New Potential Target for Alzheimer’s Drugs

Dementia is considered a major neurocognitive disorder, in which a deficit in cognitive functioning is acquired rather than developmental. Dementia is most common in elderly individuals, with advancing age being the strongest risk factor. There are many types of this condition such as Alzheimer Dementia (AD) and Vascular Dementia (VD) , among others of all-cause dementia (ACD). 

More than 6 million people in the U.S. have Alzheimer’s disease.

The human brain is sensitive to insulin, a hormone essential to life that is also at the heart of the pathophysiology and treatment of diabetes. The scientific literature is replete with studies in humans and other species reporting the effects of insulin on memory, cerebral blood flow, eating behavior and regulation of whole-body metabolism, supporting a therapeutic potential in brain-dependent metabolic disorders.

The blood–brain barrier (BBB) is a major interface between the blood and brain, controlling access to cerebral tissues. Therefore, to exert an effect in the CNS, circulating insulin must first interact with its insulin receptor (INSR) located on brain capillary endothelial cells (BCEC) forming the BBB.

Beside classical amyloid-β (Aβ) and tau pathologies, Alzheimer’s disease is characterized by defective brain uptake of glucose and impaired response to insulin.

Alzheimer’s disease is associated with a reduction of insulin receptors in brain microvessels, which may contribute to brain insulin resistance and the formation of amyloid plaques, one of the disease’s hallmarks.

The work leading to the discovery was headed by Frédéric Calon, a professor at the Faculty of Pharmacy and a researcher at the Institute of Nutrition and Functional Foods and the CHU de Québec–Université Laval Research Centre.

The research was made possible by a longitudinal study that began in 1993 and involves about 1,100 members of some 30 religious congregations in the United States. The participants have agreed to undergo annual medical and psychological tests and donate their brains after death. The Brain article is based on data from 60 deceased individuals who participated in this extensive study.

Examination of their brains revealed that: 

• Insulin receptors are found primarily in blood microvessels, not neurons, as previously thought. 
• Alpha-B insulin receptor subunits were less prevalent in the microvessels of people diagnosed with Alzheimer’s. 
• Cognitive test scores were lower in subjects with fewer alpha-B insulin receptors in their microvessels.
• Subjects with fewer alpha-B insulin receptors in their microvessels had more beta-amyloid plaques in their brains.

Experiments carried out by the researchers on transgenic mice used to study Alzheimer’s disease showed that the quantity of alpha-B receptors in microvessels decreased with age and disease progression.

Their  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.

These findings support the idea that Alzheimer’s is a neurodegenerative disease with a strong metabolic component. Metabolic dysfunction exacerbates Alzheimer’s, and Alzheimer’s amplifies the metabolic problem. It’s a vicious circle.

This 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.

SOURCE:

Manon Leclerc, Philippe Bourassa, Cyntia Tremblay, Vicky Caron, Camille Sugère, Vincent Emond, David A Bennett, Frédéric Calon (October 25 , 2022). Cerebrovascular insulin receptors are defective in Alzheimer’s disease. Brain. Retrieved from : https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awac309/6761474 

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