Hi again Julie. Sorry for the delay - it's a busy Monday! So many questions. Here is a disorganized (sorry) reply. Thanks for the paper - more good reading!HDL in the brain. I totally agree that HDL-C can cross into the brain from general circulation. HDL in general circulation seems to be a good thing. I haven't followed those studies enough yet to know if HDL getting into the brain would be helpful.
I would suspect that the HDL would contain more apoA than apoE (as is typical) and would be well-lipidated, so at least it shouldn't raise free or poorly-lipidated apoE there and, thus, would probably not have detrimental effects in the brain. I presume that HDL in the brain probably can't do it's normal job - reverse CHO transport back to the liver - so I don't know what to make of it myself. But HDL is not made in the brain, as far as I know. Most CHO synthesis in a healthy brain happens in astrocytes and they export it in particles that are somewhat similar to HDL but have only apoE as the lipoprotein (no apoA). Why did I conclude that lowering apoe in the brain was the way to go? I guess it was a general reaction....kind of sloppy on my part not pointing out specific papers (ugh)...
.to being overwhelmed by various papers showing all of the bad ("toxic" effects of apoe4 on gene expression, AB aggregation, APP synthesis and cleavage, etc. I assume that lowering apoe4 is one way to lower free/poorly lipidate E4, which seems to be the goal.
Examples convincing me that lower E4 would be good:
Like studies showing that correcting E4 structure to be E3-like (the oft discussed "Gladstone" papers)
Using gene editing to actually change E4 to E3 in human cell lines and mice. Here is one example: Huang, Y. A., Zhou, B., Wernig, M., & Südhof, T. C. (2017). ApoE2, ApoE3, and ApoE4 differentially stimulate APP transcription and aβ secretion. Cell, 168(3), 441.e21. 10.1016/j.cell.2016.12.044 Retrieved from https://www.sciencedirect.com/science/a ... 7416317603
Bredesen's gene expression paper (and other more recent, similar ones) just seem to show free E4 as the root cause of "badness". Here is that paper: Theendakara, V., Peters-Libeu, C. A., Spilman, P., Poksay, K. S., Bredesen, D. E., & Rao, R. V. (2016). Direct transcriptional effects of apolipoprotein E. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience, 36(3), 685. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/26791201Here is a not-very-organized collection of papers I was recently reading:Boehm-Cagan et al 2016 Differential effects of apoE4 and activation of ABCA1 on brain and plasmo lipoproteins PLOS ONE November 8, 2016. A good review of apoE4 and other lipoproteins and a good summary of how levels change differently and have different effects in the CNS compared to general circulation. Also: shows importance of ABCA1 for lipidating the particles and making them safe. They have a compound that encourages this in cells.Liao et al. May 2018. Targeting of nonlipidated, aggregated apoE with antibodies inhibit amyloid accumulation. Journal of Clinical Investigation 128:5 page 2144- The study shows that binding up free/non-lipidated apoe(4) with antibodies or gene-therapy type silencing decrease amyloid formation. This paper seemed important. So, here is what I am thinking, currently:
Apoe4 in general circulation can be good, in part because it is an important part of HDL which is beneficial and higher levels could be better BUT free or poorly lipidated apoe4 in the brain is toxic and, in my assessment, the root cause of most pathology. About the statins potentially limiting the ability of ABCA1 to "fill up" apoE4 particles, making things worse.
Yeah, I had the same concern you did. My readings convinced me that the availability of CHO in the brain and at the site of APOE "filling" specifically are in excess and are not limiting. I am still looking for any evidence that brain
lipoparticle size is altered by statin use - but that's a rather specific question I can't find an answer to so far. You know I tend to be on the "pro-statin side" of things. I'll admit it's a tough question. In my case I had to make a call. I was greatly encouraged by several lines of evidence supporting statin use:Love this paper!
Geifman, N., Brinton, R. D., Kennedy, R. E., Schneider, L. S., & Butte, A. J. (2017). Evidence for benefit of statins to modify cognitive decline and risk in alzheimer’s disease. Alzheimer's Research & Therapy, 9(1)10.1186/s13195-017-0237-yThis one too.
Wanamaker, B. L., Swiger, K. J., Blumenthal, R. S., & Martin, S. S. (2015). Cholesterol, statins, and dementia: What the cardiologist should know. Clinical Cardiology, 38(4), 243-250. 10.1002/clc.22361 Retrieved from https://onlinelibrary.wiley.com/doi/abs ... /clc.22361Conclusions less clear in this one.
Wood, W. G., Eckert, G. P., Igbavboa, U., & Muller, W. E. (2010). Statins and neuroprotection: A prescription to move the field forward. Annals of the New York Academy of Sciences, 1199(1), 69-76. 10.1111/j.1749-6632.2009.05359.x Retrieved from http://www.ingentaconnect.com/content/b ... 1/art00007
I've also read that the secretase enzymes that cleave APP into good or bad parts act differently when floating in lipid rafts rich in CHO. As best I can tell, the less CHO there the better.
I also want to not have a heart attack.
I'll share a bit of recent good news: my labs came back after 6 months of really serious diet, exercise, and lifestyle ReCODE-like stuff. And they were GREAT! It is absolutely amazing! Started out with all sorts of problems - and now the numbers are about as good as I could ever hope for. In this case, my own version of the program included a statin. I think the statin counteracted any tendency of the ketoflex diet to send lipids in the wrong direction (as they had been over the winter). And the diet counteracted any tendency of the statin to raise blood sugar. They worked well together. Dr. Bredesen would probably not agree, I know. But my version of the program raised my HDL more than anything my cardiologist did in the past ten years. And that was actually the least impressive of the numbers. All of the markers are unbelievable good. Even some other chronic metabolic issues - ones I couldn't ever seem to improve - were dramatically improved. Of course, I have no indication of what is really happening inside of my thick skull. But the numbers were so good, so much improved, that I'm going to stick with it as long as I can.
But again, I could be wrong. Please point out any holes in my logic.
I still hope for a nice E4 structure corrector.....
Concerned, but hopeful. Introverted, but will talk about science.