There is a dynamic pattern of mechanisms that may help explain, at least partly, how Alzhiemer’s and Down’s syndrome may impact cognitive function. This article is an investigation into the possible role of beta-amyloid, dynorphin, and a dynamic cascade of effects that may lead to the accumulation of beta-amyloid and likewise increased dynorphin levels. This dynamic between beta-amyloid and dynorphin may prevent elimination of beta-amyloid, causing a feedback loop of hypoactive glutamate signaling especially with reduced AMPAr activity. And of course, how psychedelics could be potential therapies for these conditions in the future.

A duplication of a beta-amoyloid gene is associated to both Alzheimer’s and Down’s (1). In Down’s Syndrome, the beta-amyloid plaque accumulate throughout lifetime (2). Increased dynorphin levels have been associated to both Alzheimer’s disorder and Down’s syndrome and is thought to play a role in the overlapping cognitive deficits seen in both conditions (3). Through normal aging we lose glutamate AMPA receptor subunits which some researchers hypothesized might be related to the rise in dynorphin levels seen with aging and could explain Alzheimer’s and age-related cognitive decline (4). In a related study, the researchers show that mice who lack dynorphin retain their AMPAr subunits and cognitive function (5).

The relationship of dynorphin to cognitive function seems to be mediated by anti-glutamatergic mechanisms of dynorphin. Dynorphin blocks NMDArs under most circumstances (6) and also reduces glutamate release (7). In the case that glycine levels are low, dynorphin seems to facilitate NMDAr stimulation (8), possibly by binding to glycine channels which enhance NMDAr sensitivity (9). In this case, dynorphin would appear to promote excitotoxic events mediated by excess NMDAr stimulation (10), although there may be a non-NMDAr mechanism involved in the excitotoxicity (11). It’s worth noting that dynorphin could normally potentiate its’ own antagonism of NMDAr by binding to glycine channels when dynorphin levels are high enough to occupy them both. There is evidence that NMDArs cause dynorphin to release. In a study on stimulant drugs, researchers found that dynorphin upregulation is a response to D1-NMDAr interactions, supporting that NMDAr may be critical to increasing dynorphin levels.

In the past, I’ve discussed dynorphin and cognition.

Here’s a short recap:

It appears that dynorphin may generally decrease cognitive ability and intelligence, although there may be an argument to be made that it changes cognition towards a direction that intelligence tests are typically biased against. Let’s start with evidence supporting the hypothesis that dynorphin decreases intelligence. Dynorphin seems to mediate age-related cognitive decline, which was shown when prodynorphin knockout mice did not experience cognitive decline. Dynorphin mediates alcohol-related spatial learning and memory impairment. This occurs by disrupting glutamate neurotransmission in the hippocampus. Another study found stress-induced learning and memory impairment was mediated by dynorphin. This one is interesting because it is not limited to spatial cognition. Occlusal disharmony, a problem that can cause neck stiffness and psychiatric depression was shown to cause memory and learning impairments mediated by dynorphin activity in the amygdala. It may be that pain aversion is mediated by dynorphin as well, which could explain this effect of the occlusal disharmony on learning and memory. Stress was negatively correlated to academic performance in high IQ students.

In epilepsy, NMDAr and more broadly, abherrent glutamate activity is implicated in the pathogenesis of seizures. NMDAr overstimulation is thought to play a major role in seizure-induced excitotoxicity. During seizures, dynorphin releases as an apparent neuroprotective factor to curb some of the excitotoxic glutamatergic activity. In temporal lobe epilepsy a dynamic upregulation of dynorphin was observed in response to seizure events. Dynorphin is an anti-convulsant and animals who lacked dynorphin experienced increased kindling and epileptogenesis.

Beta-amyloid binds to NMDAr as an agonist and is thought to produce excitotoxic effects by this mechanism as well as downregulate the number of NMDAr sites available on the cell surface among other mechanisms. It could be the case that the increased dynorphin seen in both Alzheimer’s and Down’s is similar because they both involve the same beta-amyloid mechanisms, including NMDAr overstimulation and ultimately dynorphin release in an attempt to curb excitotoxicity. If this is the case, AMPAr function would decline which might be a huge key to this puzzle.

Why would AMPAr be the key?

AMPAr is associated to faster firing of neurons compared to NMDAr which mediates slower signaling of neurons. NMDAr seems to fire in the ranges of 100s of ms while AMPAr fires in <10ms. Blocking AMPAr is shown to increase slow firing and decrease faster firing known as gamma frequencies in the brain. Alzheimer’s patients show a loss gamma frequencies which has lead researchers to test whether gamma frequency entrainment using strobe lights might help patients. In their animal study, the mice showed a 50% decrease in beta-amyloid plaques. Since dynorphin is shown to mediate loss of AMPAr functioning related to cognitive decline seen in aging, it could be that dynorphin leads to the loss of gamma frequencies as well. This loss of AMPAr firing might allow for the accumulation of beta-amyloid which then causes an accumulation of dynorphin activity, ultimately producing a neurotoxic feedback loop. The strobe lights are flickering at a rate (40Hz/gamma range) that surpasses the capability of NMDAr-mediated firing which should then force AMPAr firing and increased glutamate rates which might somehow lead to a cascade of mechanisms that cycles out beta-amyloid. The full mechanism isn’t clear yet, but the paper mentions the recruiting of microglia.

If this bit interests you, check out Flicker for some of the trippiest concepts surrounding brain frequencies, perception, glutamate, and hallucinogenic experiences. It is my personal favorite post yet due to its interactive-ness.

Moving along.

Since dynorphin accumulation appears to play a role in this dynamic, I couldn’t help but wonder if we should expect decreased 5HT2a functioning in Alzheimer’s due to the fact that 5HT2a agonists have been shown to attenuate dynorphin’s mechanisms. This is in fact the case: Alzheimer’s patients have decreased 5HT2a density. Beta-amyloid injections were found to decrease 5HT2a receptor levels in the hippocampus. In past posts I’ve suggested that psychedelics may have the potential to boost cognition, especially in those with trauma or prior stress, or even treat schizophrenia by attenuating dynamic loops associated with dynorphin, dopamine, and glutamate. One study found that reduced 5HT2a receptor binding is associated with cognitive impairment. It’s worth noting that schizophrenics also seem to have high beta-amyloid. Since psychedelics are explored to treat trauma and dynorphin plays a major role in PTSD/general stress, it also makes sense that those who experience earlier life traumas are more likely to experience cognitive decline or Alzheimer’s later in life. A study from 2013 found exactly this, early life trauma increases risk of cognitive decline and Alzheimer’s later in life.

Another recap:

The picture gets a little more interesting when we consider major dynorphin-implicated conditions. One such condition is PTSD. Stress and depression have also been linked to dynorphin.

So what does this mean for intelligence here? Well, PTSD has been linked to lower IQ scores. The research linked here has noted that premorbid IQ being lower also made PTSD worse, but this may be due to early life stress or prior trauma is limiting IQ and even promoting more severe stress reactions in adulthood. It was found that exposure to domestic violence suppressed IQ. Prior trauma is a risk factor for experiencing further trauma after a second event. So it seems likely that prior trauma may be at play here with premorbid IQ scores. This post on Psychology Today explores a study that showed a 10-15 IQ point drop correlated with stress. Unfortunately I was unable to find the original study. The post mentions amygdala activity suppressing prefrontal cortex activity as part of the explanation for intelligence differences and dynorphin is key to amygdala activity.

Adults with Down’s Syndrome show reduced serotonin in multiple regions of the brain. This study linked above also compared differences in serotonin among Alzheimer’s and Down’s Syndrome patients. It is possible that psychedelic intervention could restore cognitive function or prevent cognitive decline in both of these pathologies. Psychedelic drugs are known to increase gamma frequencies in the brain. THC was found to increase cognitive function in aged rats, possibly partly due to its 5HT2a enhancing mechanisms. Unfortunately, THC also enhances dynorphin release. Along with this, THC decreases glutamate functioning in a lot of similar ways that both dynorphin and aging do. This may put THC in the same area of interest as the NMDAr antagonists such as memantine (blocking beta-amyloid but having amnesiac side effects), with perhaps a slight edge due to its’ 5HT2a interactions. Psychedelics present an option for hypocognitive disorders that may not carry the issues of enhancing dynorphin release or causing glutamate hypofunction.

There are many correlations in the research that put psychedelics and THC in opposition to each other. Psychedelics have been shown to induce neurogenesis in the hippocampus while cannabis has been shown to shrink the hippocampus and impair neurogenesis. There seems to be some confusing data on how cannabis affects memory, as smaller hippocampus size associated to cannabis and nicotine use was correlated to greater memory performance only in users of the drugs. It’s critical to note that this study was testing short-term memory only. Psychedelics support structural and functional neuroplasticity, something that is shown to be dysfunctional in Alzheimer’s as well as with THC use. On the other hand, CBD was shown to enhance neuroplasticity. Psychedelics have been shown to have antidepressive, anxiolytic, and antiaddictive effects which may be mediated by disrupting dynorphin functioning since depression, anxiety, and addiction are all associated to dynorphin.

I’d recommend checking out some of the literature on how dynorphin and serotonin interact at the level of MAPK and induction of SERT (also).

Since dynorphin appears to play a significant role in the cognitive disruptions of Alzheimer’s and Down’s Syndrome it is worthwhile to explore psychedelics as potential cognitive restoration agents or even cognitive decline prevention agents.

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