{"id":1134,"date":"2020-04-30T14:30:00","date_gmt":"2020-04-30T14:30:00","guid":{"rendered":"http:\/\/blogs.dickinson.edu\/arnoldt\/?p=1134"},"modified":"2020-05-04T14:32:27","modified_gmt":"2020-05-04T14:32:27","slug":"1134","status":"publish","type":"post","link":"https:\/\/blogs.dickinson.edu\/arnoldt\/2020\/04\/30\/1134\/","title":{"rendered":"Alzheimer\u2019s Afternoon Seminar Series: Shannon Macauley"},"content":{"rendered":"

April 28, 2020<\/h3>\n
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Targeting vascular KATP<\/sub> channel activity in Alzheimer’s disease<\/h2>\n
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Takeaway:<\/strong> Sulfonylurea drugs used to treat diabetes seem to inhibit the accumulation of A\u03b2 by restoring vascular health and calming neuronal activity in the brain.<\/p>\n

Dr. Shannon Macauley is an Assistant Professor of Gerontology and Geriatric Medicine at the Wake Forest School of Medicine.\u00a0 She is interested in the connections between two \u201cdiseases of aging\u201d, Alzheimer\u2019s disease (AD) and type 2 diabetes.<\/p>\n

She uses mouse models to study \u201chow 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 (A\u00df) or tau.\u201d<\/em> \u00a0Her lab specializes in whole animal physiological experiments using glucose clamps, in vivo<\/em> microdialysis, biosensors, sleep monitoring and neuroimaging techniques.<\/p>\n

Today, Dr. Macauley discussed the importance of hyperglycemia and vascular health in AD.<\/p>\n

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.\u00a0 (The diagrams alone are worth a look at the recorded video of the seminar.)<\/p>\n

Next, she asked a seemingly simple question: does hyperglycemia alter A<\/strong>\u03b2<\/strong> levels in the brain?<\/strong>\u00a0 Her answer was, yes.\u00a0 Using glucose clamps to raise blood sugar levels in mice raised glucose levels of brain interstitial fluid (ISF) and resulted in increased A\u03b2 accumulations.\u00a0 This increase was by ~20% in young mice and ~40% in older mice.\u00a0 This is consistent with the general view that diabetes can contribute to the progression of AD.<\/p>\n

She also noticed increased levels of ISF lactate.\u00a0 She discussed the importance of the lactate shuttle<\/strong>.<\/p>\n

A reminder: We often focus on the direct flow of blood glucose to neurons and into glycolysis and the pentose phosphate pathway.\u00a0 However, the lactate shuttle refers to an alternate pathway to fuel neurons.\u00a0 In this case, astrocytes take up blood glucose and do some of the early processing \u2013 from sugar to pyruvate and then lactate \u2013 before shuttling lactate to neighboring neurons.\u00a0 Lactate can also have a signaling role, providing information to cells.<\/p>\n

Previously, lactic acid was considered to be solely a waste byproduct produced when glycolysis outpaced the supply of oxygen.\u00a0 However, more recently we have come to appreciate that most cells produce some lactate, most of the time, even under normal conditions.<\/p>\n

Dr. Macauley noticed that brain cell hyperactivity was associated with higher lactate levels which was, in turn, associated with higher levels of A\u03b2.<\/p>\n

She then pivoted to discuss KATP<\/sub> channels, which may explain this.<\/strong><\/p>\n

KATP <\/sub>channels are ATP-sensitive potassium channels.\u00a0 They open or close \u2013 depending upon the cellular levels of ATP \u2013 to control the amount of positively charged potassium ions (K+<\/sup>) which enter cells.<\/p>\n

Thus, they connect cellular energy status to membrane potentials.<\/p>\n

They occur in many cell and tissue types and can be manipulated by sulfonylurea drugs.\u00a0 Sulfonylureas are used in the management of Type 2 diabetes. \u00a0They stimulate insulin release, lowering blood glucose levels.<\/p>\n

Here, Dr. Macauley focused on their importance in neurons.<\/p>\n

When ATP levels in neurons are high, KATP<\/sub> channels close, preparing nerve cells to fire.\u00a0 This occurs because their membranes become slightly depolarized, making the \u201ctrigger\u201d more sensitive.\u00a0 Hence, neurons are more easily excited.<\/p>\n

This could, she reasoned, be a link between fuel metabolism and hyper-excitability of neurons.<\/p>\n

These channels can be opened or closed artificially using sulfonylurea drugs, commonly used to manage diabetes.\u00a0 Interestingly, these drugs do not pass the blood-brain barrier.\u00a0 In other words, they can not directly alter KATP<\/sub> channels in the brain but might have indirect effects by acting on peripheral tissues.<\/p>\n

She asked: would these drugs affect peripheral metabolism in a way that alters KATP<\/sub> channels, the levels of lactate, and A<\/strong>\u03b2<\/strong> accumulation in the brain?<\/strong><\/p>\n

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.\u00a0 Even though the drug never entered the brain, she found that it reduced A\u03b2 pathology in APP\/PS1 mice.<\/p>\n

She recorded:<\/p>\n