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.