Things Found At SFN: Iron, Cholesterol, and Alzheimer’s

Sci briefly considered just providing a short list of the many awesome things she had seen at SFN this day, for verily, she saw many awesome things. But she’s decided that she’s tired, the food at the conference is incredibly expensive and she’s VERY hungry, and that she’s got way too many things to cover. And stuff is going up late, because Sci’s LOVELY new netbook doesn’t like SFN’s wireless very well.
So she’s going to cover one cool poster she’s seen per day, and keep covering them, even after the conference. So you’ll get your SFN longer and longer and longer! And we all know we could stand a few more days of crazy conferencing.
So here we go!
Poster number 1:
HFE polymorphisms affect cholesterol metabolism: Insights into neurodegenerative diseases
So you think to yourself, WTF is an HFE polymorphism, and what does this have to do with cholesterol and Alzheimer’s?
A lot, actually.

So as I’m sure most of you know, Alzheimer’s disease is what you call neurodegenerative. This means that neurons actually do end up dying over the course of the disease, and this will be what causes the person to die in the end. Unfortunately, no one is really quite sure what CAUSES Alzheimer’s disease. We know that there is a genetic component to it, but what genes are involved? We know that there are screw-ups in protein function, but which proteins and WHY?
Well, we still don’t know, but this group decided to focus on two key pieces of the puzzle, iron and cholesterol.
I know. You’re probably thinking “what do iron and cholesterol have to do with Alzheimer’s!? It’s all about neurofibrillary tangles and holes in the brain like swiss cheese!” Well, yes, but SOMETHING has to happen before everything gets that bad. And some of the things that go wrong might have to do with iron and cholesterol.
Iron, in this case iron levels in the cell regulated by the gene HFE, doesn’t seem like a really hot ticket. But differences (we call them polymorphisms) in the HFE gene are very common in people who get Alzheimer’s, particularly the gene variant H63D. People with H63D are much more likely to get Alzheimer’s disease.
And what does this have to do with cholesterol? Interestingly, cholesterol has a lot to do with Alzheimer’s disease. People with Alzheimer’s disease suffer from rapid decreases in brain cholesterol levels as the disease progresses. Most people think of cholesterol as a bad thing, but in fact, int he brain, it’s very important. Cholesterol is a very important part of all cell membranes, and with low levels, cells become more vulnerable to cell death.
And so what these authors wanted to find out was this: what does this gene polymorphism in IRON genes have to do with CHOLESTEROL?!
Well, we know that people with both a gene variant in iron (H63D) and a gene variant in cholesterol (APOE4) are much more likely to suffer from Alzheimer’s than those with just one or none of the gene variants. So the authors of this study looked at what the iron gene in particular had to do with cholesterol levels.
And what they found was interesting. They found that cells that have the H63D gene variant have LOWER levels of cholesterol. This doesn’t seem like a big deal, but if you have lower levels of cholesterol, and your cholesterol levels decrease with age…well…
And not only that, they found that H63D directly affects cholesterol, by increasing an enzyme known as CYP46A1 (as the illustrious Abel Pharmboy points out, this is a member of the P450 brand of enzymes). This enzyme makes cholesterol slip out of the brain (normally it would stay within the blood brain barrier), and thus FURTHER decreases the cholesterol levels in the brain, potentially making the decreases in cholesterol that occur with age far worse than they would be normally. Normal levels of CYP46A1 are fine, you need SOME of your cholesterol to leave the BBB, but increased amounts of cholesterol leaving the blood brain barrier can’t be made up for very well.
This seems pretty basic, and it is, but this could have big implications for how we treat Alzheimer’s disease, particularly in the early stages, and what we look for when we are looking for possible precursors to the disease. And anything that makes Alzheimer’s disease easier to track and treat is a step in the right direction.

5 Responses

  1. This is a lovely post otherwise but you’ve obviously been drinking if you think you could get away with “an enzyme known as CYP46A1 (yeah, I don’t know what that means either)” knowing that I am reading.
    CYP46A1 is a member of the cytochrome P450 family of monooxygenases (look for “CYP” you young whippersnapper; there’s a whole international allele nomenclature org for this). In fact, neuroscientist god and 1970 Nobel laureate, Julius Axelrod and with Bernard Brodie’s group first identified this xenobiotic oxidizing system in 1955 – oh, but I’m sorry – you kids don’t read papers before 1966 that aren’t on PubMed because you can’t find the building we used to call a library. Well, rest assured, Dear Weedhopper, that the journal Science has archived their papers online and you can find one of the original papers (Science 121:603-4, 1955) without leaving your computer. Axelrod’s original solo paper is in Journal of Pharmacology 114:430-8, 1955.
    But, I digress.
    While we mostly think of P450s as hepatic, adrenal, renal, or pulmonary enzymes, we’ve known that many other tissues possess P450 activities. CYP46A1 can exist in glia and is otherwise known as cholesterol-24-hydroxylase. The product of this reaction creates a hydroxylated version (at carbon 24 if you can believe it) that cannot cross the blood-brain-barrier as you note.
    And while alcohol dehydrogenase is primarily responsible for oxidizing the EtOH coursing through your veins, the higher concentrations you were likely to encounter after writing this post would be handled by CYP2E1. But that all involves things like differences in Km (yeah, I don’t know what that means either.)
    Have fun and say hello to all of our friends!

  2. Abel, you thought I was DRUNK?! *shock and horror* Why on EARTH would ANYONE be drunk at SFN?! I am STUNNED!!!
    I do indeed know a bit about cytochromes, not nearly as much as I should know, however. I will admit I was hoping for your insight. 🙂

  3. Isn’t Km the rate constant for the enzymatic reaction
    Yours truly, old and fading former neuropharmacologist

  4. This is very interesting. I am a biologist in another field but read what I can about Alzheimer’s because my mother suffers from the disease and her mother did as well. Until reading your post I had not known that cholesterol was so important in the brain. My mom has always had high cholesterol despite being slim and having a pretty low-fat diet. Interestingly, she started displaying the first signs of dementia immediately after starting to take a cholesterol lowering drug (Lipator). We asked her doctors if the forgetfulness could be a side-effect of the medication but they said no and assured us that it was just a coincidence.

  5. My understanding is that serum cholesterol levels do not correlate directly with brain cholesterol levels. On the other hand, I doubt anyone has tested what the cholesterol levels in the brain are after cholesterol lowering drugs (though I highly doubt it’s a direct effect, I don’t think Lipator is going to cross the blood brain barrier)

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