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Category: neuroscience – Page 77

Engineering chimeric antigen receptor CD4 T cells for Alzheimer’s disease

Recent advancements in immunotherapy have led to the first successful application of chimeric antigen receptor (CAR) T-cell therapy in treating neurodegenerative diseases, specifically Alzheimer’s disease. In a study conducted by researchers at Washington University in St. Louis and the Weizmann Institute of Science, T-cells were genetically engineered to recognize and target toxic beta-amyloid plaques. When tested on mouse models, three injections of these modified cells resulted in a significant reduction of protein aggregates within just ten days of the final administration. Beyond plaque clearance, the treatment successfully mitigated neuroinflammation, as evidenced by decreased microglial and astrocytic activity. These findings demonstrate the potential of CAR-T technology to rapidly clear pathological protein deposits and restore nervous tissue function, offering a promising new frontier for the treatment of Alzheimer’s and other proteinopathies.

Alzheimer’s disease (AD) is the prevailing cause of age-associated dementia worldwide. Current standard of care relies on antibody-based immunotherapy. However, antibody-based approaches carry risks for patients, and their effects on cognition are marginal. Increasing evidence suggests that T cells contribute to AD onset and progression. Unlike the cytotoxic effects of CD8+ cells, CD4+ T cells capable of regulating inflammation show promise in reducing pathology and improving cognitive outcomes in mouse models of AD and in aging. Here, we sought to exploit the beneficial properties of CD4+ T cells while circumventing the need for TCR and peptide-MHC antigen discovery, thereby providing a potential universal therapeutic approach. To achieve this, we engineered CD4+ T cells with chimeric antigen receptors (CARs) targeting fibrillar forms of aggregated amyloid-β. Our findings demonstrate that optimized CAR-T cells can alter amyloid deposition in the dura and reduce parenchymal pathology in the brain. Furthermore, we observed that CAR-T treatment promotes the expansion and recruitment of endogenous CD4+ T cells into the brain parenchyma and leptomeninges. In summary, we established the feasibility of amyloid plaque-specific CAR-T cells as a potential therapeutic avenue for AD. These findings highlight the potential of CD4+ CAR-T therapy not only to modify amyloid pathology but also to reshape the immune landscape of the CNS, paving the way for future development of cellular immunotherapies for neurodegenerative disease.

Keywords: Alzheimer’s disease; CAR T cells; T cell; chimeric antigen receptors; neurodegeneration.

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A single oncolytic virus injection may help T cells infiltrate glioblastoma

A team led by investigators at Mass General Brigham and Dana-Farber Cancer Institute has shown that a single injection of an oncolytic virus—a genetically modified virus that selectively infects and destroys cancer cells—can recruit immune cells to penetrate and persist deep within brain tumors. The research, which is published in Cell, provides details on how this therapy prolonged survival in patients with glioblastoma, the most common and malignant primary brain tumor, in a recent clinical trial.

“Patients with glioblastoma have not benefited from immunotherapies that have transformed patient care in other cancer types such as melanoma because glioblastoma is a ‘cold’ tumor with poor infiltration by cancer-fighting immune cells,” said co-senior author Kai Wucherpfennig, MD, Ph.D., chair of the Department of Cancer Immunology and Virology at the Dana-Farber Cancer Institute.

“Findings from our clinical trial and our mechanistic study show that it is now feasible to bring these critical immune cells into glioblastoma.”

A “dormant” brain protein turns out to be a powerful switch

Researchers at Johns Hopkins Medicine report that they have uncovered a promising drug target that could allow scientists to increase or decrease the activity of specific brain proteins. The discovery may lead to new treatments for psychiatric conditions such as anxiety and schizophrenia, as well as a neurological disorder that affects movement and balance. The work was supported by funding from the National Institutes of Health.

The proteins at the center of the research are known as delta-type ionotropic glutamate receptors, or GluDs. These proteins are known to play an important role in how neurons communicate with each other. According to the researchers, mutations in GluDs have been linked to psychiatric disorders, including anxiety and schizophrenia. Despite this connection, scientists have struggled for years to understand exactly how these proteins work, making it difficult to design treatments that could regulate their activity.

“This class of protein has long been thought to be sitting dormant in the brain,” says Edward Twomey, Ph.D., assistant professor of biophysics and biophysical chemistry at the Johns Hopkins University School of Medicine. “Our findings indicate they are very much active and offer a potential channel to develop new therapies.”

The Computer That Consumes Stars

And a black hole would be a type of computer if we could use it.

What is the ultimate limit of a civilization? It isn’t conquering a galaxy. It is processing power.

A “Matrioshka Brain” is a megastructure so massive it encases an entire star. It is a Dyson Sphere upgraded to God-Mode. Instead of just harvesting energy, it uses the star to fuel a computer powerful enough to simulate trillions of universes.

If a civilization builds one of these, they don’t need to explore space. They can upload their minds to a digital heaven and live forever. This might be the terrifying reason why the universe is so silent.

Chapters:

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Neural crest cells: Miniature electric muscles that colonize embryonic organs

Neural crest cells are a population of stem cells that invade the embryo in early development. They play a big role in what you look like: the pigments of your eyes, of your skin, and the bone structure of your face are all neural crests. Inside your body, the neural crest will form the myelin sheath of your peripheral nervous system and the entire nervous system of your intestine, the so-called “second brain.”

Neurocristopathies are a range of pathologies resulting from defective neural crest migration. One of the most frequent ones is Hirschsprung disease; it affects 1 in 5,000 newborns. These babies lack a nervous system inside their colon because the neural crest cells didn’t make it all the way to the end of the digestive tract during embryogenesis. The condition is lethal if not surgically treated at birth and its causes remain unknown in more than half of cases.

Among the identified genes involved in Hirschsprung disease, one has stood out for more than half a century: the peptide endothelin 3. Mice and humans with genetic defects in either endothelin 3 or its receptor EDNRB develop the disease, in some cases accompanied with pigmentation or craniofacial defects.

Discovery of unique brain tumor subtypes offers hope for targeted glioma therapies

Researchers have uncovered the mechanisms behind three unique subtypes of mismatch repair deficient high-grade gliomas. The findings provide a clearer understanding of how these tumors develop, explain why patients respond differently to immunotherapy, and are already helping guide more precise therapies.

High-grade gliomas are a group of aggressive brain tumors and one of the deadliest tumors in children and young adults. In some children, the tumors are driven by mismatch repair deficiency (MMRD), which is characterized by hypermutation (a large and quickly accumulating number of mutations in tumor cells) and resistance to standard treatments such as chemotherapy and radiation.

Tumors driven by mismatch repair deficiency are known as primary mismatch repair deficient high‑grade gliomas (priMMRD‑HGG). Because priMMRD-HGG have high numbers of mutations, treatment has shifted to immunotherapy, which uses the body’s own immune system to fight cancer by targeting cancer cells.

This Brain Experiment Made People Choose Others Over Themselves

Scientists found that synchronizing activity between two brain regions made people more generous.

A new study suggests that synchronizing activity in specific parts of the brain can make people more likely to act generously. Research published today (February 10) in the open-access journal PLOS Biology reports that stimulating two brain regions in a coordinated way increased altruistic behavior. The study was led by Jie Hu of East China Normal University in China, working with colleagues from the University of Zurich in Switzerland.

Why some people are more altruistic than others.

Scientists Have Discovered a Protein That Reverses Brain Aging in The Lab

Our brains age along with the rest of our bodies, and as they do, they produce fewer new brain cells. Now, researchers have found a key mechanism through which the typical age-related decline in neuron production might be slowed.

In later life, the neural stem cells (NSCs) that turn into fully fledged neurons become more dormant – almost as if they’re going into retirement after a long lifetime of service. As that happens, cognitive decline creeps in.

A major reason why NSC activity fades with age is the wear and tear on telomeres, the protective caps on the ends of DNA. Telomeres fray a little more each time a cell divides, and over time, this impairs cells’ ability to grow and divide, leading to increasing cell death.

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