Reduced glucose metabolism, called glucose hypometabolism, is a known characteristic of both AD and epilepsy. It occurs even at a young age in individuals carrying apoe4 genes, which significantly increase the risk of developing AD later in life. \u00a0 Zilberter noted that glucose hypometabolism tends to become more pronounced with age and the degree to which this occurs seems to predict the conversion of mild cognitive impairment to AD later in life.<\/li>\n<\/ul>\nHere it is worth understanding how glucose metabolism normally occurs, and the speaker provided a short primer (which I have expanded a bit here):<\/p>\n
Most tissues obtain glucose mostly from the blood.\u00a0 Cells normally respond to the hormone insulin \u2013 a signal that blood sugar is available \u2013 by placing GLUT4 transporters on their surfaces, allowing glucose to enter.\u00a0 (This is disrupted in diabetes, in various ways.)\u00a0 Glucose that is to be used immediately as fuel is processes by glycolysis, generating some ATP and NADH which are common energy currencies in cells.\u00a0 In the absence of sufficient oxygen, lactic acid is produced and the process stops here.\u00a0 With sufficient oxygen, however, the remnants of glucose are shuttled into the mitochondria and completely burned up in the citric acid cycle, with a lot more ATP and NADH generated by oxidative phosphorylation (OXPHOS) in the mitochondrial electron transport chain.<\/p>\n
However, some glucose goes another way \u2013 it enters the pentose phosphate pathway where important building blocks such as nucleotides are formed and key antioxidants are produced.<\/p>\n
If there is excess glucose, beyond what is currently needed for these processes, it can be linked together to form long chains of glycogen for storage.\u00a0 This occurs most often in the liver and muscles.<\/p>\n
Conversely, if internal glucose levels fall to very low levels and the necessary glucose can not be obtained from the blood cells can starve.\u00a0 In response to this situation cells can work backwards – making some from raw materials by gluconeogenesis – but this requires a significant amount of energy.<\/p>\n
As you can see, glucose hypometabolism can occur in many ways – because there is not enough sugar in the blood, because blood sugar is not properly taken up into cells, or because glycolysis, the citric acid cycle, OXPHOS, or gluconeogenesis are inhibited.<\/p>\n
Dr. Zilberter pointed out that key steps in glucose uptake, glycolysis, and OXPHOS are inhibited in both AD and epilepsy.\u00a0 As a result, cells can not use glucose as efficiently, even if there is plenty around.<\/p>\n
He noted, as an example, that children in India that eat lychees before bedtime, on an empty stomach, sometimes have seizures ending in death.\u00a0 This reaction is caused by the natural product hypoglycin, which inhibits the production of new glucose by gluconeogenesis during the nighttime when blood sugar can also be low (hypoglycemia).\u00a0 This is one example of how glucose hypometabolism can trigger epileptic seizures.<\/p>\n
In the lab glucose hypometabolism can be simulated by the artificial compound 2-deoxy-D-glucose (2-DG), which inhibits glycolysis.\u00a0 The effect is mild, with glucose metabolism reduce by about 14%.\u00a0 Nonetheless, after 4 weeks of treatment sections of healthy brains show hyperexcited neurons and electrical seizures, similar to those found in epilepsy. \u00a0This is another example of how glucose hypometabolism can cause epilepsy, or at least related symptoms.<\/p>\n
Interestingly, simply washing healthy brain sections in amyloid beta (A\u03b2) has a similar effect.\u00a0 It induces glucose hypometabolism and hyperexcitability in nerve cells.<\/p>\n
Dr. Zilberter noted that this occurs similarly in both epilepsy and AD. \u00a0He wondered if there was a common cause that would explain the similarity.<\/p>\n
The key observation was that just moments before seizures would occur in sectioned brain slices there was a spike of hydroperoxide (H2<\/sub>O2<\/sub>).\u00a0 In fact, applying H2<\/sub>O2<\/sub> alone would trigger the response.<\/p>\nH2<\/sub>O2<\/sub> is a dangerous type of reactive oxygen, which can damage cells.\u00a0 Tiny amounts are naturally produced in mitochondria during OXPHOS.\u00a0 Too much H2<\/sub>O2<\/sub> production by old or damaged mitochondria, however, can trigger cell death, contributing to various diseases, and accelerate aging. \u00a0Most healthy cells \u2013 with young, healthy mitochondria – produce as little H2<\/sub>O2<\/sub> as possible and have various mechanisms to quickly destroy reactive oxygen species like H2<\/sub>O2<\/sub> when they are generated.\u00a0 However, there are exceptions.\u00a0 For example, some immune cells generate H2<\/sub>O2<\/sub> on purpose, to kill nearby microbes. \u00a0(Just as we often use H2<\/sub>O2<\/sub> to sanitize wounds or surfaces, i.e. to prevent microbial infection.)\u00a0 These guardian cells have NADPH oxidase (NOX) proteins on their surfaces, which generate H2<\/sub>O2<\/sub> outside of these cells.\u00a0 In the brain, microglia are primary immune defense cells and possess NOX proteins to produce H2<\/sub>O2<\/sub>.<\/p>\nThere are many types of NOX proteins; Dr. Zilberter focuses on one called NOX2 found on the surface of microglia in the brain.\u00a0 Here it all started to make sense.\u00a0 Washing healthy brain slices with A\u03b2 causes the spike in H2<\/sub>O2<\/sub>, nerve cell hyperexcitability, and glucose hypometabolism, as expected.\u00a0 But when NOX2 was inhibited, and no H2<\/sub>O2<\/sub> was produced by microglia, this was prevented.\u00a0 There was no nerve cell hyperexcitability, A\u03b2 was no longer toxic, and neurons didn\u2019t die.<\/p>\nThe same thing could be accomplished just by reducing the number of microglia that were present.\u00a0 The problem it seems is that: the brain\u2019s microglia respond to A\u03b2 in the brain by generating H2<\/sub>O2<\/sub>, which damaged nerve cells, causing hyperexcitability and reduced glucose metabolism.\u00a0 NOX2 inhibitors \u2013 such as those described here (https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6709343\/<\/a>) – \u00a0might be useful in preventing this in vivo<\/em>, and deserve further study.\u00a0 In theory, the aim would be to reduce H2<\/sub>O2<\/sub> production by NOX2 in the brain without compromising the ability of the immune system to defend the body against infection.\u00a0 For example, consider that:<\/p>\nChronic granulomatous disease (CGD) is an inherited disorder of NOX2 characterized by severe life-threatening bacterial and fungal infections and by excessive inflammation, including Crohn\u2019s-like inflammatory bowel disease (IBD).<\/em>\u00a0 Singel KL, Segal BH. NOX2-dependent regulation of inflammation. Clin Sci (Lond). 2016;130(7):479\u2013490. doi:10.1042\/CS20150660<\/p>\nDuring a long Q&A session that followed the seminar, Dr. Zilberter made two points I found very interesting:<\/strong><\/p>\nFirst, when asked if antioxidants could help prevent that accumulation of H2<\/sub>O2<\/sub> in the brain he remarked that they aren\u2019t, in his experience, fast enough to prevent the H2<\/sub>O2<\/sub> spike.\u00a0 It is, he surmised, better to stop this from happening in the first place.<\/p>\nSecond, he was asked about ketogenic diets, very low carbohydrate diets sometimes used to treat epilepsy and AD.\u00a0 He suggested that the benefit of these diets would probably be that endogenous ketones, produced by the liver and circulated in the blood, could be used as a fuel, thereby freeing up the increasingly limited glucose in apoe4 cells for use in pathways that can only be fueled by glucose.<\/p>\n","protected":false},"excerpt":{"rendered":"
Alzheimer\u2019s disease and epilepsy: what can we learn from their similarities? Alzheimer\u2019s Afternoons Seminar Series (April 14) Dr. Misha Zilberter, a staff research scientist from the Gladstone Institutes…<\/p>\n","protected":false},"author":1263,"featured_media":1088,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[79033],"tags":[],"class_list":["post-1087","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-alzheimers-afternoons-summaries"],"_links":{"self":[{"href":"https:\/\/blogs.dickinson.edu\/arnoldt\/wp-json\/wp\/v2\/posts\/1087","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/blogs.dickinson.edu\/arnoldt\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/blogs.dickinson.edu\/arnoldt\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/blogs.dickinson.edu\/arnoldt\/wp-json\/wp\/v2\/users\/1263"}],"replies":[{"embeddable":true,"href":"https:\/\/blogs.dickinson.edu\/arnoldt\/wp-json\/wp\/v2\/comments?post=1087"}],"version-history":[{"count":0,"href":"https:\/\/blogs.dickinson.edu\/arnoldt\/wp-json\/wp\/v2\/posts\/1087\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/blogs.dickinson.edu\/arnoldt\/wp-json\/wp\/v2\/media\/1088"}],"wp:attachment":[{"href":"https:\/\/blogs.dickinson.edu\/arnoldt\/wp-json\/wp\/v2\/media?parent=1087"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/blogs.dickinson.edu\/arnoldt\/wp-json\/wp\/v2\/categories?post=1087"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/blogs.dickinson.edu\/arnoldt\/wp-json\/wp\/v2\/tags?post=1087"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}