I’m convinced that in physiology, everything is connected. That is, one of your body’s systems can’t be altered without avoiding the ripple effect that change will have on every other system–however miniscule it might be. This point reinforced itself while I attended a seminar talk that I found appealing for its fusion of past and present topics of interest to me, Alzheimer’s disease and metabolic disorders. I decided to write a short synopsis of the story behind that talk (it was given by Laura Baker, mentioned below):
The study of progressive cognitive decline—specifically, Alzheimer’s disease—is one of the most frustrating areas of research in neuroscience at both the scientific and personal levels. Approximately 5 and a half million Americans live with the disease, and as our population continues to age, that number is expected to increase exponentially. All current drug therapies, most of which enhance the brain’s cholinergic system, have no more than a modest* effect. But Drs. Laura Baker and Suzanne Craft from my university, Wake Forest, are exploring a promising new focus in Alzheimer’s disease research that may lead to new treatment strategies to improve cognitive function or delay the onset of disease symptoms: brain insulin signaling.
Researchers have uncovered a strong link between dementia and a deficiency of insulin in the brain. Insulin is critical for many cells to function properly, including neurons. Most of us associate insulin with its role in diabetes, in which it is either completely absent (type 1 diabetes) or its signaling action in cells is defective (type 2)**. The latter condition is referred to as insulin resistance. As peripheral cells become resistant to insulin, more will be released into the bloodstream by the pancreas to compensate for its impaired actions. Increased release of many hormones usually means that higher levels will reach the brain, but not so with insulin. Insulin must be transported into the brain across the blood-brain barrier, and long-term elevation of circulating insulin causes down-regulation of insulin receptors and transporters at this junction. Thus, over time, less insulin is able to enter the brain. This is likely a major factor behind the observation that adults with type 2 diabetes have at least double the risk of developing Alzheimer’s later in life.
Insulin’s ability to improve memory acutely is well known, as is its contribution to the formation of new synapses. In the brains of deceased Alzheimer patients, scientists have noted a reduction in both insulin receptors and the activity of enzymes involved in insulin signaling compared to healthy brains. Others have even established an important link between brain insulin deficiency and the accumulation of β-amyloid proteins, the proximal cause of neuronal death in Alzheimer’s disease. Under normal conditions, insulin will help transport the toxic proteins out of the cell, preventing the formation of intracellular plaques that are a hallmark of the disease. As evidence for the role of insulin in progressive cognitive decline continues to mount, it seems more and more appropriate that Alzheimer’s disease is sometimes referred to as type 3 diabetes.
Drs. Baker and Craft, along with collaborators at the University of Washington, believe that enhancing levels of insulin in the brain may be one answer to the challenges of treating Alzheimer’s disease. However, this would require insulin to circumvent the blood-brain barrier because of the dangers of chronic high circulating insulin, in addition to reduced transport into the brain over time. An innovative way to accomplish this is through the intranasal inhalation of an insulin spray. Olfactory sensory neurons are directly exposed to the external environment, allowing drugs to be transported directly into the brain by traveling through nerve channels. Craft and Baker recently published their results from a clinical trial that tested the intranasal delivery of insulin into Alzheimer patients, showing that insulin improved delayed memory, preserved the ability of patients to carry out daily functions, and indicated that neuron metabolism was improved compared to patients who received placebo. Longer and larger clinical trials are currently underway, which they hope will demonstrate that intranasal insulin is a viable new treatment for Alzheimer’s disease.
*Jargon for “minimal or none; nothing, basically.”
**Type 2 diabetes can also manifest as a relative shortfall in insulin release, especially in obese patients. Meaning insulin is there, and it works, but there’s not enough of it.