Review: HDL and cholesterol handling in the brain.

[James]

This is a good review that covers cholesterol and lipoprotein production in the brain vs. body, and the limited interaction between the two.

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http://www.ncbi.nlm.nih.gov/pubmed/24907980

HDL and cholesterol handling in the brain.
Vitali C, Wellington C, Calabresi L.
Cardiovasc Res. 2014 Jun 6. pii: cvu148. [Epub ahead of print]

Abstract
Cholesterol is an essential component of both the peripheral and central nervous systems of mammals. Brain cholesterol is synthesized in situ by astrocytes and oligodendrocytes and is almost completely isolated from other pools of cholesterol in the body, but a small fraction can be taken up from the circulation as 27-hydroxycholesterol, or via SR-BI. Glial cells synthesize native HDL-like particles, which are remodeled by enzymes and lipid transfer proteins, presumably as it occurs in plasma. The major apolipoprotein constituent of HDL in the CNS is apolipoprotein E, which is produced by astrocytes and microglia. Apolipoprotein A-I, the major protein component of plasma HDL, is not synthesized in the CNS but can enter and become a component of CNS lipoproteins. Low HDL-C levels have been shown to be associated with cognitive impairment and various neurodegenerative diseases. On the contrary, no clear association with brain disorders has been shown in genetic HDL defects, with the exception of Tangier Disease. Mutations in a wide variety of lipid handling genes can result in human diseases, often with a neuronal phenotype caused by dysfunctional intracellular lipid trafficking.

[James]

I'd like readers to consider a popular argument for Paleo/similar being good for those with ApoE4, which is that providing extra cholesterol through the diet, and/or dietary increases in plasma cholesterol, could be beneficial for those with ApoE4. Stephanie Seneff is a prime example here, whose conclusions who I've seriously questioned for years.

I will provide temporary access to the full-text here: https://www.dropbox.com/s/72c57wb8ybryr ... cvu148.pdf

[Russ]

James,

Thanks. Perfect timing. Time for me to rethink some things and this has long been an unanswered question for me. Will print and read.

[Ski]

I think it is mainly used by the Paleo community as a justification for escalating lipid values. Having read up on this myself recently due to brain fog, I also came to the conclusion that serum cholesterol had little influence on brain cholesterol.

What seems to be the theory is that for those that have brain fog due to statins, is not because of low serum cholesterol but because the drug is crossing the BBB and affecting cholesterol synthesis within the brain. Now what amazes me about this is that there seems to be a challenge in producing drugs that can treat brain conditions due to the difficulty in those drugs being able to cross the BBB, yet the one drug we don't want crossing the BBB, they seem to have no issue producing...statins.

So Ive never bought into the higher cholesterol theory for E4's personally.

[Julie G]

Nice to see you posting, James This is something I've been struggling to better understand. Thanks for the article. I'm sure I'll have some questions/comments after I've read it.

Is it official, Dr. Cain?

[James]

Nice to see you posting, James This is something I've been struggling to better understand. Thanks for the article. I'm sure I'll have some questions/comments after I've read it.

Is it official, Dr. Cain?

Thanks. I have more time on my hands now that I've officially graduated!

[Julie G]

Woo hoo! My comments/questions are then officially directed to Dr. Cain- Congrats Your generous sharing of this paper came at a good time for me. This is also something I'm struggling to wrap my head around. I've been reading as much as I can of the mainstream hypothesis vs.the Seneff hypothesis and I'm left with more questions than answers. Your paper improves my understanding, BUT I'm far from fully grasping everything- understatement Part of my problem results from the scientific community's evolving understanding...

-Several papers have theorized/demonstrated that E4 carriers may have "leakier" BBBs.
http://www.urmc.rochester.edu/news/stor ... fm?id=3512

ApoE4 makes it more likely that cyclophilin A will accumulate in large amounts in cells that help maintain the blood-brain barrier, a network of tightly bound cells that line the insides of blood vessels in the brain and carefully regulates what substances are allowed to enter and exit brain tissue.

ApoE4 creates a cascade of molecular signaling that weakens the barrier, causing blood vessels to become leaky. This makes it more likely that toxic substances will leak from the vessels into the brain, damaging cells like neurons and reducing blood flow dramatically by choking off blood vessels.

Could this also lead to more crosstalk between the two cholesterol pools in E4 carriers, allowing us to benefit from increased peripheral cholesterol?

-Apparently cholesterol is necessary to maintain the integrity of the myelin sheath that comprises the BBB. Of the APOE genotypes, E4 carries cholesterol the most poorly leaving our myelin more susceptible to injury. Could that also help explain why some patients (including members here) taking medications or supplements with statin-like properties exhibit cognitive dysfunction?
http://www.medscape.com/viewarticle/465883_3

A widely accepted theory involves myelin. Cholesterol is essential in the formation of myelin. The more lipophilic statins are able to cross the blood-brain barrier and decrease the amount of CNS cholesterol below the critical value necessary for the formation of myelin. Inadequate myelin production results in demyelination of nerve fibers in the CNS, resulting in memory loss. Once the offending statin is removed from the patient's system, myelin stores are replenished and mental status returns to normal. In our two patients, as well as another patient who received simvastatin,[1] mental status returned to normal within 1 month of discontinuing the statin.

-While brain cholesterol and peripheral cholesterol remain separate pools, HDL is the exception. Small HDL can cross the BBB and perform a beneficial clearing function there. Several papers have theorized high HDL is especially beneficial for E4 carriers. http://www.ncbi.nlm.nih.gov/pubmed/23576895

Our findings suggest that an interaction between apoE and HDL is facilitated by APOE4, and is possibly linked with an enhancement of neuroplasticity and with resultant protective effects on cognitive function in later life. Preservation of higher plasma apoE and HDL from early life is proposed as a possible strategy for maintaining cognitive function in later life, especially for APOE4-positive individuals.

My understanding of the HDL maturation process is that all HDL begins small, then becomes larger & more functional (in the absence of mutations.) I'm left to assume that the maturation of the small HDL occurs within the brain for the HDL to be effective? I ask, as larger HDL particles have been found to be the most cardio-protective and, I'm assuming, neuro-protective. They must start out as small HDL (to be able to cross the BBB) before maturing in the brain and performing clearing functions.

-Lastly, we briefly "chatted" about the Federoff/Georgetown group discovery- that a deficiency in 10 lipid metabolites predicts AD. I theorized that replacing some of those metabolites might be a prevention strategy. Did you see a group in Sweden followed through with that concept and indeed boosted 5 of the 10 metabolites?

A Nutritional Approach to Ameliorate Altered Phospholipid Metabolism in Alzheimer'sDisease.
http://www.ncbi.nlm.nih.gov/pubmed/24898653

We show that a 24-week nutritional intervention in drug-naïve patients with very mild to mild AD significantly increased 5 of the 7 measured biomarker phosphatidylcholine species. By providing nutrients which normally rate-limit phospholipid synthesis, this nutritional intervention could be useful in asymptomatic subjects with a plasma lipid biomarker profile prognostic of AD.

Also, in this transcript http://www.usagainstalzheimersnetwork.o ... mers-talks Dr. Federoff surmises that cholesterol lowering medications MAY account for the drop in lipid metabolites. Aside from asking participants to refrain from morning meds, they weren't controlled for in his experiment

Thanks again for sharing, Dr. Cain. This is something I've been working on as well. I appreciate the mainstream scientific community's assertion that there is limited interaction between the two cholesterol pools, but there is enough evidence/ambiguity for me to suspect that we have more to learn on the subject. I'd appreciate any edification you can share.

[Ski]

Great post Julie. As you know I was one of those that experienced this and it took that 1 month to clear, as mentioned, after stopping what I believe to be the offending supplement, Bergamot.

Im still of the opinion it is the medication crossing the BBB but merely an opinion. I could certainly believe it more if it were dramatic reductions in cholesterol but harder to believe when we are talking drops of 40 points in TC.

Im also wondering if taking COQ10 with my supplement aids medication/supplements in crossing the BBB and whether taking them at separate times is better. Just wondering.

[Julie G]

Skibike, I totally agree with you regarding some statin-like medications/supplements crossing the BBB. Note the underline:

The more lipophilic statins are able to cross the blood-brain barrier and decrease the amount of CNS cholesterol below the critical value necessary for the formation of myelin.

I know CoQ10 helps protect muscles (including the heart,) but I'm uncertain about how that affects BBB permeability...

[Russ]

Julie, Boom! You hit that post out of the park! You know I've long felt this issue of BBB transfer/permeability was central, and I finally feel that James' post and your response are zeroing on on the truth… probably somewhere in the middle? Still need to finish reading the main paper, but feels like this small exchange could form the basis of a challenge put in front of a team of neurologists and cardiologists. Will finish reading the paper this evening.