You know the old joke about the blind guys examining an elephant and each declaring that an elephant is like a tree or a snake, etc depending on what area of the animal was being investigated. Alzheimer’s research is very similar in that every month at least one research group comes up for air and sunlight and makes a declaration about THE cause of the disease. There are a few of us out there (and hopefully that number is growing) who view Alzheimer’s as a complex illness with multiple causes, some more important than others, with no single cause working in isolation. Quinolinic Acid (QUIN) is fascinating because, while it predictably doesn’t explain everything, it does shed light on more than one common attribute or possible explanation of Alzheimer’s.
How It’s Formed
Let’s start with the multi-use amino acid tryptophan. When in balance, the body processes tryptophan into important end products such as melatonin, NAD, and serotonin.
Roughly 10% of tryptophan is converted to Serotonin and Melatonin along the methoxyindole pathway. Serotonin is important for mood and reduced levels result in depression. Melatonin is important for sleep and as an anti-oxidant and neuroprotectant. Melatonin production goes into high gear after dark when enzyme production specific to the task increases.
The remaining 90% of tryptophan is catabolized along the kynurenine pathway from which we get Niacin and then NAD. Along the way there are two important metabolites for our discussion; Kynurenic acid (KYNA) and QUIN.
The kynurenine pathway is dependent on vitamin B as a co-factor and particularly B6. A B6 deficient individual will produce xanthurenic acid, which serves no further purpose and is excreted from the body in urine. Assuming there’s enough B6 the process will skip the xanthurenic acid dead-end and move on to Quinolinic Acid (QUIN). QUIN is the final metabolite before niacin.
Our Understanding of QUIN Through The Years
QUIN was discovered in 1949 and was shown to induce convulsions in mice when injected into brain ventricles. In 1981 the key activity of QUIN was determined to be the activation of the N-methyl-d-aspartate receptor (NMDA receptor). A 1992 study of autopsied brains determined that QUIN was not involved in Alzheimer’s because the levels of QUIN in the brains of advanced stage Alzheimer’s weren’t deemed high enough to be a problem.
Fast forward 20 years to 2012 and QUIN is now recognized as “involved in several neurological disorders, including Huntington’s disease, Alzheimer’s disease, schizophrenia, HIV associated dementia (HAD) etc.”
Quoting again from 6 years ago, we know that “QUIN acts as a neurotoxin, gliotoxin, proinflammatory mediator and pro-oxidant molecule and can alter the integrity and cohesion of the blood–brain barrier. Over the last decade, QUIN has been shown to be involved in the neuropathogenesis of several major neurological diseases.”
Other negatives include depression and Tau hyperphosphorylation, and probably lots of other maladies that I’m forgetting to mention.
Mechanism of Action and Damage
Normally the NMDA receptor is activated when glutamate binds to it. When activated it allows positively charged ions to flow through the cell membrane. Magnesium and zinc ions come wandering by and bind to specific sites on the receptor, which allows them to act as gatekeepers and block sodium and calcium from entering. Depolarization of the cell dislodges and repels the gatekeepers and allows sodium and small amounts of calcium ions into the cell and potassium out of the cell. Calcium movement back and forth through the NMDA receptor appears to be critical for synaptic plasticity and thus for learning and memory.
The normal amount of QUIN in the brain and cerebrospinal fluid (CSF) is usually very small and is optimized for NAD production. In pathological conditions, QUIN levels can increase in the brain several thousand percent.
When Quinolinic acid increases to pathological levels it becomes an exitotoxin that over-activates NMDA receptors. This causes a rapid inflow of calcium into the neuron and the resulting chaos leads to mitochondrial dysfunction, ATP exhaustion, free radical formation, oxidative damage, and cell death signaling.
Some of the above could occur as one off damage, but QUIN the exitotoxin tends to start and perpetuate bad feedback loops. Here are three:
Loop 1: Glutamate
When QUIN excites the NMDA receptor there is an increase in glutamate release along with an inhibition of glutamate reuptake by astrocytes. The additional glutamate then activates more NMDA receptors and more glutamate is produced. This is like turning on the faucet and partially blocking the drain and then turning the faucet up a little bit more. Glutamate concentrations quickly reach toxic levels. Toxic levels kill neurons, increase inflammation, and produce more QUIN.
Loop 2: QPRT and Iron
QUIN is normally regulated by magnesium ions and quinolinate phosphoribosyl transferase (QPRT), which converts QUIN to NAD and carbon dioxide. QPRT is quickly saturated by QUIN such that QUIN production can rapidly outpace QPRT’s ability to keep pace.
Working against QPRT is the enzyme 3-HAO and its not a fair fight. 3-HAO combines with iron to create QUIN and has a reaction velocity 80 times greater than QPRT. In fact, the addition of iron stimulated 3-HAO activity is 4 to 6 times greater in invitro tests of striatal brain cells. This iron fueled frenzy of QUIN production is all the more concerning because iron ions are normally released when neurons are damaged, thus feeding more 3-HAO reactions and therefore more QUIN.
QUIN can also produce neurotoxicity through another mechanism. It can interact with iron to form a complex that leads to free radicals that cause oxidative stress which further increases glutamate release and inhibits its reuptake, and results in the breakdown of DNA in addition to lipid peroxidation.
Loop 3: Blood Brain Barrier
QUIN is produced in the brain, but extra sources of QUIN in the body are blocked from entering the brain by the BBB. Under inflammatory conditions the BBB can falter and this may be accelerated by QUIN’s role in destabilizing the cytoskeleton within astrocytes and brain endothelial cells. The resulting leaks in the BBB allow extra QUIN to enter the brain and join the toxic party.
Causes of Increased QUIN Levels
Aging – QUIN concentrations and metabolism increase with age. Researchers administered tryptophan and were able to increase QUIN levels in adult rats but not in newborn rats. CSF samples from 49 healthy women showed central tryptophan metabolism increased with age in women, with an apparent shift towards the production of QUIN.
TBI – No surprise that traumatic brain injury (TBI) results in highly elevated levels of QUIN and for prolonged periods. As mentioned in previous articles, the correlation between TBI and later Alzheimer’s is very high.
Vitamin Deficiency – Way back in 1950 they found that a lack of thiamine (B1), riboflavin (B2), vitamin B6, and folic acid (B9) resulted in a reduced conversion of typtophan to NAD.
Links to Alzheimer’s
If you were to culture some human neurons in a dish and add QUIN in pathophysiological concentrations and you could almost sit back and watch the increased tau phosphorylation. QUIN is also found cohabiting with hyperphosphorylated tau within Alzheimer’s diseased brains.
QUIN is at least one source of the neuron damage, mitochondrial dysfunction, oxidative stress, and apoptosis that are hallmarks of Alzheimer’s. QUIN effects all neurons but some more than others. There are a couple of NMDA receptor subtypes that QUIN is particularly drawn to and where it does increased damage. These receptor subtypes are more commonly found in the neocortex, hippocampus and striatum.
The brain areas with the lowest QPRT activity are the frontal cortex, striatum, hippocampus, and retina (areas where damage is associated with frontotemporal dementia and Alzheimer’s). That the hippocampus, as well as the striatum, do not appear to possess mechanisms either for the rapid removal of QUIN or for its metabolic degradation would mean that they are particularly susceptible to damage from excess QUIN.
QUIN’s deleterious interactions with iron might explain the “rusty brain” theory of Alzheimer’s. One study even showed that high levels of iron could be used to predict cognitive decline and that levels were higher in those with the ApoE4 allele.
Depression – Depression often goes hand in hand with Alzheimer’s. QUIN levels in the brains of 12 acutely depressed suicidal patients were analyzed and compared with 10 healthy control subjects. Depressed patients had a significantly increased density of QUIN-positive cells in key brain regions.
How To Stop/Reverse QUIN
You would think that reducing your intake of tryptophan would short circuit the process, but that’s not the case (at least in rats). When rats enjoyed a tryptophan free diet for 15 days QUIN concentrations in the cortex doubled. Fortunately, there are other ways to stop the process.
Ferritin – A protein we all produce that binds iron and releases it slowly. It was used successfully to mute the iron-dependent production of QUIN by 3-HAO.
Antioxidants
Garlic – A garlic derived antioxidant preserved the functional integrity of the striatum in the face of elevated QUIN levels.
Curcumin – Natural phenols such as curcumin, and taxifolin (a flavonoid found in plant-based foods like fruit, vegetables, wine, tea, and cocoa), reduce the neurotoxicity of QUIN via anti-oxidant and possibly calcium influx mechanisms.
B6 – Several key enzymes in the tryptophan-kynurenine pathway require the active form of B6 known as pyridoxal 5′-phosphate (PLP) or flavin adenine dinucleotide (FAD, vitamin B2) as cofactors. Despite the importance of B2, studies have usually focused on the effects of B6. More than one study on bacterial induced brain damage has shown that sufficient levels of B6 have been very helpful in mitigating the damage of QUIN.
NMDA Antagonists
Another method is to fill the NMDA receptors with something other than QUIN.
Kynurenic acid – (KYNA) is that other metabolite in the kynurenine pathway we mentioned at the beginning. KYNA binds to the NMDA receptor and acts as an antagonist, therefore it has a calming effect.
- Nicotinylalanine, an analog of KYNA, switches the kynurenine pathway from the production of QUIN over to KYNA. It’s use in rats specifically increases KYNA concentrations in the hippocampus.
- The high-fat and low-protein/carbohydrate ketogenic diet (KD) increased production of KYNA by substantial amounts. Compared to rats fed a regular diet, the ketogenic diet resulted in an increase of KYNA concentrations in the hippocampus of 256% for young rats and 363% for adult rats. The increases in the striatum were 381% for young rats and 191% for adult rats. There was no effect on KYNA concentrations in the cortex.
Drugs
Mementine – This is the first time we have mentioned a drug that is specifically used to treat Alzheimer’s. Mementine was first synthesized in 1968 to treat diabetes. In the 1980s it was shown to work as an agonist for NMDA activity while not blocking synapse receptors. It is only used to treat moderate to severe Alzheimer’s disease. Like all other Alzheimer’s drugs (and there are few) memantine produces a moderate decrease in clinical deterioration along with a small positive effect on mood, behavior, cognition, and the ability to perform daily activities. Memantine also stops the hyperphosphorylation of tau.
Ketamine – Another NMDA receptor antagonist, ketamine is a rapid acting anti-depressant originally used as an anesthesia. Ketamine is an effective anti-depressant, but is not approved for the treatment of depression.
Update March 2019 – The FDA has approved the use of a ketamine derivative called Esketamine that is sold as a nasal spray under the brand names Ketanest and Spravato. My understanding is that it can only be administered in a doctor’s office and they must monitor you for two hours before you can leave, such is the FDA’s fear of esketamine’s more dissociative or hallucinogenic effect. My concern about esketamine is that it increases glucose metabolism in the frontal cortex whereas ketamine may have a more Alzheimer’s friendly reaction of reduced glucose metabolism throughout the brain.
Licofelone – Licofelone has also demonstrated protective properties against QUIN, but as a LOX and COX-2 inhibitor I think there are better ways to go about it. Remember that COX and LOX are involved in converting omega-3 fatty acids into inflammation inhibitors.
Final Thoughts
If the blind guys from the old joke could switch their attention from the elephant to the effects of QUIN they might each claim THE cause of Alzheimer’s to be Inflammation, or Neuron Damage, or Rusty Brain, or Oxidative Stress, or Tau Phosphorylation, and they would all be partially correct. Not wrong, but not entirely correct. Correcting any one of the above has not cured Alzheimer’s.
Not to be a Debby Downer, but drugs such as Memantine that block QUIN at the NMDA receptor and should therefore fix all of the above issues (caused by QUIN) are only partially successful and can slow progression and in some cases slightly reverse but not CURE the disease.
Selenium, Garlic, and ketones had positive effects in some, but not all critical areas of the brain when it came to QUIN. In short, QUIN is an important component and may explain several paths of damage associated with Alzheimer’s, but it cannot be the only explanation. Therefore, reversing QUIN cannot by itself reverse Alzheimer’s, but it won’t hurt to add it to the list of things to fix.
[…] results in negative feedback loops of inflammation that are damaging to neurons (see QUIN is not your friend: Quinolinic Acid and Alzheimer’s for more details). A study of cerebrospinal fluid amino acids in 26 children on the ketogenic […]