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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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October 11, 2013

An Alzheimer's Cure? Not So Fast.

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Posted by Derek

The British press (and to a lesser extent, the US one) was full of reports the other day about some startling breakthrough in Alzheimer's research. We could certainly use one, but is this it? What would an Alzheimer's breakthrough look like, anyway?

Given the complexity of the disease, and the difficulty of extrapolating from its putative animal models, I think that the only way you can be sure that there's been a breakthrough in Alzheimer's is when you see things happening in human clinical trials. Until then, things are interesting, or suggestive, or opening up new possibilities, what have you. But in this disease, breakthroughs happen in humans.

This latest news is nowhere close. That's not to say it's not very interesting - it certainly is, and it doesn't deserve the backlash it'll get from the eye-rolling headlines the press wrote for it. The paper that started all this hype looked at mice infected with a prion disease, which led inexorably to neurodegeneration and death. They seem to have significantly slowed that degenerative cascade (details below), and that really is a significant result. The mechanism behind this, the "unfolded protein response" (UPR) could well be general enough to benefit a number of misfolded-protein diseases, which include Alzheimer's, Parkinson's, and Huntington's, among others. (If you don't have access to the paper, this is a good summary).

The UPR, which is a highly conserved pathway, senses an accumulation of misfolded proteins inside the endoplasmic reticulum. If you want to set it off, just expose the cells you're studying to Brefeldin A; that's its mechanism. The UPR has two main components: a shutdown of translation (and thus further protein synthesis), and an increase in chaperones to try to get the folding pathways back on track. (If neither of these do the trick, things will eventually shunt over to apoptosis, so the UPR can be seen as an attempt to avoid having the apoptotic detonator switch set off too often.

Shutting down translation causes cell cycle arrest, as well it might, and there's a lot of evidence that it's mediated by PERK, the Protein kinase RNA-like Endoplasmic Reticulum Kinase. The team that reported this latest result had previously shown that two different genetic manipulations of this pathway could mediate prion disease in what I think is the exact same animal model. If you missed the wild excited headlines when that one came out, well, you're not alone - I don't remember there being any. Is it that when something comes along that involves treatment with a small molecule, it looks more real? We medicinal chemists should take our compliments where we can get them.

That is the difference between that earlier paper and this new one. It uses a small-molecule PERK inhibitor (GSK2606414), whose discovery and SAR is detailed here. And this pharmacological PERK inhibition recapitulated the siRNA and gain-of-function experiments very well. Treated mice did show some behavioralthis really does look quite solid, and establishes the whole PERK end of the UPR as a very interesting field to work in.

The problem is, getting a PERK inhibitor to perform in humans will not be easy. That GSK inhibitor, unfortunately, has side effects that killed it as a development compound. PERK also seems to be a key component of insulin secretion, and in this latest study, the team did indeed see elevated blood glucose and pronounced weight loss, to the point that that treated mice eventually had to be sacrificed. Frustratingly, PERK inhibition might actually be a target to treat insulin resistance in peripheral tissue, so if you could just keep an inhibitor out of the pancreas, you might be in business. Good luck with that. I can't imagine how you'd do it.

But there may well be other targets in the PERK-driven pathways that are better arranged for us, and that, I'd think, is where the research is going to swing next. This is a very interesting field, with a lot of promise. But those headlines! First of all, prion disease is not exactly a solid model for Alzheimer's or Parkinson's. Since this pathway works all the way back at the stage of protein misfolding, it might be just the thing to uncover the similarities in the clinic, but that remains to be proven in human trials. There are a lot of things that could go wrong, many of which we probably don't even realize yet. And as just detailed above, the specific inhibitor being used here is strictly a tool compound all the way - there's no way it can go into humans, as some of the news stories got around to mentioning in later paragraphs. Figuring out something that can is going to take significant amount of effort, and many years of work. Headlines may be in short supply along the way.

Comments (34) + TrackBacks (0) | Category: Press Coverage | The Central Nervous System


COMMENTS

1. Anonymous on October 11, 2013 8:44 AM writes...

Prof Roger Morris, from King's College London, said: "This finding, I suspect, will be judged by history as a turning point in the search for medicines to control and prevent Alzheimer's disease."

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2. petros on October 11, 2013 8:54 AM writes...

Roger Morris is Professor of Molecular Neurobiology at King’s College London and Head of the Department of Chemistry. He is a neurobiologist with particular interests in normal and pathological reactions of molecules on the neuronal surface.

King's closed its chemistry department some years ago and has yet to properly resurrect it

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3. Anonymous on October 11, 2013 9:03 AM writes...

The BBC is notorious for hyping every test tube experiment that is remotely related to AD, as a breakthrough drug about to launch...

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4. Paul Brookes on October 11, 2013 9:04 AM writes...

For the record, there are major "creative data management" issues with a 2011 Nature paper from this group, upon which the current hoopla/paper is based. Re-use of blots to represent different conditions etc. Attempts to get the journal to correct those "mistakes" have so far fallen of deaf ears. Let's just say that the state of data handling by this group, and the prion field as a whole, does not instill confidence in the findings of this new paper. There are some minor issues in the new paper itself, but not worth getting into since the images are not of a resolution sufficient to draw conclusions.

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5. Anon part the severalth on October 11, 2013 9:35 AM writes...

It's the Leicester Uni press department happening to a press release, again.

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6. luysii on October 11, 2013 9:51 AM writes...

Do you have any idea how cruel this is for families and patients with Alzheimer's? Guess who has the pleasure of explaining how far away this is from a medication they can take (and why it isn't as good as it sounds). Yet another reason to be glad I've retired from neurological practice, along with impotently watching patients (and friends and family now that I'm older) deteriorate.

Nonetheless, the approach to protein misfolding is an interesting one. Inhibiting the process of correction is likely to have multiple side effects, as the very elaborate mechanism to correct misfolded proteins (and destroy them if uncorrectable) is there for multiple reasons having nothing whatever to do with neurodegenerative disease. The misfolded proteins probably occur in every cell.

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7. Vader on October 11, 2013 10:21 AM writes...

I suspect the great majority of Alzheimer's patients, and their families, would gladly swap Alzheimer's for drug-induced diabetes.

If the other obstacles to this new treatment were only so easy ...

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8. Worried Citizen on October 11, 2013 11:27 AM writes...

I wonder how long it will be before Dr. Oz has a bit on this like the "Dr. Oz's foods that cause Alzheimer's" shtick he did a few years back. You know, the one about nitrous oxides in food and how that causes AD?

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9. Anonymous on October 11, 2013 12:13 PM writes...

What if you deliberately build on functional groups which couldn't cross the BBB, and did direct cerebrospinal injections (not that that idea sounds like any fun at all either)? Wouldn't that allow you to target the PERKs in the CNS without the systemic issues?

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10. Andy Benson on October 11, 2013 12:22 PM writes...

Some of the news stories did indeed pick up that GSK2606414 isn't actually a development compound (although not many). GSK has actually already reported on an optimized PERK inhibitor, GSK2656157, that they are advancing into preclinical development (see http://pubs.acs.org/doi/abs/10.1021/ml400228e). As with GSK2606414, preliminary work was aimed at cancer, but it will be interesting to see if they move into Alzheimer's or other protein misfolding diseases with this.

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11. Elchert on October 11, 2013 1:49 PM writes...

This a direct attempt to hide the news out of the Symposium"Taking Control of Alzheimer's Through Research: The Road Map to Therapies" held on the 9th of October sponsored by the Cure Alzheimer's fund. Dr Rudy Tanzi's drug PBT2 is set to be the SOC in early and mid stage Alzheimer's.

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12. Elchert on October 11, 2013 1:50 PM writes...

This a direct attempt to hide the news out of the Symposium"Taking Control of Alzheimer's Through Research: The Road Map to Therapies" held on the 9th of October sponsored by the Cure Alzheimer's fund. Dr Rudy Tanzi's drug PBT2 is set to be the SOC in early and mid stage Alzheimer's.

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13. gippgig on October 11, 2013 2:05 PM writes...

I believe the reason these protein misfolding diseases selectively cause neurodegeneration is that - correct me if I'm wrong - neurons require a higher level of protein synthesis than other cells.
Note that there seem to be two different pathways to the same result: inhibition of translation initiation by PERK (UPR) and inhibition of elongation by eEF2 kinase (by low energy via AMPK). Interestingly, it appears that slightly activating many of these stress resistance mechanisms is beneficial (possibly because evolution selects for rapid reproduction rather than individual health; increasing stress resistance favors health over reproduction) but if you go too far you "fall off the edge of a cliff". For example, activating AMPK protects against a stroke but during a stroke (when AMPK is already overactivated) inhibiting it is beneficial.

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14. gippgig on October 11, 2013 2:22 PM writes...

#10: that link gives an error message.

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15. DrSnowboard on October 11, 2013 3:39 PM writes...

11 &12 : Why?

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16. Vc1023 on October 11, 2013 4:10 PM writes...

This a direct attempt to hide the news out of the Symposium"Taking Control of Alzheimer's Through Research: The Road Map to Therapies" held on the 9th of October sponsored by the Cure Alzheimer's fund. Dr Rudy Tanzi's drug PBT2 is set to be the SOC in early and mid stage Alzheimer's.

Permalink to Comment

17. Vc1023 on October 11, 2013 4:11 PM writes...

This a direct attempt to hide the news out of the Symposium"Taking Control of Alzheimer's Through Research: The Road Map to Therapies" held on the 9th of October sponsored by the Cure Alzheimer's fund. Dr Rudy Tanzi's drug PBT2 is set to be the SOC in early and mid stage Alzheimer's.

Permalink to Comment

18. sgcox on October 11, 2013 5:31 PM writes...

I thought UPR is actually evolved to help cells survive the stress. No wonder it is activated in Alzheimer and other diseases because it is normal protective mechanism. When superactivated it can of course cause a very serious damage (just think of immune system). Mouse prion model is an acute insult - mice must be sacrificed after two weeks.
No wonder inhibiting UPR can help in this setting. But when we are talking about slowly progressing over years diseases of human brain, I suspect inhibiting UPR will makes things even worse.

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19. Lane Simonian on October 11, 2013 7:14 PM writes...

The unfolded protein response likely requires the activation of p38 MAPK via peroxynitrites to result in the death of brain cells. Both PERK and p38 MAPK can contribute to the activation of CHOP proteins which leads to cell apoptosis.

The depletion of calcium from the endoplasmic reticulum may contribute to an unfolded protein response and lead to the formation of amyloid plaques but neither is likely neurotoxic in the absence of peroxynitrites and p38 MAPK.

The present study suggests that disturbed induction of the UPR and activation of the pro-apoptotic proteins contribute to neuropathological process in AD irrespective of amyloid β and senile plaque (Lee, et al. Induction of the unfolded response protein response and cell death pathway in Alzheimer's disease, but not in aged Tg2576 mice).

p38 MAPK inhibition and peroxynitrite scavenging are both easier and likely more effective ways of treating Alzheimer's disease than PERK inhibition.

Permalink to Comment

20. Alex Besogonov on October 12, 2013 2:01 AM writes...

I always wondered, why messy side-effects are a 100% barrier? Personally, if I'd trade Alzheimers for a diabetes faster than you can say Paracetomoxyfrezebendroneomycin.

Permalink to Comment

21. bank on October 12, 2013 7:27 AM writes...

@ Elchert and Vc1023

What is the news out of that symposium? ("Taking Control of Alzheimer's Through Research: The Road Map to Therapies").

Permalink to Comment

22. Lane Simonian on October 12, 2013 12:30 PM writes...

I have been looking for the connection between peroxynitrites and PERK receptors and here it is.

Our data suggested that UVB induces NOS activation and NO• production, which reacts with superoxide (O2 •−) to form peroxynitrite (ONOO−) and activate PERK.

(Wang, et al. The Roles of nitric oxide synthase and elf2alpha kinases in regulation of cell cycle upon UVB radiation).

If you knockout inducible nitric oxide synthase (and thus the formation of peoxynitrites) you in essence knockout Alzheimer's disease.

Deficiency of iNOS substantially protected the AD-like mice from premature mortality, cerebral plaque formation, increased beta-amyloid levels, protein tyrosine nitration, astrocytosis, and microgliosis. Thus, iNOS seems to be a major instigator of beta-amyloid deposition and disease progression. Inhibition of iNOS may be a therapeutic option in AD

(Nathan, et al. Protection of Alzheimer's-like disease in the mouse by genetic ablation of inducible nitric oxide synthase).

If I were working in the pharmaceutical industry, I would drop the research on amyloid antibodies immediately and begin working on synthetic peroxynitrite scavengers to treat Alzheimer's disease. But I am just an historian--what do I know.

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23. Elchert on October 13, 2013 11:54 PM writes...

http://www.livestream.com/crcmedianyc/video?clipId=pla_7172e347-e9e6-429c-98c3-e8c125283a49&utm_source=lslibrary&utm_medium=ui-thumb

watch and evaluate

Keep in mind the reputation Rudi Tanzi has.

Permalink to Comment

24. bank on October 14, 2013 7:15 AM writes...

@Eichert,

Thanks for the link. I quickly skipped through the video, it seems to be reporting the recent paper by Suh et al [1], which describes how ADAM10 mutations can alter Abeta production and pathology in mice. Unfortunately, the mice they tested don't get neurodegeneration so the experiments reported don't answer whether targeting ADAM10 can modify Alzheimer's disease.


[1] Suh et al., ADAM10 Missense Mutations Potentiate b-Amyloid Accumulation by Impairing Prodomain Chaperone Function, Neuron (2013), http://dx.doi.org/10.1016/j.neuron.2013.08.035

Permalink to Comment

25. Lane Simonian on October 14, 2013 10:42 AM writes...

Thank you for the video. This is close but not quite there. The reaction produced by the interaction of peroxynitrites with peroxynitrite scavengers is the following: ONOO- + 2h+ + 2e- = NO2- + H20. Water is a denitrating agent but NO2- in the presence of iron ions becomes a nitrating agent (NO2). Moreover in the presence of hydrogen peroxide (which is high early in Alzheimer's disease) NO2- is converted into peroxynitrites again. So a futile cycle helps to prevent an effective antioxidant defense against the disease.

Copper ions combined with nitric oxide and dioxygen helps to produce more peroxynitrites as well.

Metal chelation will slow down the process of peroxynitrite formation, but the main route to peroxynitrite formation early in Alzheimer's disease is via phospholipase C--protein kinase C--p38 MAPK. After this, the peroxynitrite-mediated nitration of NMDA receptors produces an influx of calcium that produces more p38 MAPK and more peroxynitrites. This is the vicious cycle that has to be broken in order to effectively treat Alzheimer's disease. Thus, the following part of this study makes sense.

Fe2+ alone transiently enhanced p38 MAPK and caspase-9 and -3 enzymes indicative for cell damage, but was not sufficient to cause cell death as previously indicated... [whereas] a p38 MAPK inhibitor, prevented cell damage and apoptosis. These findings further support the hypothesis that metal ion chelation and inhibitors of pro-apoptotic kinase cascades may be beneficial for Alzheimer's disease therapy (Kuperstein and Yavin 2003)

All of this may be a moot point, as many peroxynitrite scavengers are also metal chelators.
Metal chelators that are not peroxynitrite scavengers will slow down the progression of the disease. Metal chelators that are peroxynitrite scavengers and/or p38 MAPK inhibitors will partially reverse the disease.

Permalink to Comment

26. Elchert on October 14, 2013 11:32 PM writes...

-well i don't believe you have looked at Pbt2 correctly-. Human trials have already been reported and showed proven cognition improvement in 12 weeks. Pbt2 can and will (Imo) be used in early and mid alzheimer's cases, As it provides metal homeostasis. Removes abeta and clears the tau tangles. This is all part of the process. Please re watch the symposium starting from 59 minutes so you can learn from one of the foremost alzheimer's researcher on the planet Rudy Tanzi. Proven safety, the ease of use taken orally with low or no side effects.

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27. Anonymous on October 15, 2013 3:28 AM writes...

Since when did science become about who shouts the loudest? A bit of humility and data beats all that hubris and chest beating!

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28. bank on October 15, 2013 5:34 AM writes...

@ Eichert,

I had another scan through the 2 hr long video; you would have to give me a more specific indication of where Pbt2 is mentioned as I didn't find it.

As to Pbt2, the Phase II trial results are due March 2014, fingers crossed!

Permalink to Comment

29. kinaser on October 15, 2013 6:53 AM writes...

@25, Lane

SB-203580 isn't a very selective p38 MAPK inhibitor, so while what you say may be true there are other interpretations.

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30. metaphysician on October 15, 2013 5:07 PM writes...

Hasn't there been some recent evidence suggesting that Alzheimer's may actually *be* a prion disease, albeit probably one where the prions are produced internally rather than acquired externally? Or am I misremembering/the evidence is bad?

Permalink to Comment

31. Anonymous on October 15, 2013 5:15 PM writes...

All these amyloid and prion peptides form porin-like holes in cell membranes, so that the cells burn themselves out trying to maintain homeostasis. It's as simple as that, like trying to fill a bucket with big holes in the bottom.

Permalink to Comment

32. cliffintokyo on October 22, 2013 3:42 AM writes...

Very late and very probably last word:
Ahh! So that's why I felt like an empty bucket when I was having my work overload burnout/mid-life crisis! This story PERKed me up no end (Groan!)

Permalink to Comment

33. Brendan Orner on October 22, 2013 7:15 AM writes...

To provide clarification regarding comments 1 and 2:

Although it is true that King's College London closed its chemistry department some years ago, the resurrected chemistry department is already in its second year. We have nine core faculty, forty-two faculty affiliates, and both an undergraduate and a PhD program.

http://www.kcl.ac.uk/biohealth/research/divisions/chemistry/index.aspx

Roger Morris is our current Acting Head, but we are currently searching for a permanent department head and a "senior teaching lead".


Brendan Orner
Senior Lecturer in Chemical Biology
Department of Chemistry
School of Biomedical Sciences
King's College London
Britannia House
7 Trinity Street
London SE1 1DB
http://orner-lab.appsp0t.com

Permalink to Comment

34. Daniel Nebdal on January 16, 2014 11:39 AM writes...

Regarding PERK inhibitors: Diabetes 1 has a perfectly serviceable treatment available, and is probably preferable to Alzheimers. If it actually works (big if, that one), it might be an acceptable tradeoff.

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