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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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November 9, 2012

JNK3 - Something New for Alzheimer's?

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Posted by Derek

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.

Comments (10) + TrackBacks (0) | Category: Alzheimer's Disease


COMMENTS

1. luysii on November 9, 2012 9:19 AM writes...

The chemistry is even more interesting. JNK3 phosphorylates the amyloid precursor protein (APP) on threonine #668. This is in the cytoplasmic domain, hence on the other side of the membrane (and the protein) from which Abeta forms.

This is clearly some sort of conformational effect. The next amino acid (#669) is proline, which can exist in cis and trans forms. It is claimed that the isomerization cis --> trans occurs, helped by Pin1, a phosphorylation dependent proline isomererase. The cis form is thought to have a greater propensity to form Abeta. Knocking Pin1 down has the opposite effect of knocking JNK3 down -- not increases Abeta formation by 46%.

The problem with attacking either, is that both Pin1 and JNK3 likely have other substrates.

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2. Old Lab Rat on November 9, 2012 10:39 AM writes...

@1, yep lots of other signaling activity. See http://www.hindawi.com/journals/jst/2012/459265/ for more details.

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3. azetidine on November 9, 2012 10:47 AM writes...

JNK - The target that lives up to its name.

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4. Calvin on November 9, 2012 12:34 PM writes...

This is pretty controversial but HSV has been implicated in AD and there does seem to be an unusual amount of viral RNA floating around the brains of ApoE4 AD patients in particular. Curiously, HSV activates JNK3 leading to an increase in viral replication. It's amazing how viruses hijack all these kinases so it may link in to the whole infection hypothesis that has been discussed before. (Virol. 1999 October; 73(10): 8415–8426)

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5. bank on November 9, 2012 2:29 PM writes...

Recent review on drugs in Alzheimer's disease for those interested:
Corbett et al., Drug repositioning for Alzheimer's disease. Nat Rev Drug Discov. 2012 Nov;11(11):833-46. doi: 10.1038/nrd3869. PMID:23123941

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6. Lane Simonian on November 9, 2012 6:08 PM writes...

This now is close to the right target. Phospholipase C contributes to the activation of JNK which activates NADPH oxidase (and thus increases the production of superoxide anions) and NF-kB (which leads to the increased production of inducible nitric oxide). Superoxide anions and inducible nitric oxide combine to form peroxynitrites. Peroxynitrites nitrate amyloid plaques/oligomers increasing their aggregation. They also nitrate NMDA receptors leading to the efflux of glutamate and the influx of calcium which kills brain cells. They also oxidate receptors critical for short-term memory, mood, sleep, awareness, social recogntion, and brain growth.

It is much better to initially work upstream of JNK. Phenolic compounds inhibit the activation of phospholipase C gamma and polyunsaturated fats inibit both the activity of phospholipase C gamma and beta. Thus the potential benefit of a diet high in phenolic compounds and polyunsaturated fats for reducing the risk for Alzheimer's disease. As the disease progresses, it is probably easiest and best to work downstream from JNK with methoxyphenols such as eugenol, ferulic acid, coumaric acid, syringic acid, sinapic acid, and vanillic acid that scavenge and repair part of the damage done by peroxynitrites.

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7. gippgig on November 9, 2012 11:00 PM writes...

The unknown factor is likely to be A-beta inducing the unfolded protein response, similar to what happens in prion diseases (Nature 485 507, doi:10.1038/nature11058), and quite possibly most neurodegenerative diseases.

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8. Lane Simonian on November 10, 2012 8:25 PM writes...

I am trying to develop simple word charts for the pathway to Alzheimer's disease:

Phospholipase C gamma and/or beta leads to
Protein kinase C activation, JNK activation, and intracellular calcium release which results in the formation of amyloid plaques (or oligomers).

Phospholipase C gamma and/or beta---Protein kinase C---MAPK (including JNK)---Tumor necrosis factor alpha---NADPH oxidase activation (superoxide anions) and Nuclear Factor kappa B activation (inducible nitric oxide)--- peroxynitrites.

Amyloid plaques by incorporating zinc increase homocysteine levels and by incorporating zinc and copper decrease superoxide dismutase activity both of which results in the increased production of peroxynitrites.

Peroxynitrites by nitrating amyloid plaques increase their aggregation.

Again inhibit the formation of peroxynitrites by inhibiting the activation of phospholipase C early and you delay the onset of Alzheimer's disease.

Inhibit the formation of peroxynitrites later downstream from phospholipase C (as peroxynitrites will essentially cut off phospholipase C activity as the disease progresses), scavenge peroxynitrites, and repair part of their damage and Alzheimer's disease can be effectively treated.

Once the pathways are identified finding means to delay the onset of the disease and to effectively treat it become much easier to discern. The sad thing for the pharmaceutical companies is that almost all of this can be done using natural compounds. That is also the main obstacle to treating the disease within the next decade, because studies showing this to be the case from overseas will not simply be marginalized, they will be buried.

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9. Lane Simonian on November 10, 2012 11:09 PM writes...

Apologies for adding one more piece of supporting evidence that I found this evening regarding the role of phospholipase C gamma (y) in Alzheimer's disease.

Adv Biol Regul. 2012 Sep 18. pii: S2212-4926(12)00092-9. doi: 10.1016/j.jbior.2012.09.008. [Epub ahead of print]
Phospholipase C-γ1 involved in brain disorders.
Jang HJ, Yang YR, Kim JK, Choi JH, Seo YK, Lee YH, Lee JE, Ryu SH, Suh PG.
SourceSchool of Nano-Bioscience and Chemical Engineering, Ulsan National Institute of Science and Technology, Ulsan 689-798, Republic of Korea; Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.

Abstract
Phosphoinositide-specific phospholipase C-γ1 (PLC-γ1) is an important signaling regulator involved in various cellular processes. In brain, PLC-γ1 is highly expressed and participates in neuronal cell functions mediated by neurotrophins. Consistent with essential roles of PLC-γ1, it is involved in development of brain and synaptic transmission. Significantly, abnormal expression and activation of PLC-γ1 appears in various brain disorders such as epilepsy, depression, Huntington's disease and Alzheimer's disease. Thus, PLC-γ1 has been implicated in brain functions as well as related brain disorders. In this review, we discuss the roles of PLC-γ1 in neuronal functions and its pathological relevance to diverse brain diseases.

JNK is not the wrong target, there are just easier targets upstream and downstream from JNK.

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10. Debbie Johnson on November 25, 2012 2:10 AM writes...

Ok, forgive me as I'm new to all of this and still trying to learn here. HOW exactly do they delete JNK3? Thanks in advance :)

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