Experiments on post-mortem brain tissues from 60 deceased patients with Alzheimer’s disease (AD) and an AD animal model indicate that defects in insulin receptors at the blood–brain barrier contribute to brain insulin resistance in AD.

Earlier work has hinted at a role of insulin resistance in AD but mechanisms underlying the interaction between insulin and the blood brain barrier and whether perturbations in such interactions contributed to AD were unclear.

Scientists at the Université Laval in Québec and the Rush University Medical Center in Chicago clarify the mechanisms of insulin activity in microvessels of the brain and provide evidence of insulin resistance at the level of the blood-brain barrier, in the study “Cerebrovascular insulin receptors are defective in Alzheimer’s disease,” published in the journal Brain on Tuesday, supporting the idea that AD is a neurodegenerative disease with a strong metabolic component.

A mounting number of clinical trials on insulin-related drugs in AD and the importance of understanding how insulin impacts the brain inspired the current study, said senior author Frédéric Calon, PhD, a professor of pharmacy at the Institute of Nutrition and Functional Foods and the CHU de Québec–Université Laval Research Centre.

The findings may impact AD drug discovery efforts. “Several clinical trials are underway to assess the efficacy of diabetes drugs for Alzheimer’s disease,” said Calon. “Our study shows that drugs do not need to cross the blood–brain barrier of microvessels to affect brain insulin resistance. Instead, they can target insulin receptors located in cerebral microvessels. That expands the range of drugs that could be tested for Alzheimer’s.”

Elizabeth Rhea, PhD, research assistant professor at the University of Washington said, “Dr. Calon’s research team, led by graduate student Manon Leclerc, present exciting new data, uncovering an important role of the insulin receptor in cerebral microvessels. The results reveal additional information about the development of brain insulin resistance and a target for Alzheimer’s disease.” (Rhea was not involved in the current study.)

In both mice and humans, the study shows, cerebral insulin receptors (INSRs), specifically long isoforms of the receptor called INSRα-B, are found in large numbers on microvessels and not in the neurons of the brain parenchyma, as believed earlier.  The authors observed that the density of INSRα-B in the microvessels of the parietal cortex was significantly decreased in AD patients.

AD patients with fewer INSRα-B receptors in microvessels performed worse on cognitive tests.  A higher ratio of the receptors INSRα-A to B, which results from fewer INSRα-B receptors, is consistent with cerebrovascular insulin resistance reported in AD.

“The study is highly impactful, as it identifies the cerebrovascular [structure] as one of the main sites of brain insulin resistance as opposed to the brain parenchyma in patients with Alzheimer’s disease compared with controls,” said Hussein Yassine, MD, an associate professor of medicine at the Keck School of Medicine of University of Southern California, whose work also focuses on AD. (Yassine was not involved in the current study).

AD patients with fewer INSRα-B receptors in their microvessels had more beta-amyloid plaques and higher levels of β-site APP cleaving enzyme1 in the brain. However, vascular INSRα was positively correlated with levels of the insulin-degrading enzymes, neprilysin and P-glycoprotein, the investigators observed.

“We used a combination of intracarotid brain perfusion with capillary extraction to differentiate the activation of the insulin receptor in microvessels versus parenchyma,” said Calon.

Using intracarotid perfusion, the researchers quantified the transport rate of insulin across the blood–brain barrier and found it to be low (less than 0.03 μl/g·s). Moreover, administration of insulin receptor antagonist did not inhibit insulin transport across the blood–brain barrier. However, perfusion of insulin into the carotid artery activated INSRβ receptors in the microvessels through phosphorylation.

In mouse models of AD (3xTg-AD mice) activation of INSRβ receptors in the microvessels upon  intracarotid insulin perfusion was blunted. INSRβ receptors in microvessels decreased with age and disease progression. This indicates, neuropathological mechanisms of AD induce insulin resistance at the level of the blood–brain barrier.

“Our findings suggest that the loss of alpha-B insulin receptors in brain microvessels contributes to insulin resistance in the brain and cognitive decline in people with Alzheimer’s disease,” said Calon. “Metabolic dysfunction exacerbates Alzheimer’s, and Alzheimer’s amplifies the metabolic problem. It’s a vicious circle.”

“Leclerc et al, show a modest correlation of the loss of insulin receptor action at the blood-brain barrier with clinical outcomes,” said Yassine. “This raises the prospect that this change may lead to cerebrovascular dysfunction. Important questions remain on whether type-2 diabetes without AD pathology can lead to similar changes providing a mechanism for the association of type-2 diabetes with increased AD risk.”

Calon’s future studies will focus on better understanding downstream mechanisms in astrocytes and neurons, and their impact on ongoing and future clinical trials.

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