(My apologies for no update today - it's been hectic around here, for reasons that I hope to be able to reveal soon).
Some of the first work I did in the industry was on Alzheimer's disease. It's hard stuff to deal with, and it was even hard seventeen years ago, I can tell you. You may have noticed that there isn't much that anyone can do about AD, even now, and there's most definitely a reason for that: it's a hard disease in a hard field.
One of the most promising areas (for an unnervingly long time) has been the inhibition of the formation of beta-amyloid, long thought (though not by everyone) to be a primary cause of Alzheimer's pathology. (There's no doubt that AD patients show abundant deposits of beta-amyloid plaques in their brain tissue - the argument has been about whether amyloid gives you Alzheimer's, or if Alzheimer's gives you amyloid). The protein is clipped off a larger precursor protein (APP, which is an acronym for just what you think), and back when I started in the field, the major race was on to find out which proteases did the clipping.
That's been worked out in the intervening years. One of them, the beta-secretase enzyme BACE1, has been a target of a lot of work for quite a while now. Getting good, selective, non-peptidic inhibitors hasn't been easy, though, but here's some from Merck, and there have been other reports. Will one of these be the Alzheimer's drug that everyone's been waiting for?
Well. . .maybe not. A recent PNAS paper from a large academic/industrial collaboration has raised a disturbing possibility. They found that mice that produced extra APP (but did not show beta-amyloid pathology) had improved spatial memory. Disrupting their beta-secretase was downright harmful to their performance, as well, suggesting that some of the beta-secretase cleavage products might actually be beneficial. It would be just like the natural world to have beta-amyloid turn out to be memory-enhancing in smaller quantities, but no one's sure if it's the player here - it could also be the intracellular hunk of APP that's also liberated by the secretase.
The authors finish the paper with an unmissable warning:
"A practical implication of this work involves safety considerations for experimental therapies of AD. To ensure that experimental therapies do not prevent BACE1-mediated facilitation of memory by APP, preclinical studies of experimental beta-secretase inhibitors should be done not only in animal models of AD, but also in natural animals to evaluate their effects on normal cognitive function."
One wonders what GlaxoSmithKline has made of this, in light of their recent paper on in vivo dosing of a BACE1 inhibitor. And there may be others. . .