Alzheimer's, p62, and coffee

Today the biggest trending health-related topic on Facebook is Alzheimer's disease. Just yesterday, a study was published linking Alzheimer's to a multipurpose protein called p62, also called sequestome-1 (encoded by the SQSTM1 gene). It's been known for a while now that p62 is involved in autophagy, and that autophagy is involved in Alzheimer's. Here's the abstract from the study published today:

Mol Psychiatry. 2016 Aug 30. doi: 10.1038/mp.2016.139. [Epub ahead of print]
p62 improves AD-like pathology by increasing autophagy.
Caccamo A, Ferreira E, Branca C, Oddo S.
Abstract
The multifunctional protein p62 is associated with neuropathological inclusions in several neurodegenerative disorders, including frontotemporal lobar degeneration, amyotrophic lateral sclerosis and Alzheimer's disease (AD). Strong evidence shows that in AD, p62 immunoreactivity is associated with neurofibrillary tangles and is involved in tau degradation. However, it remains to be determined whether p62 also plays a role in regulating amyloid-β (Aβ) aggregation and degradation. Using a gene therapy approach, here we show that increasing brain p62 expression rescues cognitive deficits in APP/PS1 mice, a widely used animal model of AD. The cognitive improvement was associated with a decrease in Aβ levels and plaque load. Using complementary genetic and pharmacologic approaches, we found that the p62-mediated changes in Aβ were due to an increase in autophagy. To this end, we showed that removing the LC3-interacting region of p62, which facilitates p62-mediated selective autophagy, or blocking autophagy with a pharmacological inhibitor, was sufficient to prevent the decrease in Aβ. Overall, we believe these data provide the first direct in vivo evidence showing that p62 regulates Aβ turnover. Molecular Psychiatry advance online publication, 30 August 2016; doi:10.1038/mp.2016.139.

This is a great advance. So now how do we increase the brain p62 expression so as to have sufficient p62 for the needed autophagy?

If you read back a bit, you'll see in one blog post I used some data about Alzheimer's and country/state coffee consumption to conclude that high coffee consumption appears linked to increased Alzheimer's prevalence. However, in light of the recent research, I admit that I could be wrong about such a correlation and that I need to know much more about autophagy. There is one study looking at p62 and coffee. Here's the abstract for it:

Cell Cycle. 2014 Jun 15; 13(12): 1987–1994.Published online 2014 Apr 25. doi:  10.4161/cc.28929PMCID: PMC4111762
Coffee induces autophagy in vivo
Federico Pietrocola, Shoaib Ahmad Malik, Guillermo Mariño, Erika Vacchelli, Laura Senovilla, Kariman Chaba,  Mireia Niso-Santano, Maria Chiara Maiuri,  Frank Madeo,  and Guido KroemerEpidemiological studies and clinical trials revealed that chronic consumption coffee is associated with the inhibition of several metabolic diseases as well as reduction in overall and cause-specific mortality. We show that both natural and decaffeinated brands of coffee similarly rapidly trigger autophagy in mice. One to 4 h after coffee consumption, we observed an increase in autophagic flux in all investigated organs (liver, muscle, heart) in vivo, as indicated by the increased lipidation of LC3B and the reduction of the abundance of the autophagic substrate sequestosome 1 (p62/SQSTM1). These changes were accompanied by the inhibition of the enzymatic activity of mammalian target of rapamycin complex 1 (mTORC1), leading to the reduced phosphorylation of p70S6K, as well as by the global deacetylation of cellular proteins detectable by immunoblot. Immunohistochemical analyses of transgenic mice expressing a GFP–LC3B fusion protein confirmed the coffee-induced relocation of LC3B to autophagosomes, as well as general protein deacetylation. Altogether, these results indicate that coffee triggers 2 phenomena that are also induced by nutrient depletion, namely a reduction of protein acetylation coupled to an increase in autophagy. We speculate that polyphenols contained in coffee promote health by stimulating autophagy.

Here are the questions I'm left with: Are there different kinds of autophagy that may or may not clean up amyloid-beta plaques? Or is every single autophagy process that uses p62 as a substrate going to going to clean up amyloid-beta plaques? If there are different kinds, which kinds are stimulated by coffee? Ones that will clean up amyloid-beta plaques? Or ones that do not do so yet will use up the p62 needed for the kinds of autophagy that do clean up amyloid-beta plaques? Does it matter that study on coffee didn't investigate brain tissue? And does this second study tell us anything about long-term effects of coffee? Does the body somehow adjust to chronic coffee exposure and downregulate p62 to protect from too much autophagy?

I didn't wake up this morning wondering about autophagy. I think tomorrow morning that will be different. This is a fun thought experiment, but one sadly riddled with unknowns.

Sulfite could be behind migraines, too

As noted in my last post, I recently published a theory of excess sulfite accumulation being behind nausea and vomiting in pregnancy (NPV) (online now at http://www.sciencedirect.com/science/article/pii/S0306987716300986).

It has so far proven very effective for myself and a friend to ameliorate nausea in pregnancy by avoiding sulfite compounds in/on food and increasing molybdenum intake. Molybdenum is used by the body in sulfite oxidase, an enzyme that catalyzes the conversion of toxic sulfite to excretable sulfate. But our bodies can only make so much sulfite oxidase, so it's important to limit intake of sulfites. Molybdenum isn't a "now eat whatever you want" cure.

As I was putting together this theory, I started seeing similarities between morning sickness and migraines, specifically

1) both are quite involved with hormones,

2) both appear to be associated with similar food intake, and 

3) they share similar patterns of gradual onset and varied duration and intensity.

I realized that just as sulfite accumulation in the gastrointestinal tract could lead to nausea and vomiting, similarly sulfite accumulation in the brain could lead to migraine headaches. The brain damage experienced over time from migraine headaches lends support to the idea that migraines are caused by a toxic chemical in the brain. Because of recent research on endogenous hydrogen sulfide, we now know that hydrogen sulfide--a catabolite of which is sulfite--is a neuromodulator in the brain. 

A friend in her early 40s has been suffering terribly from migraines and, realizing that that all her migraine medications only made her feel worse, weaned herself off of the medications. Then about 3 weeks ago I told her of my theory's possible application to migraines and gave her some capsules of a 500 mcg molybdenum supplement (it was this one). She informed me this week that she takes molybdenum when a migraine starts coming on, and the migraine goes away. She feels better now than she has for a while.

If someone suffers from migraines, I think avoiding heavily-sulfite-treated grapes and other sulfite-containing foods would be a very good idea. It might also be a good idea to look at whether one's molybdenum intake might be too low. Molybdenum is highest in pulses, some whole grains (especially barley and oats), and liver (I'm not a fan of long-term high liver intake, though, due to its high retinol content); molybdenum naturally occurs in milk, too, but it's mostly found in the cream, which in large amounts poses its own health-related risks.

(Disclaimer: I do not prescribe the use of pharmaceutical drugs in any way. I am not a physician, and I reject out of hand any attempt to hold me liable for what boils down to a discussion of food. Any use of a molybdenum supplement should be prudent and guided by the tested tolerable upper intake levels for its usage (see http://lpi.oregonstate.edu/mic/minerals/molybdenum for those limits). Any use of an isolated molybdenum supplement during pregnancy should be under the direction of a medical professional as such supplements have apparently not been tested during pregnancy.)

+ Molybdenum - Sulfites = Less Morning Sickness

Here's the link to my published theory on "morning sickness," published online at the end of last week:

http://www.sciencedirect.com/science/article/pii/S0306987716300986

And here's the abstract if you don't want to follow the link:

Medical Hypotheses

Volume 95, October 2016, Pages 31–33

A novel treatment for “morning sickness”: Nausea of pregnancy could be induced by excess sulfite which molybdenum can help alleviate

Abstract

Nausea and vomiting of pregnancy (NVP) remains difficult to treat. Last century, thalidomide was used to alleviate NVP, but it caused teratogenesis by interfering with angiogenesis. The gasotransmitters hydrogen sulfide (H2S) and nitric oxide are mutually dependent on each other for their angiogenesis-related functions. Pregnancy-related requirements for increased endogenous H2S could create a temporary excess of sulfite, an H2S catabolite, which is toxic and can induce nausea. Sulfite oxidase, a molybdenum-containing enzyme, catalyzes oxidation of sulfite to sulfate, which can then be excreted or reused by the body. Supplementation with molybdenum should facilitate enhanced sulfite oxidase activity, thus lowering gestationally-elevated sulfite levels in the gastrointestinal tract and easing NVP.

(Disclaimer: I do not prescribe the use of pharmaceutical drugs in any way. I am not a physician, and I reject out of hand any attempt to hold me liable for what boils down to a discussion of food. Any use of a molybdenum supplement should be prudent and guided by the tested tolerable upper intake levels for its usage (see http://lpi.oregonstate.edu/mic/minerals/molybdenum for those limits). Any use of an isolated molybdenum supplement during pregnancy should be under the direction of a medical professional as such supplements have apparently not been tested during pregnancy.)

Excess Endogenous Hydrogen Cyanide and Epileptic Seizures

I have an acquaintance with epilepsy (i.e., repeated seizure disorder), a consequence of encephalitis around eight years ago. Because of his illness--which has yet to respond to the usual medications--I looked into epilepsy over the past couple of months to see if there was anything diet-related that he could do to lessen his seizures. This is a result of that research. (If it's wrong, please let me know how and where, and I'll note that or scrap the hypothesis entirely.):

Here is a description of grand mal seizures (also known as generalized tonic-clonic seizures), a common manifestation of epilepsy:

Generalised Tonic Clonic Seizures Generalised tonic-clonic seizures are sometimes called a fit or convulsion. They are the most universally recognised seizures.
They often begin with a sudden cry. If standing, the person will fall to the ground and lose consciousness.
The body becomes quite stiff (tonic) shortly followed by jerking of the muscles (clonic). Breathing is shallow or temporarily suspended causing the lips and complexion to look grey/bluish. Saliva (sometimes also blood if the tongue has been bitten) may come out of the mouth, and there may be loss of bladder control.
The seizure usually lasts approximately two minutes and is followed by a period of confusion, agitation and extreme tiredness. Headaches and soreness are also common afterwards.

And here is the CDC's description of what happens in a case of poisoning by sodium cyanide, which releases hydrogen cyanide gas:

• EFFECTS OF SHORT-TERM (LESS THAN 8-HOURS) EXPOSURE: Early symptoms of cyanide poisoning include lightheadedness, giddiness, rapid breathing, nausea, vomiting (emesis), feeling of neck constriction and suffocation, confusion, restlessness, and anxiety. Accumulation of fluid in the lungs (pulmonary edema) may complicate severe intoxications. Rapid breathing is soon followed by respiratory depression/respiratory arrest (cessation of breathing). Severe cyanide poisonings progress to stupor, coma, muscle spasms (in which head, neck, and spine are arched backwards), convulsions (seizures), fixed and dilated pupils, and death. The CNS is the most sensitive target organ of cyanide poisoning. Cardiovascular effects require higher cyanide doses than those necessary for CNS effects. In serious poisonings, the skin is cold, clammy, and diaphoretic. Blue discoloration of the skin may be a late finding. Severe signs of oxygen deprivation in the absence of blue discoloration of the skin suggest cyanide poisoning.

INHALATION EXPOSURE:

• Mild to moderate: CNS effects: headache, confusion, anxiety, dizziness, weakness (malaise), and loss of consciousness. Cardiovascular effects: palpitations. Respiratory effects: respiratory tract irritation, difficulty breathing or shortness of breath (dyspnea), and transient increase in rate and depth of breathing (hyperpnea). GI effects: nausea and vomiting (emesis).

• Severe: CNS effects: coma, seizures, and dilated pupils (mydriasis). Cardiovascular effects: shock, abnormal or disordered heart rhythms (dysrhythmias), critically low blood pressure, and cardiac arrest. Respiratory effects: abnormally rapid, followed by abnormally slow respirations; accumulation of fluid in the lungs (pulmonary edema); and respiratory arrest. Eye effects: dilated pupils, inflammation of the surface of the eye, and temporary blindness.

I highlighted the parts of these two descriptions that appear to overlap. Whether there are dilated pupils (mydriasis) in a grand mal seizure isn't clear, for apparently the eyes roll back into the head during such a seizure. Also, I couldn't find much information about whether cyanide poisoning causes a sudden cry; it can cause gasping, though, when injected into the brainstems of cats (the study cats were anesthetized), and abrupt onset gasping is sometimes seen in severe cyanide poisoning cases.

Why am I pointing out these similarities? Our bodies make endogenous hydrogen cyanide ("HCN"). Yes, the same poisonous gas used in the Nazi death camps. HCN is a little molecule--just one hydrogen, one carbon, and one nitrogen together in a linear bond--so it's not surprising that it would be a product of some of the many chemical reactions that occur in a body. When dissolved in water, HCN releases a cyanide ion that halts cellular respiration. Fortunately we have internal methods of detoxifying cyanide, the primary mechanism being the rhodanese-catalyzed conversion of cyanide to thiocyanate; these methods can, however, be overwhelmed by acute cyanide poisoning.

Cyanide is generated in neuronal tissue. So could epileptic seizures be the result of cyanide poisoning, localized in the brain, that is caused by the body’s own production of hydrogen cyanide? That is my hypothesis.

A seizure is defined as "a temporary dysfunction of the brain consisting of an excessive synchronous neuronal discharge." Cyanide appears to dramatically (by 300%) increase the spontaneous discharge of a type of neuron found in the brainstem, which is where grand mal seizures are suspected to originate. A 1997 study documented that endogenous cyanide generation in neuronal tissue was increased significantly by mu opiate receptor agonists (the 1997 study was confirmed per this 2004 article), and per this 2012 study mu opiate receptors are known to be involved in seizures and are enhanced in the hippocampus (located in the medial temporal lobe) of patients with drug-resistant temporal lobe epilepsy (this 1988 study also seems to connect mu opiate receptors with epileptic seizures). And this might be too big a stretch, but a very recent study found that 3-MST, an enzyme which helps detoxify cyanide and is required for biosynthesis of thiosulfate (which rhodanese uses to convert cyanide into thiocyanate), was mainly located in living, not dead, neurons after traumatic brain injury (TBI), which suggests the possibility that cyanide accumulation in a TBI-caused lesion might be implicated in post-TBI epilepsy.

If this cyanide-epilepsy theory has merit, then does it point to something a person can do diet-wise to decrease the risk of experiencing seizures? I haven't come across any medical websites citing trigger foods that are clearly associated with the occurrence of epileptic grand mal seizures, although such websites do sometimes warn against caffeine, especially if it interferes with sleep patterns. Cyanide is found in several foods, including almonds, soy, cereal grains, tapioca (also known as cassava or yuca), lima beans, cherry juice, and bamboo shoots. Interestingly, a study last year in Ghana linked cassava consumption to active convulsive epilepsy. Also, a couple years ago a UW-A seizure researcher found that replacing soy protein mouse chow with a casein-based chow resulted in a 50% decrease in seizures; she suspected the component of soy that might be causing the increased seizures is phytoestrogens, but perhaps cyanide could be partially to blame. Further, since cereal grains contain cyanide, perhaps avoiding them is one reason why ketogenic diets have been observed to alleviate epilepsy. I therefore conclude that decreasing consumption of cyanide-containing foods will likely help diminish the occurrence of epileptic seizures.

Another thing that might be helpful--if this theory has merit, of course--is taking multivitamins that contain the hydroxocobalamin form of B12 instead of the cyanocobalamin form of B12 and avoiding cyanocobalamin-fortified foods. Rather than ingest extra cyanide, it makes sense instead to supplement with hydroxocobalamin, for hydroxocobalamin is a form of B12 that just happens to be an approved, effective treatment for cyanide poisoning.

More on chloride ions and allergies

My Aged P ("aged parent") was here visiting last night. He is a retired family practice physician, so I told him about my recent research on retinol metabolism pathways, immune tolerance, and diet differences that appear implicated in various undesirable immune and autoimmune reactions. Specifically, we discussed the Israeli peanut snack, Bamba and its ability to help keep at-risk children from developing peanut allergies. As I talked about the chloride ions provided by the dissolved salt in Bamba, my father pointed out that people already have chloride ions in their stomachs because gastric acid's most important constituent is hydrochloric acid, which dissociates into hydronium and chloride ions.

Not having gone to medical school, I appreciated his insight. And then I thought, well, then people with low hydrochloric acid, i.e., "hypochlorhydria," should be more likely to suffer from food allergies than people with adequate stomach acid. I did a little research, and found that over 80 years ago, researchers were noticing an association between low gastric acidity and various allergic conditions. Recent research still finds this association. For example, a study published three years ago found that children with GERD who were given gastric acid suppressing medications were more likely to develop food allergies than children with GERD who were not given gastric acid suppressing medications.

I grew up hearing from TV ads that stomach acid is a bad thing that must be neutralized. I don't think that's generally true. It's bad to have the acid get into the esophagus--we call that "heartburn"--but stomach acid performs many important functions, including perhaps helping our bodies not become allergic to foods.

Another publication

It's been months since I submitted the article to the journal, but that's apparently how long it takes to get peer reviews back. My theory about how to alleviate morning sickness has been approved for publication. When it becomes available online, I'll post a link to it together with a summary of the theory.

It has begun

For years, I've told my husband, "Our girls will have crushes on boys starting as early as fourth or fifth grade. They'll dream about them. They'll write their initials plus the boys' initials in secretive places. It's just part of being a girl."

And my husband with a glower would say, "We're moving three hours away from the nearest boys! Three hours!"

I would laugh and hope he wasn't even a tiny bit serious. I love my home, and I don't want to move to Montana or Alaska.

Today my oldest (dd11) was pulling out school notebooks from last year to get ready for the new school year and showing them to me when I noticed on the last page of a notebook an elaborate drawing pairing her first initial with a letter that doesn't match anyone in the family. I called attention to it, asking whose it was, and she blushed and ran away with her notebook. Hello, puberty, I don't know if we adults are ready for you yet.

The salt of the earth...might help prevent allergies from developing?

There is a much lower rate of peanut allergies in children in Israel than is seen in genetically similar Jewish children in the USA and UK. The main theory to explain the difference is early exposure to peanuts in the form of a favorite snack food called Bamba.

A study was done in the UK where some parents were instructed to give their babies peanuts, preferably in the form of Bamba snacks, 3 times a week, while other parents were instructed to have their babies avoid peanuts.

Of the children who avoided peanut, 17% developed peanut allergy by the age of 5 years. Remarkably, only 3% of the children who were randomized to eating the peanut snack developed allergy by age 5.   Therefore, in high-risk infants, sustained consumption of peanut beginning in the first 11 months of life was highly effective in preventing the development of peanut allergy.
“For decades allergists have been recommending that young infants avoid consuming allergenic foods such as peanut to prevent food allergies,” notes Professor Lack, the lead investigator for the LEAP study. “Our findings suggest that this advice was incorrect and may have contributed to the rise in the peanut and other food allergies.”

http://www.leapstudy.com/leap-study-results#.V6uC8VQrIdU

I don't think it's just the early exposure to peanuts. Many parents can tell you how their children developed allergies to foods given in infancy. I think it's specifically the ingredients of Bamba: peanuts, corn, palm oil, and salt. 

As discussed below, food allergies appear more likely to develop when we do not promote optimal expression of an enzyme called RALDH2. Optimal expression of RALDH2 is key to developing oral tolerance of foods. This enzyme is activated by magnesium chloride. Bamba includes both magnesium (in peanuts and pulverized corn) and chloride (in table salt, i.e., sodium chloride). Both sodium chloride and magnesium chloride are ionic compounds that dissolve easily and dissociate in water, raising the possibility that Bamba, in the process of being digested, essentially provides dissociated magnesium chloride. Thus every time an Israeli child eats Bamba, they could be activating RALDH2 and promoting oral tolerance of peanuts. Osem, the maker of Bamba, recently promised to lower the salt content in Bamba by 15% over the next 2 years. It will be interesting to see if Israeli children start developing more peanut allergies over the next 2 years, as well.

One allergy that is common in Israeli children is sesame, which they eat in halvah (a sweet snack) and tahini (sesame paste used in hummus). Sesame contains a small amount of Vitamin E, but sesame lignans enhance Vitamin E activity. From the recipes and products I'm finding on the internet, Israeli halvah is typically just sesame seeds and sweeteners with no added salt. When tahini is used in hummus, it is combined with salt, but hummus also contains lemon juice, which if bottled likely has added lemon oil, which means it has citral, a RALDH2 inhibitor. If I were an Israeli parent trying to head off sesame allergies, I think I'd begin putting a little Dead Sea salt--it's half magnesium chloride--into my halvah and check my lemon juice to be sure I'm not putting extra lemon oil into my hummus.

So now I'll raise the question that would get me shunned in many nutritionist circles: Is it possible that the low-sodium push is partly responsible for the increase in allergies? And perhaps autoimmune diseases? Good thing I have no professional career in the field to be damaged. :)

Anecdotes about developing quinoa allergies

As seen in the preceding post, I've got a theory about what might be behind the rise in food allergies. 

I was surprised to learn today that quinoa is considered a low-allergenic food, despite it being a good source of tocopherols (Vitamin E) like wheat. According to my theory, quinoa should be likely to trigger an allergy when eaten together with Vitamin C and beta carotene (non-meat form of Vitamin A), especially if a lemony oil is also eaten. 

I was fascinated to come across this blog post and see that quinoa allergies have been triggered under many conditions that accord with my theory. The original poster developed a quinoa allergy after eating a quinoa/bean/raw pepper dish; raw pepper is a good source of both beta carotene and Vitamin C. Then a commenter reports developing the allergy upon eating quinoa with turkey after Thanksgiving Dinner; while the comment doesn't say whether sweet potatoes--a very good source of beta carotene and Vitamin C--were eaten as part of the Thanksgiving Dinner, they're considered a standard part of a US Thanksgiving meal. Another commenter mentions ending up in the hospital overnight with a horrific allergic reaction (memory loss can result from an allergic reaction?!) after eating a quinoa-stuffed pepper. Another commenter reports starting to notice a quinoa allergy when eating quinoa with tomatoes, which contain the entire triad mentioned below, Vitamins A, C, and E! (Maybe this vitamin richness of tomatoes is why my mother-in-law was allergic to tomatoes for a decade or so, although she seems to be over it now.) A later commenter links developing an allergy to quinoa to eating it in a Mexican salad with tomato and lime juice (citral!). 

The only comment not connecting development of a quinoa allergy to a food item in alignment with my theory is from a woman who was eating it with rice milk, but she does mention that she was breastfeeding at the time, so maybe she was taking postnatal multivitamins steadily. I know that I'm far more attentive to my vitamin needs when I'm pregnant or breastfeeding.

I wonder if quinoa just got labeled as unlikely to be allergenic because it used to be primarily eaten boiled in water or chicken stock, the way it has been traditionally eaten in the Andes. There is not a lot of Vitamin A and C in porridge or chicken soup. (Also, both the porridge and soup are likely to have added salt, but more on the salt aspect in a later post....) Will we see an increase in quinoa allergies as people going gluten-free eat it regularly in their bread, crackers, salads, tabouleh, etc.?