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.