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Psych! Prions and Ice Nine

3D structure of amyloid fibrils

I saw this post about the possibility that Alzheimer’s is an infectious disease at Derek Lowe’s blog, In the Pipeline.  There’s a new paper out that reports that animals whose brains were exposed to misfolded amyloid-β protein extracted from patients with Alzheimer’s disease will go on to also develop amyloid plaques while control animals do not.  While there is a reputed genetic component to the development of Alzheimer’s disease, this study suggests that it can be induced by the transmission of a prion from one animal to another.  Prions are infectious bits of protein.  They’re teensier than viruses even.  In the case of amyloid disease, the protein under investigation is about 42 amino acids long, which is tiny.

The principle is this: in order to function properly, proteins need to fold into distinct secondary patterns and then a specific 3D shape.  If the protein is misfolded, it doesn’t work properly or it can aggregate, ie form clumps.  The sneaky think about prions is that they can induce other proteins to misfold.  The misfolded protein is in a lower energy state than the properly folded state so the protein can’t unfold itself and refold properly.  It’s stuck.

If any of you have read Kurt Vonnegut’s novel, Cat’s Cradle, and can remember anything beyond spritual footrubs and Bokononism, you may recall that one of the characters created a substance called Ice-9.  A single crystal of Ice-9 had the potential to freeze all contiguous bodies of water.  Throw it into a bathtub, the bath water freezes.  Throw it into an ocean, the ocean freezes.  I can’t recall if it stayed that way permanently but after Ice-9 was released, the world started to die of thirst.

The introduction of amyloid-β prions into a healthy brain may be doing an analogous thing by inducing newly formed amyloid protein to misfold.  And an excess of misfolded protein tends to aggregate, triggering inflammation and, down the road, dementia.  Mad cow disease is also a prion disease that in sheep manifests itself as scrapies.

Er, no one knows how to fix it yet.  One of the problems with developing a drug for Alzheimer’s disease is that the enzyme that normally would be targeted for inhibition, γ-secretase, is also used to cleave a protein called Notch, which the cell can’t really do without.  So, there’s that.  Drug discovery is much harder than it sounds, as Derek says in this recent podcast that he did with Paul Howard from the Manhattan Institute.

The frustrations of the drug discovery process that Derek describes reminds me of the central tenet of Bokononism:

Beware of the man who works hard to learn something, learns it, and finds himself no wiser than before. He is full of murderous resentment of people who are ignorant without having come by their ignorance the hard way.

Well, we *are* learning but the truth comes slowly and the answers to the questions are frequently accompanied by a whole new set of questions that must be answered.  This is in part why the pressures of the financial industry have been particularly harmful to the pharmaceutical industry and may have contributed to the high price of drugs.  Drug discovery is a long term process.  It can’t be sped up just to meet the numbers on a spreadsheet for the bean counters.  Cost controls that are intended to whip researchers to pick up the pace are bloody useless and counterproductive when applied to the complexity of the cell, something that the guys with executive hair may just now be realizing.  There’s not a whole lot more of mergering, cutting and restructuring that can be done at this point.  And the patent cliff still looms.  It’s going to be a rough ride for the drug industry for the next couple of years.

Derek also points out that the drugs that are now being approved were probably first discovered or synthesized in the mid 1990’s.  That means the patent clock has been running down for some of them and if there’s not a lot of time left to recoup the costs of discovery, it gets passed on to the consumer as higher prices.  There are other contributing factors to the cost of drugs but the length of the process is a significant one.

I encourage readers to check out the podcast.  Derek also discusses a new therapy for cancer that involves harnessing the immune system.  Fascinating and promising.

15 Responses

  1. Great post. I have a brilliant relative in their fifties who has recently been diagnosed with this. It’s hard to articulate how devastating and life-changing this thing is…and of course I’m now fearing for the next generation inheriting it as well. I will follow your links on this topic with interest.

  2. I remember listening a few months ago to this woman researcher (sorry, forgot her name) calling Alzheimer disease “diabetes of the brain”. She said that her experiments proved that, genetic components aside, the mechanism of the disease suggest insulin deficiency effects – and they were concluding that how you eat may prevent/ameliorate your chances. I was in the process of removing processed sugar from my diet anyway, so this came right up my alley.

    • My aunt died of Alzheimer’s. She had to be on a very bland diet for about the last 30 years of her life due to a bile duct injury she had sustained during gallbladder surgery. She had delicate surgery to repair it, but it was never 100% again. Don’t know how that affected her insulin, but she wasn’t diabetic.

    • That sounds pretty weird. Never heard of the insulin connection and can’t really picture how it fits in. But I do know that there are two types of diabetes. Type one is what you get when there is an autoimmune response to insulin producing cells in your pancreas. Type 2 is what you get when your cells stop responding to insulin. The connection to alzheimers isn’t clear to me with either type but then again, I haven’t done research on Alzheimer’s for about 8 years.
      In any case, sugar in infrequent to moderate doses probably won’t give you alzheimer’s.

  3. I love coming over here an encountering science– thank you!

  4. This is particular interest to me, RD. My sister who just turned 59 is having diagnostic [basically an MRI to rule out tumors or other problems] and cognitive tests this month, but the physician suspects Alzheimer’s. She started with symptoms three years ago and is getting progressively worse. Our father had similar symptoms but the disease progressed very slowly over a 20-year period. He died at age 86, the last year barely aware of anything.

    Interestingly enough, my sister has elevated sugar levels, not off the wall but in the 150-160 levels. I’ll have to keep my eye out for updates but the initial headline caught my attention–the possibility that this could be an infectious disease, something on the order of Mad Cow. Devastating for my sister in any case. Very scary although it appears there are drugs available to slow the progression. Guess we’ll find out.

  5. easy for you to say

  6. That’s pretty cool. Well, I hope it gets researched in other countries if the US won’t do it.

  7. So eating (infected) meat and drinking (infected) milk may cause alzheimer’s disease. There are researchers who have known this for quite a while. Autopsies on alzheimer’s patients in the 90’s showed that 13% of the alzheimer’s patients actually had the human form of mad cow.
    http://www.mad-cow.org/Alzheimer_cjd.html

    There’s also a strong link between leukemia and milk, especially among dairy farmers and veterinarians who tend to dairy cows. And some doctors readily admit that milk consumption causes type 1 diabetes in genetically predisposed people. Of course none of this will become common knowledge.

    Alarm bells are silent because multi-billion dollar corporate interests are at stake. No pun intended.

    • Lol! I doubt that you’re going to get the world to give up drinking milk.
      Why not wait and see what the source is?

  8. no one here gets out alive

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