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November 9, 2012
JNK3 - Something New for Alzheimer's?
There's been an interesting recent development in the biology of Alzheimer's disease. c-Jun N-terminal kinase 3 (JNK3, known to those in the field, semi-affectionately, as "Junk-Three") is expressed mostly in the CNS, and has been implicated as a player in Parkinson's and neurodegeneration in general. There's been evidence of its relevance to Alzheimer's (for example, here's a connection to tau protein), but it's hard to say what's actually going on.
A group at Ohio State has cranked up the interest level. They found that deleting JNK3 in a mouse model of amyloid deposition showed some rather dramatic effects, knocking the amyloid levels down by 90% and improving the cognitive function of the mice relative to controls. The hypothesis is that some unknown factor in Alzheimer's pathology leads to increased JNK3 activity, which sets off downstream effects in the mTOR and AMPK systems. (Given how central those proteins are, I can believe almost anything if you tell me that they're involved). These effects (on protein production and other systems) increase JNK3 activity even more, and a vicious cycle could be well underway.
Now, inhibitors of these enzymes have been the subject of research for quite a while now. Here's the most recent paper on such compounds, but there are quite a few others scattered through the literature - here's a 2010 review of them. Selectivity has been a problem, as has cell penetration - and if you're targeting the CNS, which you'd surely have to do for this approach to Alzheimer's, you have the blood-brain barrier to think about, too. (That link goes to a new paper that's worth a post of its own next week).
So no, there aren't any obvious JNK3 inhibitors ready to go into human Alzheimer's trials. On the other hand, a lot of companies have chemical matter in this area, and this new result makes it worthwhile to go back and see what there might be in the files. AD is one of the biggest "unmet medical need" areas out there, and plausible targets for it are always going to attract attention. Watch this area to see who goes for this one.
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