed tumor progression and increased survival times in mice with GBM. The combination, they discovered, disrupts the immune defenses of the tumor via multiple mechanisms, unleashing a powerful anti-tumor immune response characterized by the recruitment of both helper and cytotoxic T cells, which are critical to anti-tumor immunity.
An analog of human-specific bevacizumab that targets the VEGF angiogenic factor in mice proved to remodel the tumor blood vessels in ways that are known to promote the infiltration of T cells. At the same time, imipramine’s hyperactivation of autophagy stimulated anti-tumor immunity.

Researchers have uncovered a novel pathway that explains how cancer cells become resistant to chemotherapies, which in turn offers a potential solution for preventing chemo-resistance.
Experimental DNA fibers with fluorescence were used to reveal the speed of DNA replication forks.
The research describes for the first time how a type of enzyme — previously known for its roles in DNA repair — prevents DNA damage in cancer cells, making them tolerant to chemotherapy drugs.
“It provides us tools to manipulate and then break chemo-resistance in cancer cells,” said Marcus Smolka, interim director of the Weill Institute for Cell and Molecular Biology and professor of molecular biology and genetics in the College of Agriculture and Life Sciences. Diego Dibitetto, a former postdoctoral researcher in Smolka’s lab who is currently at the University of Bern in Switzerland, is the paper’s first author.
Many anti-cancer drugs work by creating blocks on the DNA of cancer cells as they replicate. During replication, DNA strands entwined in a double helix separate into two individual strands so each strand can be copied, eventually leading to two new double helixes. The junction where this separation and copying occurs is called a replication fork, which unzips down the double helix.
If these replication forks were cars on a road, chemotherapy drugs can be imagined as obstacles that interfere with the flow of the cars, thus stopping replication and breaking DNA. But cancer cells have a way of slowing down these forks, which allows them to avoid such collisions and protect their DNA, leading to drug tolerance.