Neurally-produced estradiol enhances the neuroprotective actions of insulin

Alzheimer’s disease is a debilitating disorder that is on the rise in British Columbia’s aging population. A growing pool of evidence suggests that Alzheimer’s disease may involve insulin, a hormone whose activity in the pancreas is linked with type 1 and type 2 diabetes. Insufficient action of insulin in the brain can be a cause of Alzheimer’s disease, which is increasingly being called “type 3 diabetes” because of this.

During my graduate studies, I observed that insulin is produced in the brains of mice and humans, with highest expression in the hippocampus. My preliminary results also suggested that deletion of brain insulin in mice leads to cognitive deficits.

Estradiol enhances insulin production and response in the pancreas. However, these effects of estradiol in the brain have never been confirmed. Yet when expressed together in the hippocampus (a brain structure critically involved in memory), estradiol and insulin promote neuron growth and survival as well as synapse formation and maintenance.

I will test the hypothesis that estradiol produced by neurons enhances the production and action of insulin in the brain, and that this has beneficial effects in a rat model of Alzheimer’s disease.

I will inhibit estradiol production in the brain and then test how local insulin expression and signalling are affected in the brains of the rats. I will also examine the neurons and synapses in adult rats and will perform behavioural and cognitive tests. A drug that blocks insulin receptors will be used to confirm that insulin signalling is the true cause of any changes I observe.

I predict that inhibition of brain estradiol production will reduce brain insulin expression/action and increase negative effects associated with Alzheimer’s disease in this rat model.

Studying the role of brain estradiol production and its potential to increase brain insulin activity in the brain could ultimately lead to new treatments for Alzheimer’s disease.

End of Award Update

Source: CLEAR Foundation

Dr. Mehran’s hypothesis was that estradiol produced by neurons enhances the production and action of insulin in the brain, and that this would have beneficial effects in a rat model of Alzheimer’s disease. However, even using some of the most sensitive assays, they failed to yield a difference.

However, Dr. Mehran discovered that second-generation antipsychotic medications inhibit insulin maturation. This finding is important because these medications are used to treat patients with psychosis and Alzheimer disease. These medications may be contributing to cognitive harm, by reducing levels of brain insulin.