New insights into how obesity and insulin resistance can alter cognition

Obesity can destroy our protective blood-brain barrier, leading to learning and memory problems, scientists have reported.

They knew that the chronic activation of the Adora2a receptor on the endothelial cells that border this important barrier in our brain can let blood factors enter the brain and affect the functioning of our neurons.

Today, scientists at the Medical College of Georgia have shown that, when they block Adora2a in a diet-induced obesity model, this important barrier function is maintained.

"We know that obesity and insulin resistance suppress the blood-brain barrier in humans and animal models, but the mystery remains," said Dr. Alexis M. Stranahan, neuroscientist at the Department of Neuroscience and Regenerative Medicine at MCG at Augusta University. . Stranahan is the corresponding author of the study published in The Journal of Neuroscience this provides a new overview.

In the brain, adenosine is a neurotransmitter that helps us sleep and regulate our blood pressure. in the body, it is also a component of adenosine triphosphate, or ATP, a fuel for cells. Adenosine also activates Adora1a and Adora2a receptors on endothelial cells, which normally promotes healthy relationships between brain activity and blood flow.

Problems arise with chronic activation, especially in the brain, which happens with obesity, Stranahan says.

People suffering from obesity and diabetes have high rates of cognitive impairment as they age and most of the related structural changes relate to the hippocampus, a learning and memory center and the Stranahan Study Center. Fat is a source of inflammation and there is evidence that reducing chronic inflammation in the brain helps prevent memory loss badociated with obesity.

In a model that mimics what happens to some of us, young mice fed on a high-fat diet got fat in two weeks and, after 16 weeks, their fasting glucose and insulin levels increased , sign of diabetes in the future.

The researchers found that obesity increased the permeability of the blood-brain barrier to very small molecules such as fluorescein sodium fluorophore, or NaF1, in the vasculature of the hippocampus. The diet-induced insulin resistance increases this permeability, so that a larger molecule, Evans Blue, which has a high affinity for serum albumin, the most abundant protein in the body. blood, can also pbad.

In the electron microscope, they noticed a change of scenery. The resulting diabetes facilitated the narrowing of the usually narrow junctions between the endothelial cells and the actual holes in these cells. They also saw muscle cells called pericytes that wrap the outer microscopic blood vessels in the brain to give them more strength and allow them to advance the blood, begin to lose their adhesion, so that the blood vessels begin to lose their tone, become dysfunctional and inflamed. Pericytes are known to express higher levels of Adora2a than endothelial cells, notes Stranahan. The high-fat diet also promoted the swelling of protrusions on astrocytes called the extremities of the feet, which are also part of the blood-brain barrier. Astrocytes are brain cells that normally feed neurons, but the pathological condition of obesity has also altered their shape and support.

Angiogenesis, the body's natural attempt to make more blood vessels – although these are usually dysfunctional and leaking – in response to a deficiency of blood flow and oxygen in the hippocampus occurred after 12 weeks. After careful inspection, the blood vessels were inflamed.

When they gave a drug to temporarily block Adora2a, it also blocked barrier permeability issues. It remains to be seen if this could work in humans and in the long run as a way to avoid cognitive decline in obese humans, notes Stranahan.

Then they developed a mouse in which they could selectively eliminate Adora2a from endothelial cells.

In this transgenic mouse, they deactivated Adora2a in the endothelial cells at 12 weeks and at 16 weeks, whereas the mice had to have a cognitive deficit and a blood-brain barrier, their cognitive function and barrier function were normal, without inflammation.

When they compared transgenic mice that followed a rich or low-fat diet, they found evidence that increasing the permeability of blood vessels in the brain triggers the cycle of inflammation. and cognitive disorders.

Although it is generally difficult to move from the mouse to the human, the fact that this type of work has started with human discoveries probably means that avoiding resistance to it is not an easy task. Insulin could potentially put an end to the increased permeability of the blood-brain barrier and a decrease in cognitive function, says Stranahan.

"If an individual has already progressed toward insulin resistance, these studies emphasize the importance of controlling blood sugar and avoiding progressing to insulin deficiency (diabetes), which opens up further. the blood-brain barrier. "

Scientists report that the relative accessibility of blood vessels in the brain could also make it a good way to prevent the effects of obesity on the brain.

This also highlights the fact that a variety of drugs given to obese patients can have a greater impact on their brains, which patients and their doctors might possibly consider. Stranahan notes that for drugs intended to act on the brain, such as those used in Alzheimer's disease, this could be a good thing, but still needs to be taken into account. In contrast, some commonly prescribed medications, such as prednisone, are already highly effective and can potentially be harmful to the brain, she says.

The next steps in his lab are determining where is the signal that chronically activates Adora2 in large mice. She suspects that it is actually a cascade involving stressed endothelial cells, which increases their metabolism, which means that they use more ATP, which means can activate Adora2a and trigger a vicious circle that ends up damaging the blood-brain barrier.

The concept that obesity could affect the blood-brain barrier began a dozen years ago, when Swedish researchers discovered that obese patients had higher levels of major antibody, Immunoglobulin G, in their cerebrospinal fluid, while it should have been in their blood. This was an important finding suggesting that obesity and diabetes could allow brain elements to reach the brain that should not, Stranahan adds. Animal studies confirmed that this was happening, but again, few studies have examined why, says Stranahan.

The blood vessels come out of the body and become extremely small and fragile as they plunge into the brain. While the blood vessels that supply areas such as the arms and heart are more porous, they can share a lot of glucose, oxygen and immune cells, among other things whose body, the cerebrovascular system, is supposed to be much more restrictive. leaving relatively few things.

"It's more like a door than a barrier," says Stranahan, and it's a dynamic barrier to that, based on what the brain is preparing. "It has carriers that can move things and what happens in the brain and in the blood can change the way it works."

She notes that the brain consumes a lot, absorbing 70 to 80% of our oxygen and glucose, but also more fragile than other tissues, extremely sensitive even to our own immune cells.

"It's as if a child growing up in the mud would have a stronger immune system than a child who would grow up indoors and play video games," says Stranahan.

Cognitive tests on study mice included object recognition and maneuvering of an aquatic labyrinth. Scientists have examined other normal functions, such as simple motor functions, to see if there were any other effects and, at least at these early times, do not have any identified from others.