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February 11, 2008
Fast Plaques in a Slow Disease
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. . .
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