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Category: neuroscience

CRISPR-Based Screen Reveals Possible Anti-Tau Mechanism

This screening platform washed cells with a broad range of retroviruses to determine which ones affect tau. In follow-up testing, the gene CUL5 was singled out as being crucial for tau degradation. Mitochondrial function was also found to be a key part of preventing tau pathology.

Using an ingenious CRISPR-based screening technique, scientists have found a protein that tags tau for degradation and is more strongly expressed in tau-resilient neurons [1].

Some neurons are more equal than others

The accumulation of tau protein fibrils in neurons is a hallmark of Alzheimer’s and several other diseases [2]. Scientists have long noticed that even in the brains of people who died of Alzheimer’s, some neurons are markedly healthier than others, suggesting that neurons differ in how they handle tau and that these differences may explain selective vulnerability in tauopathies [3].

Securing the Neural Frontier: Cybersecurity and Privacy Risks in Brain-Computer Interfaces and Neurotechnology

Please see my LinkedIn article: “Securing the Neural Frontier.”

We are poised to witness one of the most significant technological advancements in human history: the direct interaction between human brains and machines. Brain-computer interfaces (BCIs), neurotechnology, and brain-inspired computing have already arrived and need to be secure.

Link.

High-risk EPN models present the immunotherapeutic target GD2 and are sensitive to GD2–CAR T cell therapy in vitro and in vivo

Research Letter: CAR T cells targeting the glycoprotein GD2 show potent antitumor efficacy in high-risk ependymoma models.

Antonio Carlos Tallon-Cobos & team establish a new ependymoma model for preclinical research and demonstrate a promising immunotherapeutic approach for this largely aggressive pediatric brain cancer.

1Princess Máxima Center for pediatric oncology, Utrecht, Netherlands.

2Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.

3Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Consortium (DKTK), Heidelberg, Germany.

Immunotherapy could prevent the loss of neurons in Parkinson’s disease

Parkinson’s disease is characterized by the progressive loss of dopaminergic neurons in a specific brain region known as the substantia nigra. This neuronal degeneration is closely linked to inflammatory processes mediated by microglia, the immune cells of the central nervous system. However, the precise mechanisms that trigger this destructive process are still not fully understood.

Now, in an article published in npj Parkinson’s Disease, researchers from the Institut de Neurociències of the Universitat Autònoma de Barcelona (INc-UAB) and the UAB Department of Biochemistry and Molecular Biology report that brain tissue from Parkinson’s disease patients contains a higher proportion of reactive microglia, meaning cells that are primed to respond. But most importantly, these reactive microglial cells also show an increased density of receptors known as Fc gamma on their membranes.

Scientists Uncover a Hidden Early Stage of Alzheimer’s That They Can Stop

The researchers suggested that higher concentrations of charged ions weaken the interaction between tau proteins and heparin, making cluster formation more difficult. This occurs because charged molecules such as tau and heparin become less able to interact due to electrostatic “screening,” which effectively masks their charges from one another.

A New Direction for Treating Neurodegenerative Disease

These results point toward a different strategy for developing therapies. Rather than attempting to break apart fully formed tau fibrils, future treatments could focus on blocking the reversible precursor stage before irreversible damage takes place. This approach could have implications beyond Alzheimer’s disease, potentially influencing research into other neurodegenerative disorders, including Parkinson’s disease.

Ferroptosis as a therapeutic target in glioblastoma: Mechanisms and emerging strategies

Ferroptosis: a promising therapeutic strategy in glioblastoma👇

✅Glioblastoma multiforme (GBM) is an aggressive brain tumor characterized by rapid growth and resistance to conventional therapies. Recent research highlights ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, as a novel and promising approach for GBM treatment.

✅One key mechanism underlying ferroptosis in GBM is glutathione depletion. Inhibition of the cystine/glutamate antiporter system (xCT) limits cystine uptake, leading to reduced glutathione synthesis. As a consequence, the antioxidant enzyme GPX4 becomes inactivated, impairing the cell’s ability to detoxify lipid peroxides.

✅Lipid peroxidation is a central event in ferroptosis. Polyunsaturated fatty acids (PUFAs) incorporated into membrane phospholipids are highly susceptible to oxidative damage. Their conversion into peroxidized phospholipids (PL-PUFA-PE) disrupts membrane integrity and drives lethal oxidative stress.

✅Iron metabolism further amplifies ferroptotic signaling in GBM cells. Elevated intracellular iron, particularly the Fe²⁺ pool, catalyzes redox reactions that generate reactive oxygen species (ROS). This iron-driven ROS production accelerates lipid peroxidation and pushes tumor cells toward ferroptotic death.

✅Collectively, glutathione depletion, GPX4 inactivation, uncontrolled lipid peroxidation, and dysregulated iron metabolism converge to induce ferroptosis. Targeting these interconnected pathways offers a potential strategy to overcome therapy resistance and selectively eliminate GBM cells.

Continue reading “Ferroptosis as a therapeutic target in glioblastoma: Mechanisms and emerging strategies” | >

Speaking multiple languages appears to keep the brain younger for longer

A study of 86,000 adults across Europe links multilingualism to slower biological aging. Researchers found that people who speak multiple languages tend to maintain better cognitive function and physical health than their monolingual peers.

EGFR activation sensitizes trigeminal NMDA receptors to promote pain and morphine analgesic tolerance in oral cancer

Oral squamous cell carcinoma (OSCC) is a painful disease that severely impairs eating, drinking, and talking (1–5). Patients with OSCC are less opioid responsive and develop opioid tolerance quicker than patients with other chronic pain conditions (6, 7). Escalating doses of opioids are required as tolerance develops, causing not only severe adverse effects (6) such as addiction but also prolonged hospitalizations and increased readmission rate in patients (8). The mechanisms underlying oral cancer pain and opioid tolerance are not well understood.

Epidermal growth factor receptor (EGFR) is a member of the receptor tyrosine kinases (RTKs) subfamily named HER/ERBB that is aberrantly expressed in 80 to 100% of the OSCC cases (9–11). EGFR antagonism including antibodies and tyrosine kinase inhibitors (TKIs) are US Food and Drug Administration (FDA) approved to treat many cancers, including OSCC (12–14). Clinical studies report pain relief in patients with neuropathic pain, including those associated with cancer after treatment with EGFR inhibitors (15, 16). Human genetic studies find associations between painful disease conditions and EGFR and its ligands, such as epiregulin, heparin-binding EGF (HB-EGF), and transforming growth factor–α (TGFα) (17–19). In animal models, HB-EGF directly causes dorsal root ganglion (DRG) cell excitation and elicits pain-like behaviors, whereas epiregulin mainly works in conjunction with underlying inflammation or tissue injury to generate pain (17, 19, 20). EGFR has also been implicated in opioid tolerance in human (21) and animal studies (20, 22, 23). Although elegant mechanistic studies suggest that EGFR can activate various pathways—through the ion channel transient receptor potential vanilloid 1 (TRPV1), the kinase cascade phosphatidylinositol 3-kinase (PI3K)–AKT–mammalian target of rapamycin (mTOR), the protease matrix metalloproteinase–9 (MMP-9), or the oncogene KRAS [to tetrahydrobiopterin (BH4)]—to increase pain sensitivities in mice (17, 24), these studies were done at the spinal level of noncancer pain models. It has been shown that EGFR involvement in pain is ligand and disease dependent (17, 25, 26), which warrants the investigation of EGFR signaling both in the setting of oral cancer pain that involves the trigeminal system and in opioid analgesic tolerance.

In this study, we aimed to determine how EGFR signaling contributes to oral cancer pain and opioid tolerance. We found that EGFR activation sensitizes trigeminal ganglion (TG) neurons and enhances glutamate N-methyl-d-aspartate receptor (NMDAR) signaling, resulting in heightened cancer pain and diminished opioid analgesic efficacy. EGFR ligands abundant in the OSCC tumor microenvironment trigger calcium influx, NMDAR phosphorylation, and protein kinase C (PKC) up-regulation in TG neurons. Last, we showed that EGFR activation induces presynaptic and postsynaptic hypersensitivity of NMDARs in the trigeminal nucleus caudalis (TNc) of the brainstem. Together, these findings establish EGFR-mediated NMDAR sensitization as a central mechanism underlying oral cancer pain and opioid tolerance and highlight EGFR as a promising therapeutic target.

Higher Prevalence of Coronary Microvascular Dysfunction in Patients With HFpEF Without Obesity

Advanced psc-based strategies for leukodystrophy therapy👇

✅Pluripotent stem cell (PSC)–based technologies are opening new avenues for the treatment of leukodystrophies by combining cell replacement, gene correction, disease modeling, and drug discovery within a unified framework.

✅One major approach focuses on the development of off-the-shelf PSC-derived neural progenitor cells (NPCs). By precisely editing immune-related genes, PSCs can be engineered to evade immune rejection. Strategies include knocking out core components of HLA class I and II pathways while introducing protective molecules such as HLA-E, or selectively removing highly immunogenic HLA alleles. These modifications allow the generation of universal donor NPCs that are resistant to T cell– and NK cell–mediated killing.

✅Autologous induced pluripotent stem cell (iPSC) therapy represents a personalized treatment strategy. Patient-derived somatic cells are reprogrammed into iPSCs, followed by genetic correction of disease-causing mutations using viral vectors or CRISPR/Cas9-based editing. Corrected iPSCs are then differentiated into neural stem cells (NSCs), NPCs, or oligodendrocyte progenitor cells (OPCs) and transplanted back into the same patient, minimizing immune complications.

✅Beyond therapy, iPSC-based disease models provide powerful tools to study leukodystrophy pathogenesis. Disease-specific iPSCs recapitulate key cellular phenotypes such as impaired differentiation, lysosomal dysfunction, oxidative stress, and apoptosis. These models enable direct investigation of early developmental defects that are difficult to access in patients.

✅Corrected iPSCs restore normal cellular phenotypes, allowing direct comparison between diseased and healthy isogenic cells. This approach clarifies causal mechanisms and validates gene correction strategies at the cellular level, supporting precision medicine.

✅iPSC-derived neural systems also support advanced drug discovery platforms. By generating complex neural cultures or myelinating organoids (“myelinoids”), researchers can model neuron–glia interactions and myelination in vitro. Coupled with immunofluorescence, transcriptomics, and high-throughput screening, these systems enable systematic identification of small molecules that promote myelination or correct metabolic defects.

Continue reading “Higher Prevalence of Coronary Microvascular Dysfunction in Patients With HFpEF Without Obesity” | >

Scientists discover how to reactivate cancer’s molecular “kill switch”

(Farmington, Conn. – March 13, 2025) – Alternative RNA splicing is like a movie editor cutting and rearranging scenes from the same footage to create different versions of a film. By selecting which scenes to keep and which to leave out, the editor can produce a drama, a comedy, or even a thriller—all from the same raw material. Similarly, cells splice RNA in different ways to produce a variety of proteins from a single gene, fine-tuning their function based on need. However, when cancer rewrites the script, this process goes awry, fueling tumor growth and survival.

In a recent study reported in the Feb. 15 issue of Nature Communications, scientists from The Jackson Laboratory (JAX) and UConn Health not only show how cancer hijacks this tightly regulated splicing and rearranging of RNA but also introduce a potential therapeutic strategy that could slow or even shrink aggressive and hard-to-treat tumors. This discovery could transform how we treat aggressive cancers like triple-negative breast cancer and certain brain tumors, where current treatment options are limited.

At the heart of this work, led by Olga Anczuków, an associate professor at JAX and co-program leader at the NCI-designated JAX Cancer Center, are tiny genetic elements called poison exons, nature’s own “off switch” for protein production. When these exons are included in an RNA message, they trigger its destruction before a protein can be made—preventing harmful cellular activity. In healthy cells, poison exons regulate the levels of key proteins, keeping the genetic machinery in check. But in cancer, this safety mechanism often fails.

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