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New Alzheimer’s Research in the UK

Oxford University’s new Drug Discovery Institute is making a big push in dementia and Alzheimer’s. Update: link fixed, I hope. One one level, that’s good news, because this is a tough area that needs all the well-placed shots that can be aimed at it. The folks Oxford will be staffing this institute with will surely not be dummies, and there’s a lot of currently underused drug discovery and development talent in the UK that I hope that they’ll tap into.
The Alzheimer’s Research UK charity is helping to launch three such institutes – one at Oxford, one in Cambridge, and one with University College, London, so they’re also planning to get plenty of academic firepower as well (and it’s not like people at all three institutions haven’t been working in the field already, in various ways). All this makes me hope that this part is just some hyperbole for the press release:

The research team at Oxford will develop multiple projects to design and develop new therapies. It plans to deliver up to three new therapies for further clinical development and trials within the next five years.
‘This has never been done before, and we believe that it will transform dementia research’, said Professor Chas Bountra, the other project leader at Oxford University, ‘We will work with the best academic and industrial scientists to identify potential new drug targets for dementia. We will then generate high quality starting points for making new medicines, but then uniquely, make them freely available to the world’s biomedical community. By doing so we will catalyse new biology, new disease understanding and importantly accelerate those few molecules which are likely to slow down the progression of this dreadful disease. We are crowd sourcing the discovery of new medicines for Alzheimer’s disease. This is unprecedented.’

Three good starting points in five years surely would be that. They’d better have about eight or nine really good ideas in hand right now if they want to have any chance at all. And honestly, I’m not sure if there are as many as eight or nine separate good ideas in Alzheimer’s drug therapy at all. I certainly hope I’m wrong about that. But I also hope that this strong, well-intentioned effort doesn’t start off by promising more than anyone can deliver.
Note: there’s been a trend towards Alzheimer’s optimism (or over-optimism) in the UK. I wonder if you just have to join along in this chorus in order to participate at all?

43 comments on “New Alzheimer’s Research in the UK”

  1. petros says:

    Nice to see Chas on the breakfast news yesterday and hopefully they’ll get lucky. I assume that this is one of the precompetitive projects that he has been pushing for.
    As for the UK’s attitude to Alzheimer’s, perhaps it reflects on all the former industry people who worked in CNS in the UK. It probably used to account for 50% of UK pharma R&D
    Lost efforts include Wyeth, Parke Davis, Organon, SB/GSK, Merck, Novartis, Cereberus with Lilly still flying the flag

  2. On that Note…it’s really just Discworld fans hoping to restore Sir Terry to health so he can keep on writing more crack, I mean novels, for them (us?).

  3. JK says:

    To be fair your quote does say “up to three”, which could mean they have three ideas they think might pay off.

  4. annon says:

    All I can say is “it’s the Brits.” Very doubtful anything will come of this.

  5. Lane Simonian says:

    I hesitate to comment any more on this site. I will stop when there is nothing more for me to say but I am not quite there yet.
    Maybe they could start with the UK pomegranate study last year, but I doubt that will be the starting point. I read the UK press which seems to have a breakthrough finding on Alzheimer’s disease about once every month. And then nothing comes of the studies.
    The only new point is this: most if not all the amyloid precursor protein mutations either increase g protein-coupled receptor activity or directly activate g proteins (the same is also true of the c-terminal fragment of the amyloid precursor protein). Along with overactivation of receptor tyrosine kinases these are the two pathways that lead not only to amyloid and tau tangles, but also to oxidative stress. And given the multiple factors that can activate these pathways (various environmental “toxins”, various chronic bacterial and viral infections, certain medications, glucose, high fructose corn syrup, etc.) it is not surprising how widespread the disease is.
    If you inhibit g protein-coupled receptor overactivation, in some cases you may delay the onset of Alzheimer’s disease (the same is also probably true of inhibiting receptor tyrosine kinases through a Mediterranean diet). The Icelandic mutation, for instance, which may prevent beta secretase activity protects against Alzheimer’s disease but that protection is not absolute (see Alzheimer’s Research Forum: Let’s All Move to Iceland: Anti-Dementia Allele Rare in United States–at least one person with the mutation likely has Alzheimer’s disease albeit at the age of 89). What this may tell us is that a perfect Bace 1 secretase inhibitor without side effects can at least delay the onset of Alzheimer’s disease. It is not likely to help most of those who already have the disease, as g protein-coupled receptor activity declines anyway as the disease progresses.
    Alzheimer’s disease research is stuck in a big rut (or as one well-titled article put it: an intellectual cul-de-sac). No amount of cheerleading or re-analysis of failed clinical trial analysis is going to get us out of it. Why people keeping ignoring or bashing the trials that produced positive results is largely beyond me. It is one thing to give people false hope based on poor results. It is another thing to deny people real hope by turning a blind eye to positive results.

  6. Anonymous says:

    Jobs Jobs Jobs. I will be surprised if these are not either post-doc positions or short term contracts for chump change. Also possibly the three most expensive places in UK to live. Hold me back!
    The link also doesn’t work.

  7. David Cockburn says:

    I see a lot of doubters commenting here and I’m not going to argue with them. Even if they come up with three great leads they still have to find the patients for a clinical trial and get a read-out in less than a decade.

  8. Brit Anon says:

    #4. Have to comment back. Brits have contributed greatly to drug discovery ever since industrial drug development was formulated. Every decade has seen a significant number of drugs from UK labs, if not UK companies. Not sure where you are commenting from, but I would hazard a guess that a per capita comparison would have the UK at least matching.

  9. Anonymous says:

    @6: Surely someone must have tried modulation of various GPCRs in transgenic mouse models with impaired/altered APP processing?
    In any case, misactivation of GPCRs certainly seems like it could cause defects in cellular homeostasis but I question if APP processing and beta/gamma-secretase activity is really the causative agent in AD. I don’t think any data is convincing enough, yet.

  10. DCRogers says:

    It’s hard not to feel cynical reading press releases, but bottom line, anyone who wants to toss more money studying this fiendishly difficult indication has my support.

  11. diver dude says:

    Chas is a smart boy. I used to work with him at GlaxoWellcome and he knows early stage drug development. If he says they can do this, I’d be inclined to give him the benefit of the doubt for now.

  12. Doug Steinman says:

    There is no question that there is a real need for new research directions in Alzheimer’s. The devastation caused by having a friend or a loved one affected by this disease is enormous as I know from personal experience. I was not able to access the link but I wonder if it wouldn’t be more fruitful for this academic consortium to concentrate more on the basic aspects of the disease and / or disease markers and less on developing agents that might be useful in the treatment of the disease. While the pharmaceutical industry is subject to a great degree of criticism (and rightly so) for their drug development efforts, the industry is probably better suited to the development of new treatment entities that would be based on the basic research that bests takes place in an academic environment.

  13. FarmHand says:

    @14 Link didn’t work for me, either..”ACCESS DENIED”
    I found an alternate link to the same info that does work and sent it in a comment but it seems to have been lost in the ether. Let’s try again:
    “http://www.ox.ac.uk/news/2015-02-16-oxford-drug-discovery-institute-fast-track-development-new-dementia-treatments-0”

  14. Lane Simonian says:

    @10. It likely that high beta secretase/gamma secretase activity is not the causative agent in Alzheimer’s disease. The causative agent is likely oxidative stress. Oxidative stress increases beta secretase activity and can increase gamma secretase activity. And while it is possible that amyloid oligomers and tau tangles can contribute to oxidative stress they are not likely the primary causes of this stress. It is possible to have Alzheimer’s disease with only the c terminal fragment of the amyloid precursor protein and with hyperphosporylated and nitrated tau.
    Most researchers likely are going after largely the wrong targets and this is probably why simply targeting either amyloid oligomers or plaques has not worked to date and why targeting tau tangles is not likely to work either. It also explains why the most powerful antioxidants have partially reversed Alzheimer’s disease in small-scale clinical trials so far.
    http://jpet.aspetjournals.org/content/321/3/823.full

  15. Anonymous says:

    @Lane: beta secretase/gamma secretase are implicated as causes of AD because mutations in the genes coding those proteins correlate with familiar cases of AD. So how would oxidative stress precede those genetic mutations as the ultimate cause of AD, rather than follow the mutations as a downstream effect? You seem to think information flows backwards in time, with the effect preceding the cause. That is plain nonsense.

  16. Lane Simonian says:

    Oxidative stress does not precede the mutations that lead to familial Alzheimer’s disease, they follow from them.
    For most amyloid precursor protein mutations, the sequence is this: amyloid precursor protein mutation, g protein-coupled protein receptor activation, peroxynitrites, caspase-3 activation, beta secretase activation, c terminal fragment of the amyloid precursor protein, further g protein-coupled receptor activation (or direct g protein activation) early on. Thus, the following study makes sense.
    http://www.ncbi.nlm.nih.gov/pubmed/11432978
    For presenilin gene mutations, the process begins with the inhibition of the phosphatidylinositol 3-kinase/Akt kinase which leads to oxidative stress.
    The key point is that the mutations that lead to Alzheimer’s disease cause/increase oxidative stress. Yes, the mutations also lead to amyloid oligomers and plaques, but the mistake is to assume that the latter are the causal links to Alzheimer’s disease rather than oxidative stress.

  17. Lane Simonian says:

    This one partially supports my point.
    http://www.ncbi.nlm.nih.gov/pubmed/16478525
    My only dissent is that oxidative stress is only partially a function of amyloid. Each stage from c-terminal fragment of the amyloid precursor protein to amyloid oligomers to amyloid plaques likely represents a decrease in the amount of oxidative stress. Other factors such as NMDA receptor activation or in some cases continued g protein activation likely drive the progression of the disease.

  18. Dolph says:

    Research in the UK? Isn’t that an oxymoron?

  19. Anonymous says:

    @Lane: So how come all those steps you mentioned also precede gamma secretase, if and when the disease is linked to mutations in gamma secretase. Again, you are mixing up cause and effect by getting the flow of information backwards. I suggest you should read more about basic physics, and why time doesn’t run backwards.

  20. cpchem says:

    @20 – Well, no.

  21. Ann O Mouse says:

    @21 “I suggest you should read more about basic physics, and why time doesn’t run backwards.”
    Actually, a physics professor of mine once described a postulate that a positron is in fact an electron moving backward in time. When a positron and electron meet and appear to be annihilated with production of a gamma ray, what is actually happening is the electron is being struck by a gamma ray, causing the same particle to now travel backward in time.
    OK, most physicists don’t buy into this, but as far as I know there is no mathematical way to disprove it.
    Which is all my way have saying, let’s all remember that in the vast universe of causalities for AD our miniscule knowledge of the facts leaves room for multiple theories, none of which are likely to be totally correct and absolutely none of which have significant clinical backing…at least not yet.

  22. Lane Simonian says:

    #21 This really is the big question. You are right if some of the mutations directly caused gamma secretase activity, but this may very well not be the case.
    Presenilin genes may also activate g protein-coupled receptors which can lead not only to the formation of peroxynitrites but also to the release of intracellular calcium, which results in the activation of calpains which drive the gamma secretase.
    Presenilin gene mutations result in a loss of this function (due to the loss of leucine), so one would think that it would cause a loss of gamma secretase activity. But the loss of leucine also leads to the loss of phosphatidylinositol 3-kinase activity without affecting receptor tyrosine kinase activity. The result is intracellular calcium release via phospholipase C gamma. This likely explains the connection between presenilin gene mutations and gamma secretases.
    Peroxynitrites via the nitration of the phosphatidylinositol 3-kinase and via cytochrome c-release and subsequent intracellular calcium release can also increase gamma secretase activity.
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3402223/
    Again, though, it is not the activation of gamma secretases and the subsequent formation of amyloid oligomers that is the key step in Alzheimer’s disease. It is oxidation and nitration. Compounds that lower levels of amyloid oligomers and plaques have little effect on the progression of the disease. Compounds that partially reduce oxidation and nitration do.

  23. Harrison says:

    As a long-time lurker I have to thank Lane for writing significantly shorter posts, for not posting abstracts, and for staying with the basic science and not venturing into more tenuous areas.
    I think there is a good point in all the speculating that the way a person develops familial AD (1-5% of AD cases, depending on your source) may NOT recapitulate the way Late-Onset (95-99%) AD develops. There is a genetic relationship (apoE) that explains ~50% of late-onset AD cases, but for reasons perhaps lost to time, it has been severely understudied since its discovery over 20 years ago.

  24. jtd7 says:

    “It plans to deliver up to three new therapies for further clinical development and trials within the next five years.”
    Always remember that “up to” means “less than.”

  25. Lane Simonian says:

    @25. I am able to post links on this site again which is indeed much better than posting abstracts.
    The ApoE4 gene is also connected to g protein-coupled receptors via low density lipoprotein receptors.
    http://www.ncbi.nlm.nih.gov/pubmed/11223431

  26. Lane Simonian says:

    And an interesting study on what happens to children with the Apoe4 gene exposed to high levels of particulate matter (and other air pollutants) in Mexico City. Particulate matter and diesel fumes act through epidermal growth factor receptors; a receptor tyrosine kinase. Many of these children had cognitive deficits, and substantial amounts of amyloid plaques and hyperphosphorylated tau in their brains, but of course not Alzheimer’s disease yet.
    http://www.iospress.nl/ios_news/decreases-in-short-term-memory-iq-and-altered-brain-metabolic-ratios-in-urban-apolipoprotein-%CE%B54-children-exposed-to-air-pollution/

  27. Ann O Mouse says:

    @24 Lane,
    If memory serves me, at least some of the Presenilin mutations associated with AD do not cause an overall change in GS activity but rather shift the cleavage site to favor the more amyloidogenic Ab42 over Ab40. This seems more consistent with a direct effect of Presenilin mutations on GS activity, especially since GS is part of the presenilin complex. Any thoughts?

  28. Lane Simonian says:

    @25 Here is one study suggesting this effect of presenilin gene mutations on amyloid processing.
    http://www.molecularbrain.com/content/3/1/7
    More in the next post, as I can only post one link at a time on this site.

  29. Lane Simonian says:

    @29 Ann (got it right this time)
    Peroxynitrites also affect amyloid processing in almost the same way as presenilin gene mutation.
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3402223/
    Presenilin gene mutations increase peroxynitrite formation and alter the processing of amyloid via inhibition of the phosphatidylinositol 3-kinase/Akt pathway.
    In late onset Alzheimer’s disease, peroxynitrite mediated nitration also inhibits this pathway. In both cases peroxynitrite formation leads to neuronal cell death.
    Two distinct signaling pathways regulate peroxynitrite-induced apoptosis in PC12 cells
    The effect of various mutations on amyloid processing is likely indirect rather than direct and involves the increased production of peroxynitrites.

  30. Lane Simonian says:

    One more shot at this for tonight. Presenilin gene 1 mutations may actually decrease gamma secretase activity by decreasing g protein-coupled receptor activity whereas presenilin gene 2 mutations may do the opposite.
    Relevant articles:
    Single Transmembrane Spanning Heterotrimeric G Protein-Coupled Receptors and Their Signaling Cascades
    Tarun B. Patel
    The Presenilin-1 ΔE9 mutation results in reduced γ-secretase activity, but not total loss of PS1 function, in isogenic human stem cells
    However by severely inhibiting the phosphatidyinositol 3-kinase/Akt pathway, presenilin gene mutations prevent the processing of the amyloid precursor protein in a non-amyloidgic way.
    Relevant articles:
    Wild-Type But Not FAD Mutant Presenilin-1 Prevents
    Neuronal Degeneration by Promoting Phosphatidylinositol 3-Kinase Neuroprotective Signaling
    http://www.nature.com/ncomms/2013/130802/ncomms3250/full/ncomms3250.html?message-global=remove&WT.ec_id=NCOMMS-20130807
    There are four factors (in some combination) that lead to Alzheimer’s disease: high levels of myo-inositol, overactivation of receptor tyrosine kinases, overactivation of g protein-coupled receptors, and inibition of the phosphatidylinositol 3-kinase. These combinations lead to peroxynitrite formation and except in the cases of inhibiton of intracellular calcium release they also lead to amyloid formation. Oxidative stress leads to amyloid formation. Amyloid oligomers in turn can contribute to oxidative stress. But if you prevent oxidative stress, there is no Alzheimer’s disease and if you partially reverse oxidative stress, you partially reverse the disease. The same is not true for amyloid.

  31. bank says:

    One of the leaders of the Oxford group is the same guy who recently announced the (now derided) discovery of a blood test for Alzheimer’s disease.

  32. Anonymous says:

    @ Luke,
    Having only quickly read that paper and a related previous one, the drawbacks are common ones in AD research, i.e. the mice used in their previous paper to demonstrate the efficacy of their compounds in vivo are highly artificial (in this case injection of Abeta into the brain), and so likely don’t reflect the actual disease. The studies on transgenic mice suffer from another common problem, i.e. while those mice have behavioral defects, they do not get neurodegeneration. So it is unclear if their data predicts any ability of their compounds to treat AD. Note also that *all* compounds that previously showed efficacy in similar models went on to fail in clinical trials.
    Their human brain studies are underpowered (8 brains in total), and their in vitro studies on cultured neurons use levels of Abeta that far exceeds the levels ever found in a brain.
    So, while at first glance their work seems solid, its relationship to mechanisms in actual AD are unclear.

  33. Lane.Simonian says:

    I agree on a general level in regards to the limited value of mice studies for understanding Alzheimer’s disease. Nevertheless, just uncovering a mechanism can be of some help.
    Progesterone receptors directly activate the Src family of kinases and this family of kinases has been linked to Alzheimer’s disease.
    http://www.ncbi.nlm.nih.gov/pubmed/11545730
    But many receptors activate Src kinases, so it does not seem likely that inhibiting one would make a huge difference.

  34. Lane Simonian says:

    The role of progesterone receptors in binding heme may also play some role in Alzheimer’s disease.
    http://www.ncbi.nlm.nih.gov/pubmed/20666389

  35. Anon says:

    It is great to see the money been put into these drug discovery institutes but why in three different locations and I agree in three of the most expensive locations in the UK? This means three separate labs, with three separate management structures and CSO’s? Surely a more cost effective way would be to have one lab, and put the money into hiring more lab personnel and less into ‘management’. I think it is the usual of trying to cater to the ‘big three’ in the UK. In the end it will be the patient loosing out.
    http://www.alzheimersresearchuk.org/careers/

  36. Luke says:

    @34-
    I thought it was well established that hAPP transgenic mice with the Swe/Lond mutation did show signs of synaptotoxicity and neuron loss. Am I mistaken?
    You mention that this mouse model hasn’t led to a single approved drug, but couldn’t that be said about every AD mouse model? Is there an industry accepted AD mouse model that is thought to be better the the hAPP Swe/Lond model?
    @Lane-Thank you for the links. This hypothesis that PGRMC1 ligands block the binding of Abeta oligomers seems interesting.

  37. bank says:

    @ Luke,
    Synaptotoxity doesn’t directly lead to neuron loss, which has only been shown when the transgenic mice also express mutated versions of presenilin, which itself has a wide variety of substrates in addition to APP.
    hAPP mice are indeed the “industry standard”, but perhaps that is part of the problem… More than 300 separate treatments have “cured” hAPP mice, and none translate to AD.
    Search for the review article below, which covers the topic:
    “‘Too much good news’ – are Alzheimer mouse models trying to tell us how to prevent, not cure, Alzheimer’s disease?”

  38. Anonymous says:

    @38,
    The Director of research at ARUK is Dr Eric Karran, formerly of J&J, Lilly, Pfizer, SmithKline and GSK. Apparently their goal is to have multiple independent approaches to the problem, and reduce “contagion” by politics that could occur.

  39. Luke says:

    bank,
    Thanks for the clarification and very nice review article.

  40. Lane Simonian says:

    You are welcome, Luke. Here is a study that establishes a more direct link between progesterone receptor activation and oxidative stress (albeit for the liver).
    http://www.ncbi.nlm.nih.gov/pubmed/16284289

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