April 28, 2020

Targeting vascular KATP channel activity in Alzheimer’s disease

Takeaway: Sulfonylurea drugs used to treat diabetes seem to inhibit the accumulation of Aβ by restoring vascular health and calming neuronal activity in the brain.

Dr. Shannon Macauley is an Assistant Professor of Gerontology and Geriatric Medicine at the Wake Forest School of Medicine.  She is interested in the connections between two “diseases of aging”, Alzheimer’s disease (AD) and type 2 diabetes.

She uses mouse models to study “how metabolic perturbations, either systemically or within the brain, affect the progression of AD-related pathology, such as the production, clearance, and aggregation of amyloid-beta (Aß) or tau.”  Her lab specializes in whole animal physiological experiments using glucose clamps, in vivo microdialysis, biosensors, sleep monitoring and neuroimaging techniques.

Today, Dr. Macauley discussed the importance of hyperglycemia and vascular health in AD.

She began with an introduction to AD and diabetes, using beautiful diagrams to highlight the various brain cell types, and the progression of each disease from preclinical to symptomatic.  (The diagrams alone are worth a look at the recorded video of the seminar.)

Next, she asked a seemingly simple question: does hyperglycemia alter Aβ levels in the brain?  Her answer was, yes.  Using glucose clamps to raise blood sugar levels in mice raised glucose levels of brain interstitial fluid (ISF) and resulted in increased Aβ accumulations.  This increase was by ~20% in young mice and ~40% in older mice.  This is consistent with the general view that diabetes can contribute to the progression of AD.

She also noticed increased levels of ISF lactate.  She discussed the importance of the lactate shuttle.

A reminder: We often focus on the direct flow of blood glucose to neurons and into glycolysis and the pentose phosphate pathway.  However, the lactate shuttle refers to an alternate pathway to fuel neurons.  In this case, astrocytes take up blood glucose and do some of the early processing – from sugar to pyruvate and then lactate – before shuttling lactate to neighboring neurons.  Lactate can also have a signaling role, providing information to cells.

Previously, lactic acid was considered to be solely a waste byproduct produced when glycolysis outpaced the supply of oxygen.  However, more recently we have come to appreciate that most cells produce some lactate, most of the time, even under normal conditions.

Dr. Macauley noticed that brain cell hyperactivity was associated with higher lactate levels which was, in turn, associated with higher levels of Aβ.

She then pivoted to discuss KATP channels, which may explain this.

KATP channels are ATP-sensitive potassium channels.  They open or close – depending upon the cellular levels of ATP – to control the amount of positively charged potassium ions (K+) which enter cells.

Thus, they connect cellular energy status to membrane potentials.

They occur in many cell and tissue types and can be manipulated by sulfonylurea drugs.  Sulfonylureas are used in the management of Type 2 diabetes.  They stimulate insulin release, lowering blood glucose levels.

Here, Dr. Macauley focused on their importance in neurons.

When ATP levels in neurons are high, KATP channels close, preparing nerve cells to fire.  This occurs because their membranes become slightly depolarized, making the “trigger” more sensitive.  Hence, neurons are more easily excited.

This could, she reasoned, be a link between fuel metabolism and hyper-excitability of neurons.

These channels can be opened or closed artificially using sulfonylurea drugs, commonly used to manage diabetes.  Interestingly, these drugs do not pass the blood-brain barrier.  In other words, they can not directly alter KATP channels in the brain but might have indirect effects by acting on peripheral tissues.

She asked: would these drugs affect peripheral metabolism in a way that alters KATP channels, the levels of lactate, and Aβ accumulation in the brain?

To assess this, she formulated pellets of glyburide, a sulfonylurea drug, and placed them subcutaneously in mice for slow-release between months 4 and 7.  Even though the drug never entered the brain, she found that it reduced Aβ pathology in APP/PS1 mice.

She recorded:

  • 50% decrease in Aβ deposition
  • A 40% decrease in plaque pathology
  • A 30-40% decrease in insoluble Aβ40 and Aβ42
  • A 25% decrease in ISF Aβ

How did this occur?  Interestingly, she observed no change in the rate of Aβ clearance or degradation, by neurons or microglia.  She did, however, find some evidence that the initial production of Aβ was decreased.

She noted that the drug seemed to calm neuronal activity.  Specifically, the drug (which did not enter the brain) reduced the amplitude of neuronal activity measured by EEG.

This was another hint that neuron hyperactivity and Aβ pathology are linked.

How is this possible?  She hypothesized that this occurred because of a change in blood flow throughout the brain.

To test this, her lab group measured blood flow and oxygen utilization in the brains of mice, using a system of LED lights, lasers, and sensors, to “see” through the intact skull.

They found that glyburide altered the neurovascular response of the brain.

When regions of the brain become active they require extra blood flow and capillaries usually dilate to facilitate this.

However, this response can weaken due to aging or vascular disease, as vessels become stiff.

Here the drug improved vaso-reactivity.  In short, glyburide seemed to encourage the brain to control blood flow and use oxygen more efficiently.  Arterial stiffness was reduced by roughly 50%.  The number of KATP channels was increased.

Dr. Macauley summarized that:

  • the accumulation of Aβ causes vasoconstriction, lowering blood flow and the availability of oxygen to brain regions and starving them of ATP.
  • without adequate ATP the KATP channels are activated, cells membrane are hyperpolarized, neurons become hyperactive and uncoordinated.
  • Aβ accumulates further in a cycle.
  • drugs such as glyburide seem to break this cycle, even though they do not penetrate the blood-brain barrier.