Researchers have created a human iPS-cell-derived 3D model of the blood-brain barrier

 Good news!

"Researchers have created a 3D model of the blood-brain barrier — a membrane that protects the brain from pathogens — entirely from human induced pluripotent stem cells. The model provides an alternative to rodent and in vitro models which fall short on translatability and hinder drug discovery. Stem cells are induced to become endothelial cells, astrocytes and pericytes or smooth muscle cells, which then develop into vessel-like tubes (pictured) mimicking the blood-brain barrier. Malfunctions of the barrier can cause neurodegenerative disorders and other health problems."

From the abstract:
"Blood–brain barrier (BBB) integrity is critical for brain homeostasis, with malfunctions contributing to neurovascular and neurodegenerative disorders. Mechanistic studies on BBB function have been mostly conducted in rodent and in vitro models, which recapitulate some disease features, but have limited translatability to humans and pose challenges for drug discovery.
Here we report on a fully human induced pluripotent stem (iPS)-cell-derived, microfluidic three-dimensional (3D) BBB model consisting of endothelial cells (ECs), mural cells and astrocytes. Our model expresses typical fate markers, forms a barrier in vessel-like tubes and enables perfusion, including with human blood. Deletion of FOXF2 in ECs, a major risk gene for cerebral small vessel disease, induced key features of BBB dysfunction, including compromised cell junction integrity and enhanced caveolae formation.
Proteomic analysis revealed dysregulated endocytosis and cell junction pathways. Disease features phenocopied those seen in mice with EC-specific Foxf2 deficiency. Moreover, lipid-nanoparticle-based treatment with Foxf2 mRNA rescued BBB deficits, demonstrating the potential for drug development."

Nature Briefing: Translational Research

A fully iPS-cell-derived 3D model of the human blood–brain barrier for exploring neurovascular disease mechanisms and therapeutic interventions (open access)

Fig. 2: Generation and characterization of a fully iPS-cell-derived human 3D BBB model to investigate neurovascular disorders. [what a busy figure]

Scientists reverse Alzheimer's in mice using nanoparticles

Good news!

"... Unlike traditional nanomedicine, which relies on nanoparticles as carriers for therapeutic molecules, this approach employs nanoparticles that are bioactive in their own right: "supramolecular drugs." ...

Instead of targeting neurons directly, the therapy restores the proper function of the blood-brain barrier (BBB) ... By repairing this critical interface, the researchers achieved a reversal of Alzheimer's pathology in animal models. ...

The team demonstrated that targeting a specific mechanism enables undesirable "waste proteins" produced in the brain to pass through this barrier and be eliminated in the blood flow. In Alzheimer's disease, the main "waste" protein is amyloid-β (Aβ), whose accumulation impairs the normal functioning of the neurons. ..."

From the abstract:

"The blood‒brain barrier (BBB) is a highly selective permeability barrier that safeguards the central nervous system (CNS) from potentially harmful substances while regulating the transport of essential molecules. Its dysfunction is increasingly recognized as a pivotal factor in the pathogenesis of Alzheimer’s disease (AD), contributing to the accumulation of amyloid-β (Aβ) plaques.

We present a novel therapeutic strategy that targets low-density lipoprotein receptor-related protein 1 (LRP1) on the BBB. Our design leverages the multivalent nature and precise size of LRP1-targeted polymersomes to modulate receptor-mediated transport, biasing LRP1 trafficking toward transcytosis and thereby upregulating its expression to promote efficient Aβ removal.

In AD model mice, this intervention significantly reduced brain Aβ levels by nearly 45% and increased plasma Aβ levels by 8-fold within 2 h, as measured by ELISA.

Multiple imaging techniques confirmed the reduction in brain Aβ signals after treatment.

Cognitive assessments revealed that treated AD mice exhibited significant improvements in spatial learning and memory, with performance levels comparable to those of wild-type mice.

These cognitive benefits persisted for up to 6 months post-treatment.

This work pioneers a new paradigm in drug design, where function arises from the supramolecular nature of the nanomedicine, harnessing multivalency to elicit biological action at the membrane trafficking level.

Our findings also reaffirm the critical role of the BBB in AD pathogenesis and demonstrate that targeting the BBB can make therapeutic interventions significantly more effective.

We establish a compelling case for BBB modulation and LRP1-mediated Aβ clearance as a transformative foundation for future AD therapies."

Scientists reverse Alzheimer's in mice using nanoparticles

Rapid amyloid-β clearance and cognitive recovery through multivalent modulation of blood–brain barrier transport (open access)

Fig. 1 Schematics of LRP1 shuttling across brain endothelial cells

How typhoid fever triggers severe neurological symptoms

Good news! Amazing stuff!

"About 15% of patients with typhoid fever develop serious neurological complications, including delirium and seizures, that are collectively described as acute encephalopathy. Until now, however, scientists have not clearly understood the mechanisms behind these life-threatening neurological effects. 

A new ... provides critical insights into how typhoid fever leads to encephalopathy. Researchers found that typhoid toxin, a key virulence factor only produced by the bacterium Salmonella Typhi, does not directly damage brain cells, as previously thought. Instead, it targets the endothelial cells lining the blood-brain barrier (BBB), causing significant barrier disruption and subsequent brain pathology.  ...

mice engineered to protect endothelial cells from toxin binding showed no neurological symptoms. ..."

From the abstract:

"Typhoid fever, primarily caused by Salmonella Typhi, can result in severe life-threatening complications such as encephalopathy. Here we elucidate the mechanisms by which typhoid toxin, a unique virulence factor of S. Typhi, mediates the neuropathology associated with typhoid fever.

Utilizing mice engineered to have specific tissues protected from toxin action and an in vitro model of the blood–brain barrier (BBB), we demonstrate that, rather than direct action on neuronal or glial cells, typhoid toxin causes neuropathology by disrupting the BBB.

Intravenous tracer studies confirmed significant BBB permeability changes following toxin exposure, an effect we found to be mediated by typhoid toxin’s CdtB catalytic subunit. We demonstrate that corticosteroids are effective at mitigating BBB disruption in vivo, supporting their use for managing typhoid fever neurological complications. Our data reveal mechanistic insight into how typhoid toxin causes encephalopathy and suggest targeted therapeutic interventions to alleviate the severe neurological manifestations of typhoid fever."

How typhoid fever triggers severe neurological symptoms | Yale News "Yale researchers have discovered how typhoid fever triggers neurological symptoms, offering new insight into treatment options."

Typhoid toxin causes neuropathology by disrupting the blood–brain barrier (no public access)

Changes in brain’s ‘sugar shield’ could be key to understanding effects of aging

Good news! This could be a breakthrough!

Is this where the sweet tooth comes from? 😊

"What if a critical piece of the puzzle of brain aging has been hiding in plain sight? While neuroscience has long focused on proteins and DNA, a team of Stanford researchers dared to shift their gaze to sugars – specifically the complex sugar chains that cover all our cells like chain mail. ...

In a study in aging mice, Shi has uncovered striking age-related changes in the sugary coating – called the glycocalyx – on cells that form the blood-brain barrier, a structure that protects the brain by filtering out harmful substances while allowing in essential nutrients. ...

These age-related changes to the glycocalyx weaken the blood-brain barrier, Shi found. As the barrier becomes leaky with age, harmful molecules can infiltrate the brain, potentially fueling inflammation, cognitive decline, and neurodegenerative diseases. ...

The results were striking: In older mice, bottlebrush-shaped, sugar-coated proteins called mucins, a key component of the glycocalyx, were significantly reduced. This thinning of the glycocalyx correlated with increased permeability of the blood-brain barrier and heightened neuroinflammation.

When the team reintroduced those critical mucins in aged mice, restoring a more “youthful” glycocalyx, they improved the integrity of the blood-brain barrier, reduced neuroinflammation, and measurably improved cognitive function. ..."

From the abstract:

"The blood–brain barrier (BBB) is highly specialized to protect the brain from harmful circulating factors in the blood and maintain brain homeostasis.

The brain endothelial glycocalyx layer, a carbohydrate-rich meshwork composed primarily of proteoglycans, glycoproteins and glycolipids that coats the BBB lumen, is a key structural component of the BBB. 

This layer forms the first interface between the blood and brain vasculature, yet little is known about its composition and roles in supporting BBB function in homeostatic and diseased states.

Here we find that the brain endothelial glycocalyx is highly dysregulated during ageing and neurodegenerative disease. We identify significant perturbation in an underexplored class of densely O-glycosylated proteins known as mucin-domain glycoproteins.

We demonstrate that ageing- and disease-associated aberrations in brain endothelial mucin-domain glycoproteins lead to dysregulated BBB function and, in severe cases, brain haemorrhaging in mice.

Finally, we demonstrate that we can improve BBB function and reduce neuroinflammation and cognitive deficits in aged mice by restoring core 1 mucin-type O-glycans to the brain endothelium using adeno-associated viruses. Cumulatively, our findings provide a detailed compositional and structural mapping of the ageing brain endothelial glycocalyx layer and reveal important consequences of ageing- and disease-associated glycocalyx dysregulation on BBB integrity and brain health."

Changes in brain’s ‘sugar shield’ could be key to understanding effects of aging | Stanford Report "New findings about the sugary armor on the brain’s frontline cells could shed light on cognitive decline and diseases like Alzheimer’s – and open new avenues for treatment."

Glycocalyx dysregulation impairs blood–brain barrier in ageing and disease (open access)

What a sweet smile! Sophia Shi, the study’s lead author and a Stanford Bio-X Graduate Fellow and PhD student in the Department of Chemistry.

Fig. 1: The brain endothelial glycocalyx is highly dysregulated during ageing.

Fig. 3: Reduced brain endothelial mucin-type O-glycosylation increases BBB leakiness and brain bleeding.

In young mice (left), a dense layer of sugar molecules (shown in black on this transmission electron micrograph) coats the inner lining of the brain vasculature.

In older mice (right), that layer becomes sparse and thinner.

Fish Have a Brain Microbiome. Could Humans Have One Too?

Recommendable!

"... Recently, a study published in Science Advances provided the strongest evidence yet that a brain microbiome can and does exist in healthy vertebrates — fish, specifically. Researchers at the University of New Mexico discovered communities of bacteria thriving in salmon and trout brains. Many of the microbial species have special adaptations that allow them to survive in brain tissue, as well as techniques to cross the protective blood-brain barrier. ..."

Fish Have a Brain Microbiome. Could Humans Have One Too? | Quanta Magazine "Scientists have discovered the strongest evidence yet that healthy vertebrates can have brain microbiomes."

Questions Raised About Widely Used Blood-Brain Barrier Model

Recommendable!

"well-known in vitro model of the blood-brain barrier that is widely used in studies of neurodegenerative diseases and in preclinical research is made from the wrong kind of cells ... Researchers report in the study that cells produced using a popular lab protocol, which involves reprogramming human pluripotent stem cells (hPSCs), show gene expression patterns typical of the epithelial cells coating human organs, rather than of the blood-brain barrier (BBB) endothelial cells they’re supposed to mimic."

"Human PSC [pluripotent stem cells]-derived iBMECs  [induced brain microvascular endothelial cells] have been generated to study disease mechanisms and drug development for neurological disorders. However, their full transcriptomic characterization is unclear, which could result in inaccurate physiological studies and development of treatments with ineffective clinical outcomes. ..."

Questions Raised About Widely Used Blood-Brain Barrier Model | The Scientist Magazine® A study has sparked controversy by suggesting that cells made using a popular lab protocol have been misidentified, with potentially serious repercussions for brain research. Critics say the significance of the findings has been overstated.

Here is the link the referenced paper:

Pluripotent stem cell-derived epithelium misidentified as brain microvascular endothelium requires ETS factors to acquire vascular fate