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Amyloid in Trouble

Here’s an interesting look at the current state of the Alzheimer’s field from Bloomberg. The current big hope is Wyeth (and Elan)’s bapineuzumab, which I last wrote about here. That was after the companies reported what had to be considered less-than-hoped-for efficacy in the clinic. The current trial is the one sorted out by APOE4 status of the patients. After the earlier trial data, it seems unlikely that there’s going to be a robust effect across the board – the people with the APOE4 mutation are probably the best hope for seeing real efficacy.
And if bapineuzumab doesn’t turn out to work even for them? Well:

“Everyone is waiting with bated breath on bapineuzumab,” said Michael Gold, London-based Glaxo’s vice president of neurosciences, in an interview. “If that one fails, then everyone will say we have to rethink the amyloid hypothesis.”

Now that will be a painful process, but it’s one that may well already have begun. beta-Amyloid has been the front-runner for. . .well, for decades now, to be honest. And it’s been a target for drug companies since around the late 1980s/early 1990s, as it became clear that it was produced by proteolytic cleavage from a larger precursor protein. A vast amount of time, effort, and money have gone into trying to find something that will interrupt that process, and it’s going to be rather hard to take if we find out that we’ve been chasing a symptom of Alzheimer’s rather than a cause.
But there’s really no other way to find such things out. Human beings are the only animals that really seem to get Alzheimer’s, and that’s made it a ferocious therapeutic area to work in. The amyloid hypothesis will die hard if die it does.

21 comments on “Amyloid in Trouble”

  1. Lucifer says:

    Have you considered that beta-amyloid is a rather unconventional target?
    It is too flexible for developing high affinity small molecule ligands. However, it’s conformational flexibility also hinders the development of antibodies that can target all versions of it’s soluble oligomers.
    It is quite obvious that cell death in mid- to late- stage AD is not mediated through beta-amyloid, however the process cannot start without beta-amyloid oligomers.
    Of course, we can believe that it is not so based on the results of poorly designed ligands and business decisions. Many “great scientists” of the 19th century also ‘proved’ that powered heavier-than-air flight was not possible. They did consider electric and steam engines, but ignored IC engines.

  2. TheSwine says:

    Perhaps small molecules, or even proteins can cure this disease. We should not forget about some of the exciting aspects of stem cell treatment!

  3. remember says:

    These are describing the MAB or vaccine approaches to testing the amyloid hypothesis. There are a different set of issues both on the efficacy and tolerability side with these approaches. Small molecule candidates that slow the production of Abeta I think will overtake some of the biological approaches. BMS phase II candidate at the moment looks like a front runner in this regards.

  4. remember says:

    These are describing the MAB or vaccine approaches to testing the amyloid hypothesis. There are a different set of issues both on the efficacy and tolerability side with these approaches. Small molecule candidates that slow the production of Abeta I think will overtake some of the biological approaches. BMS phase II candidate at the moment looks like a front runner in this regards.

  5. Don B. says:

    It appears that Pfizer’s Dimebon works in humans & increases amyloid plaques in animals.
    If true, that may be the amyloid killer.

  6. Jan Teller Tr says:

    Well, I remember a very (i mean very) distinguished academic who devoted his last decade to synthesise any sesquiterpene and diterpene, with significant neurological activity.
    Not a clue werther there is a cure or not for something as complex as AD, but I am sure a combined approach looking to tackle all the neurological events happening at the molecular level could alleviate the symptoms and halt the terrible progression of the disease.
    Probably one of the harder targets in medchem, nowadays, isn´t it?

  7. I’d be interested in your take on the studies reported in the July 2009 issue of _Journal of Alzheimer’s Disease_ that found that moderate daily doses of caffeine significantly reduced beta amyloid in mice and not only slowed the progress of the disease but actually reversed it. The researchers hope to start human trials soon.
    WikiNews has a summary here:
    http://en.wikinews.org/wiki/Alzheimer%27s_disease_reversed_in_mice_using_caffeine paper about the effect of caffeine >

  8. A lot of people are now going back to the drawing board and rethinking amyloid. The original amyloid cascade hypothesis is being severely suspected. Tau is another area of focus that is being investigated. An article in nature called Plaque Plan talked about it (cannot find link right now) a couple of months back

  9. Moody Blue says:

    “Human beings are the only animals that really seem to get Alzheimer’s”
    Just wondering……Aren’t the memory impaired aged rats the animal models with AD? On the other hand, perhaps we humans have made our lives so comfortable and therefore live longer to suffer from AD. There is an interesting article which hypothesizes that the human brain takes metabolic downturn as it ages as a survival mechanism – to paraphrase. Alzheimer’s disease and natural cognitive aging may represent adaptive metabolism reduction programs
    Behavioral and Brain Functions 2009, 5:13 doi:10.1186/1744-9081-5-13 Jared E Reser (reser@usc.edu)
    Another promising new target for AD would be brainderivedneurotrophic factor (BDNF), which has shown neuroprotective effects in both mouse transgenics and aged rats.Nagahara, A. H. et al. Neuroprotective effects of brain-derived
    neurotrophic factor in rodent and primate models of Alzheimer’s disease. Nature Med. 15, 331-337 (2009)

  10. CF says:

    Some of my former colleagues of mine investigated a Drosophila model of Alzheimer disease in which toxicity was negatively correlated with a propensity to form amyloid.
    Luheshi LM, et. al. PLoS Medicine 5(11) 2007.
    This finding makes me increasingly interested in theories which relate amyloid toxicity to a-beta remaining stuck in the membrane.
    Another concern with some of the emerging Alzheimer’s targets is their overlap with cancer targets. Targeting Alzheimer’s drugs to the brain, or clumsy or novel modes of delivery, may be very important.

  11. Austin P says:

    Allow myself to introduce myself…:)

  12. Cannabinoid says:

    isn’t there proof that smoking pot prevents Alzheimer’s?

  13. Kay says:

    The bit about the necessity to re-think the amyloid hypotheses strikes me as completely off the mark.
    I can think of dozens of possible explanations for reconciling the amyloid hypothesis with the ineffectiveness of an anti-amyloid antibody. Actually, I find it rather naive to expect that this antibody could make the amyloid go away.
    This is not your typical antigen circulating in the bloodstream. It is a highly aggregated protein deposit in the brain with a major intracellular component.
    It would require the inefficacy of a drug that prevents amyloid formation to make me re-think the amyloid hypothesis.

  14. Moody Blue says:

    Kay,
    Not sure how you mean by ‘major intracellular component’. Aren’t the amyloid plaques formed due to extracellular aggregation of amyloid fibrils? And that it’s the tau tangles that are formed intracellularly? Thanks

  15. Kay says:

    @14:
    Sure, the plaques are extracellular deposits and clearly contain the majority of detectable Abeta. However, there is no real proof that these deposits are the cause for neuronal loss. There is also a significant portion of intraneuronal Abeta, which cannot be excluded as the culprit.
    The main point I wanted to make is that I would not really expect an externally administered antibody to clear disease-causing amyloid from the brain.

  16. Moody Blue says:

    Thanks Kay. There is an article which was accepted for publication in JBC (but never got published?? what does it mean??) wherein they show intraneuronal accumulation of ABeta(1-42) induce apoptosis.
    http://www.jbc.org/cgi/reprint/M200887200v1.pdf

  17. Lu says:

    That would be sad… It’s hard to think that I spent last 5 years of my life chasing shadows.
    From the other hand, there were quite a few fashionable but ultimately dead-end approaches in science. High-temperature superconductivity and cold fusion in cavitation bubbles come to mind first.

  18. Jason says:

    According to the article Derek referenced, “In the U.S., almost 73,000 people died from the illness in 2006, a 47 percent increase in just six years, according to the Alzheimer’s Association.”
    Is this true?
    Life expectancy probably (I haven’t checked) hasn’t changed much from 2000 to 2006, so isn’t it impossible to reconcile a 47% increase with the hypothesis that “Alzheimer’s disease and natural cognitive aging may represent adaptive metabolism reduction programs” that Moody Blue points to above?

  19. The Next Phil baran says:

    Has anyone else heard of the link between blood flow and alzeheimers? Its seems to be the result of insufficient circulation of sugars to the brain. This doesn’t mean an increase in dietary sugar will help, its more about blood flow. Also, diabetics (read sugar) have a higher rate of alzeheimers too. Why its higher in people who also have herpes is unknonw.

  20. Slothy says:

    @Lucifer
    One of the problems with developing drugs targeting beta-amyloid directly is that we still don’t have a structure. Amyloid is a very difficult molecule to work with–it’s essentially a blob of sticky fat. Difficult to isolate and impossible to crystallize.
    That’s one reason why, outside of antibody-based approaches, most of the current drug development work is being directed toward targets that are upstream of beta-amyloid.
    @Moody Blue
    Mice do not develop amyloidosis with age, but there are several transgenic mouse models that do (PSAPP, APPswe, PS1, APP), and these show age-related cognitive deficits.
    It’s also important to keep in mind that beta-amyloid can have very different biological effects depending on the size of its aggregates, from soluble to oligomers to plaques.
    @The Next Phil baran
    Soluble beta-amyloid decreases blood flow in the brain, which might explain why cognitive deficits seem to precede plaque formation, both in humans and transgenic mice.

  21. SiegCabbit says:

    I’m of strong opinion that tau mutative properties aare the most apt target, and in the near future will reveal their perpetual role as the forerunning villain, the culprit of cerebral decline.
    There is tons of research and many things have been made with destroying amyloid plaques in mind, and I’m sure its a more than managable area to cope in; what of FTD and other similar dementias?

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