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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: Twitter: Dereklowe

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May 17, 2007

Beta-Secretase: Not So Fast?

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Posted by Derek

(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. . .

Comments (7) + TrackBacks (0) | Category: Alzheimer's Disease


1. Morten on May 18, 2007 4:20 AM writes...

Ok, it's easy for me to say Duh! when I'm just coming into the field now and the literature is pretty good (Rogaeva 2007 Nature Genetics for instance) but since A-beta exists in healthy brains (and skin of course) and only precipitates at high concentrations it seems dangerous to inhibit the protease. Not to mention that proteases are horrible drug targets. But like I said hindvision is 20/20.

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2. sjb on May 18, 2007 5:54 AM writes...

Bit of a sidetrack, but how's the job hunt going?

One of the annoying things I've found with redunancies and the like is lack of access to current literature, but this doesn't seem to have affected you (much). Do you have lots of personal subscriptions to things like pubmed (as in this instance) or are you merely commenting with what Joe Public can read in the abstracts?


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3. NJBiologist on May 18, 2007 6:22 AM writes...

Derek--good luck with your "reasons that I hope to be able to reveal soon."

Derek and everyone else--what ever happened to amyloid-depleting immunotherapy? Was that an academic-only non-starter?

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4. Dave H on May 18, 2007 9:01 AM writes...

Elan's died. Someone else is working on one:

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5. BACE on May 18, 2007 9:24 AM writes...

Nice piece of work, but is it really surprising? They are basically demonstrating that some enzyme that's ubiquitous in the brain and is involved in a disease has a beneficial function. We knew that.

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6. biohombre on May 19, 2007 2:51 PM writes...

There are other amyloid peptides. One such an example is on the market- Pramlintide. The protein is known as Islet Amyloid Polypeptide (IAPP), or also amylin (yep, as in Amylin Corp. manufactureres of Pramlintide). The rodent form is not amyloidogenic, but when human IAPP is overexpressed in transgenic rodents amyloid is formed (see- So this is an example of a therapeutically used molecule, when overexpressed forms amyloid. Of course, IAPP is not THE amyloid-forming molecule (of AD), nonetheless, it is a clear therapeutic example of dosing- clinically benefit at correct doses, pathologic, even cytotoxic at high levels...

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7. Morten on May 29, 2007 5:14 PM writes...

Don't both glucagon and insulin produce amyloid fibers when concentrated (or if pH is lowered)? Seems like a fairly common mode of protein precipitation then.

Derek I know this is an old post but I think you read most comments. Could you please explain why peptides are so unpopular as drug leads? I know that mono-amine GPCRs are considered highly drugable and peptide GPCRs poor targets but that can't be all. Is it because of rotable bonds? I think it could be a nice post subject if you need something to do ;)

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