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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

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February 11, 2008

Fast Plaques in a Slow Disease

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Posted by Derek

One of the first projects I ever worked on when I started in industry was targeting Alzheimer's disease. Things could have easily worked out to find me still targeting Alzheimer's disease, nearly twenty years later, because the standard of care really hasn't advanced all that much in the intervening years.

It's a hard, hard area to work in. CNS programs are always difficult, since we understand less about the brain's workings than those of any other organ, and since the brain's own blood supply is another barrier to getting a drug through to do anything. And Alzheimer's has tough features on top of that, since (for one thing) we're the only animal that gets the disease, and (for another) the clinical trials needed to show efficacy can be hideously long, large, and expensive. And the underlying biochemistry has been a tangle, too: I've said for years that if you'd told me back in 1990 that people would still be arguing in 1999 (or 2002, or 2007. . .) about whether amyloid caused Alzheimer's or not, that I probably would have buried my head in my hands.

Well, it's 2008, and the arguments may finally get settled. There's a report in Nature from a group at Harvard who did an experiment that's simultaneously brute-force and elegant. The elegant part was the monitoring live brain cells in mutant mice as amyloid protein deposited among them - and the brute force part was that this monitoring involved surgically implanting a small window into their skulls to do it.

What they found was that the characteristic amyloid plaques of Alzheimer's can form startlingly quickly - on a time scale of hours. This is beyond what anyone had suspected, for sure. And the further pathologies (microglia, etc.) that form around the plaques definitely come later, settling a long-standing dispute. There's always the worry that the mouse model (which was engineered to develop amyloid within the brain) might not reflect the human disease, but this is pretty compelling (and alarming) stuff.

If this is even close to what's going on in humans, a therapy that tries to prevent amyloid formation or deposition is going to have some real work to do. We'll be finding that out, though, and good luck to everyone involved. . .

Comments (6) + TrackBacks (0) | Category: Alzheimer's Disease | The Central Nervous System


COMMENTS

1. QE on February 11, 2008 10:21 AM writes...

Longitudinal in vivo multiphoton microscopy - wow

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2. MTK on February 11, 2008 3:15 PM writes...

Alzheimer's only exists in humans?

I don't know anything about the field, but I guess that's reasonable in the sense that it's about loss of higher mental capabilities which may be tough to lose if a mouse or other animal never had them to begin with.

Like I said I don't anything about the field, but I guess what you would need is a mouse strain that would forget how to get to the cheese at the end of the maze as it aged. Of course, even if you accomplished that it may be tough to relate that to the human condition, huh?

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3. milkshake on February 11, 2008 4:27 PM writes...

did you see that one piece of info on a patient who had a dramatic and instant (but only a temporary) recovery from Alzheimer when injected with anti-TNF antibody into his spinal canal?

It is quite possible that the plaques trigger slow brain inflammation process, mediated by microglial cell - which are the actual damaging agent.

Also plaqus are found in many brains of elderly people who do not manifast symptoms of Alzheimer. There is a patologist doing autopsy studies on brains of nuns (nuns are as close to controled environment people as possible, with perfectly documneted medical history). He found out that typically the nuns that had plaques combined with vascular disease (with signs of microscopic strokes) had symptoms of Alzheimer. Those that had only plaques often stayed mentally sharpall the way to their 90s.

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4. NJBiologist on February 11, 2008 6:57 PM writes...

MTK: Difficult to relate to humans, but even more difficult to do differential diagnosis. C3H mice will have trouble finding the cheese as they age, but that's because they get macular degeneration and have trouble navigating as they age. Even if you pin the pathology on the brain, you have to distinguish from things like multi-infarct dementia; I haven't heard about that in mice, but I'm pretty sure monkeys get it.

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5. MTK on February 11, 2008 10:40 PM writes...

Thanks NJBiologist. That's what I figured. I guess until a reliable validated biomarker is found it's going to be darn tough.

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6. Anonymous BMS Researcher on February 15, 2008 7:56 AM writes...


While I can't go into any details of how BMS is working on Alzheimer's, I doubt it comes as much of a surprise to readers of this blog that (1) we're working on this disease and (2) it is a challenge to say the least -- and we haven't even got to the HARD parts yet.

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