Alzheimer’s disease and epilepsy: what can we learn from their similarities?
Alzheimer’s Afternoons Seminar Series (April 14)
Dr. Misha Zilberter, a staff research scientist from the Gladstone Institutes at the University of California San Francisco Medical Center, presented a seminar entitled “Brain glucose hypometabolism and network hyperexcitability in Alzheimer’s disease”.
For more information consider reading their open access article:
The vicious circle of hypometabolism in neurodegenerative diseases: Ways and mechanisms of metabolic correction Yuri Zilberter Misha Zilberter 02 May 2017 https://doi.org/10.1002/jnr.24064
Dr. Zilberter began by pointing out that both Alzheimer’s disease and epilepsy are associated with neuron hyperexcitability and a reduction in glucose metabolism.
- Hyperexcitability occurs when neuron membrane potentials fall too low, causing rapid and uncontrolled nerve cell firing.
- 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. 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.
Here it is worth understanding how glucose metabolism normally occurs, and the speaker provided a short primer (which I have expanded a bit here):
Most tissues obtain glucose mostly from the blood. Cells normally respond to the hormone insulin – a signal that blood sugar is available – by placing GLUT4 transporters on their surfaces, allowing glucose to enter. (This is disrupted in diabetes, in various ways.) 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. In the absence of sufficient oxygen, lactic acid is produced and the process stops here. 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.
However, some glucose goes another way – it enters the pentose phosphate pathway where important building blocks such as nucleotides are formed and key antioxidants are produced.
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. This occurs most often in the liver and muscles.
Conversely, if internal glucose levels fall to very low levels and the necessary glucose can not be obtained from the blood cells can starve. In response to this situation cells can work backwards – making some from raw materials by gluconeogenesis – but this requires a significant amount of energy.
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.
Dr. Zilberter pointed out that key steps in glucose uptake, glycolysis, and OXPHOS are inhibited in both AD and epilepsy. As a result, cells can not use glucose as efficiently, even if there is plenty around.
He noted, as an example, that children in India that eat lychees before bedtime, on an empty stomach, sometimes have seizures ending in death. 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). This is one example of how glucose hypometabolism can trigger epileptic seizures.
In the lab glucose hypometabolism can be simulated by the artificial compound 2-deoxy-D-glucose (2-DG), which inhibits glycolysis. The effect is mild, with glucose metabolism reduce by about 14%. Nonetheless, after 4 weeks of treatment sections of healthy brains show hyperexcited neurons and electrical seizures, similar to those found in epilepsy. This is another example of how glucose hypometabolism can cause epilepsy, or at least related symptoms.
Interestingly, simply washing healthy brain sections in amyloid beta (Aβ) has a similar effect. It induces glucose hypometabolism and hyperexcitability in nerve cells.
Dr. Zilberter noted that this occurs similarly in both epilepsy and AD. He wondered if there was a common cause that would explain the similarity.
The key observation was that just moments before seizures would occur in sectioned brain slices there was a spike of hydroperoxide (H2O2). In fact, applying H2O2 alone would trigger the response.
H2O2 is a dangerous type of reactive oxygen, which can damage cells. Tiny amounts are naturally produced in mitochondria during OXPHOS. Too much H2O2 production by old or damaged mitochondria, however, can trigger cell death, contributing to various diseases, and accelerate aging. Most healthy cells – with young, healthy mitochondria – produce as little H2O2 as possible and have various mechanisms to quickly destroy reactive oxygen species like H2O2 when they are generated. However, there are exceptions. For example, some immune cells generate H2O2 on purpose, to kill nearby microbes. (Just as we often use H2O2 to sanitize wounds or surfaces, i.e. to prevent microbial infection.) These guardian cells have NADPH oxidase (NOX) proteins on their surfaces, which generate H2O2 outside of these cells. In the brain, microglia are primary immune defense cells and possess NOX proteins to produce H2O2.
There are many types of NOX proteins; Dr. Zilberter focuses on one called NOX2 found on the surface of microglia in the brain. Here it all started to make sense. Washing healthy brain slices with Aβ causes the spike in H2O2, nerve cell hyperexcitability, and glucose hypometabolism, as expected. But when NOX2 was inhibited, and no H2O2 was produced by microglia, this was prevented. There was no nerve cell hyperexcitability, Aβ was no longer toxic, and neurons didn’t die.
The same thing could be accomplished just by reducing the number of microglia that were present. The problem it seems is that: the brain’s microglia respond to Aβ in the brain by generating H2O2, which damaged nerve cells, causing hyperexcitability and reduced glucose metabolism. NOX2 inhibitors – such as those described here (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709343/) – might be useful in preventing this in vivo, and deserve further study. In theory, the aim would be to reduce H2O2 production by NOX2 in the brain without compromising the ability of the immune system to defend the body against infection. For example, consider that:
Chronic granulomatous disease (CGD) is an inherited disorder of NOX2 characterized by severe life-threatening bacterial and fungal infections and by excessive inflammation, including Crohn’s-like inflammatory bowel disease (IBD). Singel KL, Segal BH. NOX2-dependent regulation of inflammation. Clin Sci (Lond). 2016;130(7):479–490. doi:10.1042/CS20150660
During a long Q&A session that followed the seminar, Dr. Zilberter made two points I found very interesting:
First, when asked if antioxidants could help prevent that accumulation of H2O2 in the brain he remarked that they aren’t, in his experience, fast enough to prevent the H2O2 spike. It is, he surmised, better to stop this from happening in the first place.
Second, he was asked about ketogenic diets, very low carbohydrate diets sometimes used to treat epilepsy and AD. 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.