Down the research rabbit hole and finding a root

I couldn’t even wait till the next morning after posting last night. I had to learn more about autophagy. Staying up too late, I found this good review of the topic: http://www.cell.com/fulltext/S0092-8674(11)01276-1. There are different kinds of autophagy, and the one that uses p62 is “selective autophagy”:

One of the best characterized substrates of selective autophagy is p62, which is also known as sequestosome 1/SQSTM1. p62 is an ubiquitously expressed cellular protein, which is conserved in animals but not in plants and fungi. p62 directly interacts with LC3 (microtubule-associated protein light chain 3) on the isolation membrane through the LC3-interacting region (Figure 3). (LC3 is the mammalian homolog of Atg8 in yeast.) Subsequently, p62 is incorporated into the autophagosome and then degraded (Johansen and Lamark, 2011, Weidberg et al., 2011).

http://www.cell.com/fulltext/S0092-8674(11)01276-1

Further, per this article, “the intracellular level of p62 is tightly regulated by autophagy through the direct interaction of LC3 with p62 and reveal that selective turnover of p62 via autophagy controls inclusion body formation,” which seems to mean that the body tries to keep roughly the same level of p62 around.

As we saw from the study published 2 days ago, p62 regulates the degradation of amyloid-beta aggregation (aggregation of which we do not want), so we want to have enough p62. What could decrease the amount of p62?

To deal with the coffee issue, since I did bring it up again yesterday, coffee appears to very rapidly cause the body to go through p62 as it stimulates autophagy. Imagine if a person drinks coffee regularly throughout the day and is constantly stimulating autophagy, even when it’s not needed? In line with homeostasis, the body could perhaps downregulate p62 expression in order to keep autophagy from occurring to frequently. I didn’t find anything directly showing coffee’s long-term effect on p62 expression, but I did find that 1) elevated p62 promotes the development of liver cancer (https://www.ncbi.nlm.nih.gov/pubmed/27404485), and 2) chronic coffee drinkers are less likely to develop liver cancer (https://www.ncbi.nlm.nih.gov/pubmed/25305507), which findings together are circumstantial evidence indicating that coffee drinkers likely do not have p62 levels higher than coffee non-drinkers. That doesn’t necessarily mean coffee drinkers have too little p62 expression, though.

What is actually known to decrease p62 expression? I’m sure this isn’t an exhaustive list but these are the ones I found first:

1. Zebularine downregulates p62. (http://www.nature.com/articles/srep03219). Zebularine is ”a cytidine analog, [] a DNA methylation inhibitor that acts by forming a covalent complex with DNA methyltransferases.” (https://www.stemcell.com/zebularine.html)
2. Hypoxia (inadequate oxygen supply to tissues) downregulates p62 (https://www.ncbi.nlm.nih.gov/pubmed/23345396). “Prolonged hypoxia can induce formation of Abetas (amyloid beta peptides), the primary neurotoxic elements of AD, which accumulate over years to form the extracellular plaques that are the hallmark feature of the disease.” (https://www.ncbi.nlm.nih.gov/pubmed/17705799)
3. Homocysteine - High homocysteine levels are a well-established risk factor for Alzheimer’s (https://www.ncbi.nlm.nih.gov/pubmed/24644038). To aid the body in converting homocysteine to methionine, make sure to consume enough betaine (https://www.ncbi.nlm.nih.gov/pubmed/23157378), zinc, folate (not folic acid), and cobalamin (preferably not cyanocobalamin) (https://www.ncbi.nlm.nih.gov/pubmed/21860088). And watch intake of chlorogenic acid (consumed by many in large amounts via coffee, but present in many other foods) and black tea, both of which are known to increase homocysteine (http://ajcn.nutrition.org/content/73/3/532.long). Also, hydrogen sulfide has been shown effective in alleviating a homocysteine-induced decrease in p62 (https://www.ncbi.nlm.nih.gov/pubmed/25056869), so eat a diet with sufficient cysteine, for cysteine is what our bodies turn into hydrogen sulfide; Alzheimer’s disease patients do show decreased hydrogen sulfide synthesis in the brain (https://www.ncbi.nlm.nih.gov/pubmed/15221504, https://www.ncbi.nlm.nih.gov/pubmed/12054683).
4. Hydrogen peroxide (H2O2) - 

Increased mitochondrial hydrogen peroxide is associated with Alzheimer’s and age-associated cognitive decline (https://www.ncbi.nlm.nih.gov/pubmed/24906890, https://www.ncbi.nlm.nih.gov/pubmed/16141213). Peroxidases are enzymes that neutralize peroxides, including hydrogen peroxide. Hydrogen peroxide appears to make the blood-brain barrier more permeable, and a recent study found blood-brain barrier leakage in patients with early Alzheimer’s that is associated with cognitive decline (https://www.ncbi.nlm.nih.gov/pubmed/27243267).

Tea and coffee contain a lot of hydrogen peroxide:

Several beverages commonly drunk by humans can contain H2O2 at concentrations above 100 μM, including green and black tea and especially instant coffee [45–47]. When such beverages are ingested, the H2O2 they contain presumably rapidly diffuses into the cells of the oral cavity and upper part of the gastrointestinal tract [48]. Oral bacteria also produce H2O2 [49,50], although the resulting levels of exposure of the oral tissues are uncertain. It is often suggested that H2O2 released into saliva is used by salivary peroxidase to oxidize thiocyanate (CNS−) into products toxic to certain bacterial strains [50].

http://onlinelibrary.wiley.com/doi/10.1016/S0014-5793(00)02197-9/full (I promise I'm not obsessed with coffee. I don't even like coffee flavor. There's just a lot of research on coffee, I guess.)

But our spit helps us detoxify hydrogen peroxide in our food and drink:

In the mouth there is a special need for defense against hydrogen peroxide, because hydrogen peroxide is not only formed by bacteria colonizing the mucous membranes but also by the cells of the salivary glands. In saliva the most important part of this defense is salivary peroxidase, which detoxifies hydrogen peroxide in the presence of thiocyanate by converting it into hypothiocyanite, dioxygen and water. In addition, hypothiocyanite stops hydrogen peroxide production by the oral bacteria.

https://www.ncbi.nlm.nih.gov/pubmed/2826736

Low levels of salivary peroxidase are linked to periodontitis (https://www.ncbi.nlm.nih.gov/pubmed/1705074), an advanced gum disease which is associated with an increase in Alzheimer’s-related cognitive decline (http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0151081). While salivary peroxidase concentration in saliva goes up with age, the amount of saliva decreases with age, meaning there is less overall salivary peroxidase function in older people; If I’m reading this study--(http://biomedgerontology.oxfordjournals.org/content/62/4/361.full)--correctly, as we age, we become only half as able to break down hydrogen peroxide with saliva as younger people. That fits well with Alzheimer’s being an old age disease that appears in all cultures and locales.

A commonly eaten peroxidase is horseradish peroxidase, found in horseradish roots. Horseradish has been tested and found effective at protecting cells from oxidative damage (https://www.ncbi.nlm.nih.gov/pubmed/24637991). Horseradish (a main ingredient of "wasabi" paste nowadays) is commonly consumed with fish and seafood (https://www.hort.purdue.edu/newcrop/med-aro/factsheets/HORSERADISH.html), and it has long been observed that fish consumption is inversely correlated with Alzheimer’s (https://www.ncbi.nlm.nih.gov/pubmed/12873849). However, adding fish and fish oil to Alzheimer’s patients’ diets hasn’t made much of a difference in preventing cognitive decline (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947325/, https://www.ncbi.nlm.nih.gov/pubmed/24077434, https://www.ncbi.nlm.nih.gov/pubmed/17030655).

What if Japan’s fish consumption is so good for their brains because of the wasabi (which also contains a peroxidase) and horseradish peroxidases they are eating with it? Peroxidases that help get rid of H2O2 in the mouth and so lessen the exposure of the nearby brain to H2O2? South Korea, which has a population genetically similar to Japan and which lives mostly surrounded by water, reportedly has a much higher Alzheimer’s mortality rate than Japan (http://www.worldlifeexpectancy.com/cause-of-death/alzheimers-dementia/by-country/). At the same time, Koreans seem less likely to eat unfermented wasabi and/or horseradish with kimbab, their version of sushi rolls; they seem to prefer pickled daikon radish to get that “bite” instead. While daikon radish almost certainly contains a peroxidase of its own, any daikon peroxidase would be basically inactivated in the acidic environment that is part of kimchi.

My husband isn’t a big horseradish fan, even on sushi, so I had to call him up at work and tell him my newest hypothesis. Eat the wasabi! Like on this painful-looking Japanese game show!

Exercise appears to be a way to up salivary peroxidase activity. After high intensity exercising, salivary peroxidase activity increases for a short time (https://www.ncbi.nlm.nih.gov/pubmed/20035343). Exercise is associated with decreased Alzheimer’s risk (https://www.ncbi.nlm.nih.gov/pubmed/22703631), and high-intensity exercise might help preserve cognition, per this recent study (https://www.ncbi.nlm.nih.gov/pubmed/26682695). Of course, the exercise could be helping in other ways that have nothing to do with salivary peroxidase.

Finally, one can inhibit production of hydrogen peroxide by ingesting flavonoids, including quercetin (https://www.ncbi.nlm.nih.gov/pubmed/11063442). Quercetin shows great promise to ameliorate Alzheimer’s (https://www.ncbi.nlm.nih.gov/pubmed/25666032).

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All this concern about p62 levels might be moot in light of recent news about aducanumab, which appears able to completely remove amyloid-beta aggregations, although there's no clear indication of cognitive benefit (remember the tau tangles are what seem most correlated to cognitive problems). But it's been fun looking into p62, and sometimes people prefer trying diet and lifestyle changes to taking newly-developed medications with all their yet-to-be-discovered side effects.