Why does the brain with Alzheimer’s become resistant to insulin?

Resume: Insulin-binding receptors are found predominantly on microvessels within the blood-brain barrier. In Alzheimer’s patients, the abundance of these receptors is decreased. This decline could lead to loss of insulin response in the Alzheimer’s brain.

Fountain: The conversation

As the population ages, the number of people with neurodegenerative diseasessuch as Alzheimer disease, increases. About 75,000 Canadians are diagnosed with Alzheimer’s disease each year and experience a decline in their cognitive abilities. The ordeal usually lasts several years while their relatives watch helplessly.

Neurodegenerative diseases are characterized by proteinopathies — abnormal accumulations of proteins in the brain that impair the function of neurons. The most widely studied therapeutic approach to develop drugs for Alzheimer’s is to try to reduce the aggregation of beta amyloid peptide Y protein number in neurons.

However, to reach their targets, the drugs must first cross the blood brain barrier (BBB) ​​from the blood to the brain. This is because endothelial cells, cells that line the smallest blood vessels in the brain, regulate the exchange between the blood and the brain. They maintain a balance that allows access to essential molecules such as glucose, but restricts the passage of most pharmaceuticalsincluding new and highly publicized drug lecanemab.

When these brain endothelial cells become diseased, the balance is upset. The brain fights to get the substances it needs back into circulation and rejects those that could harm it.

The brain and the other organs of the body are thus in constant communication, both in health and in disease.

As experts in neurodegenerative diseases and at the BBB, we have conducted a study on insulin receptor dysfunction in Alzheimer’s disease.

Insulin and the brain

Insulin It is an essential hormone for life. It is best known for its effect on the regulation of sugar in the blood and remains an essential part of the pharmaceutical treatment of diabetes. In recent decades, investigators have observed vascular and metabolic abnormalities in a high proportion of patients with dementia.

In fact, type 2 diabetes, characterized in the later stages by insulin resistance, is a major risk factor for Alzheimer’s disease. There is some evidence to suggest that the Alzheimer’s brain responds less to insulin. Rather, studies have shown that insulin can improve memorypromoting the development of clinical trials on the effect of insulin in Alzheimer’s disease.

However, we do not yet know what cell types and mechanisms are involved in the action and loss of action of insulin in the brain. The vast majority of insulin is produced by the pancreas and secreted into the bloodstream. Therefore, to affect the brain, insulin must first interact with the BBB and its endothelial cells, which are in contact with the blood and can absorb insulin through receivers.

Alzheimer’s and the insulin receptor

To measure the number of these insulin receptors in the brain, we perform analyzes directly on human tissues. These samples came from a cluster of more than a thousand people who agreed to donate their brains after their death. We have access to them through a partnership with researchers at Rush University in Chicago.

We found that the insulin binding receptor it is found predominantly in the microvessels, therefore within the BBB itself. Furthermore, the abundance of this receptor is decreased in Alzheimer’s patients. This decline could lead to loss of insulin response in the Alzheimer’s brain.

Insulin receptor dysfunction

To better control the experimental variables and measure the insulin receptor response, we tested our hypotheses in mice. The in the place The cerebral perfusion technique consists of injecting insulin directly into the carotid artery (an artery located in the neck) so that it reaches the entire brain. We have shown that circulating insulin primarily activates receptors located in brain microvessels.

Although it was generally accepted that insulin crosses the BBB to reach cells such as neurons deeper in brain tissue, our results show that the proportion of insulin that crosses the BBB is low.

These two observations confirm that most insulin must interact with BBB cells before it can exert an action in the brain.

We then apply the same method to transgenic mice, which were genetically modified to model Alzheimer’s disease. We found that the insulin response in the BBB was dysfunctional, with no insulin receptor activation in these diseased mice.

Therefore, in both humans and rodents, the brain’s insulin receptor is located primarily on the BBB, and its ability to respond to blood insulin is impaired in Alzheimer’s disease.

See also

a significant advance

In summary, our results suggest that alterations in the number, structure, and function of insulin receptors at the BBB endothelial cell level may contribute to the brain insulin resistance observed in Alzheimer’s disease.

Alzheimer’s research efforts are currently focused on drugs that, in order to reach their therapeutic target, neurons, must first traverse the BBB, severely restricting their passage. By focusing instead on metabolic dysfunction in the brain, we propose a research alternative that has two main advantages.

The first is that we can use treatments that do not have to cross the BBB barrier, since it is the endothelial cells themselves that become the therapeutic target. The second implies “reuse of medicines”, which consists of taking advantage of the phenomenal therapeutic arsenal already approved to combat diabetes and obesity, but using it in the context of Alzheimer’s.

It must be remembered that the few medications available to us provide only a modest improvement in symptoms. Fighting insulin resistance in the brain would make it possible to break the vicious circle between neuropathology (a disease that affects the brain) and diabetes, and theoretically slow the progression of the disease.

the work is not finished

On the basic research side, we will continue to study the mechanisms downstream of microvessels to understand the action of insulin in the deep layers of the brain.

We hope that clinical research will follow the lead of human studies to repurpose drugs that target certain metabolic diseases, such as diabetes, to fight Alzheimer’s.

Meanwhile, while waiting for pharmaceutical solutions, each of us would do well to adopt the preventive cocktail that we all know well: a healthy diet combined with frequent physical and mental exercise.

About this Alzheimer’s disease research news

Author: Federico Calon, manon leclercY Vincent Emond
Fountain: The conversation
Contact: Frederic Calon, Manon Leclerc and Vincent Emond – The Conversation
Picture: The image is in the public domain.