Diabetes of the brain
Insulin receptors in the microvessels of the brain do not work well in Alzheimer's disease
Anastasia Gorshkova, PCR.news
In Alzheimer's disease (AD), there is a violation of the phosphorylation of insulin receptors associated with a decrease in cognitive abilities. Scientists from Canada and the USA set a task to find out how insulin interacts with the blood-brain barrier (BBB), and to understand what role it plays in the pathogenesis of AD. They showed that the loss of the number and functionality of insulin receptors in the microvessels of the brain make a significant contribution to the insulin resistance of the central nervous system in AD associated with the deposition of amyloid plaques.
The insulin receptor consists of four chains — two extracellular alpha (INSRa) and two intracellular beta (INSRß), and the alpha chain has two isoforms: long INSRa-B and short INSRa-A. These proteins are encoded by a single gene.
The scientists worked with postmortem brain samples from humans and with a mouse model of AD. To determine the location of insulin receptors, they stained both INSRa isoforms with antibodies in the tissues. In experiments on mice, in addition, the activity of INSRß phosphorylation receptors was evaluated — it is this that has a metabolic significance.
Parietal cortex tissue samples were taken from patients participating in a long—term study of aging and memory in elderly representatives of Catholicism Religious Orders Study, which began back in 1993. The researchers analyzed 60 samples from patients from three groups: patients with Alzheimer's disease, patients with other cognitive impairments and healthy people.
Immunological examination of brain tissues showed that insulin receptors are located mainly in microvessels, and not in the parenchyma, as previously thought. But the most interesting thing was the fact that in the microvessels of people with AD and low results of cognitive tests, the expression of a specific, longer isoform of INSRa-B decreased. Moreover, the smaller the INSRa-B, the more beta-amyloid plaques were detected in the sample. No such dependencies were found for patients without BA.
Next, the scientists conducted experiments on 3xTg-AD transgenic mice simulating AD to find out which of the phenomena is primary: central insulin resistance or deposition of amyloid plaques. They found that the rate of insulin transport through the BBB in normal mice is very low. The introduction of labeled insulin did not increase it, that is, insulin receptors of the BBB do not increase its permeability, but at the same time phosphorylation of INSRß in microvessels was triggered. This effect was blunted in 3xTg-AD mice. This suggests that pathological manifestations of AD induce insulin resistance at the BBB level.
The data obtained confirm the view of AD as a neurodegenerative disease with a strong metabolic component. It has previously been shown that intranasal insulin administration prevents hypoglycemia of brain cells and improves the condition of patients with cognitive impairment. Clinical trials of the effectiveness of drugs for diabetes mellitus, such as metformin, thiazolidinediones and glucocorticoids, against Alzheimer's disease are also underway.
"Metabolic dysfunction exacerbates Alzheimer's disease, and Alzheimer's disease exacerbates the metabolic problem. This is a vicious circle," says study leader Frederic Calon, a professor at the Faculty of Pharmacy at Laval University.
Article by Leclerc et al. Cerebrovascular insulin receptors are defective in Alzheimer's disease published in the journal Brain.
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