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Prana Biotechnology Limited Message Board

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  • A flat line might be enough...at least they maybe didn't get worse over the two years.

  • Well said TB. Its just amazing to me that Lily is still attempting to trial their drug. At least maybe Prana will benefit from the cognition assessment work they are doing!

    Let's hope not many more. With the signals we saw in the first year of SUVR and HA reductions I cant' imagine those would have stopped in the second year. Additional safety data is the important piece right now too for the HD trial and the AD future.

  • Reply to

    Rethinking the Hippocampus

    by interestingtome 12 hours ago

    The reason for posting this below--- longitudinal slices showed different results than perpendicular cross section slices.

    The authors used high-powered techniques to demonstrate the existence of these connections, as well as reveal their anatomy, functionality, and plasticity,” said Howard Eichenbaum of Boston University. “This tells us there are powerful connections along the longitudinal axis, and we need to find out what those connections are doing.”

    The longitudinal connections might explain how the hippocampus encodes temporal sequences, Tang said. “A chain of nearly identical neurons could transform a time sequence into a spatial one,” he told Alzforum. Such short-term “memory buffers” are essential for correctly interpreting information, such as the order of words in a sentence. The brain cannot function if it does not have such buffers to store the information in the correct temporal order, he said. Tang next plans to study how these connections work in animals receiving a sequence of inputs.

  • Reply to

    Rethinking the Hippocampus

    by interestingtome 12 hours ago

    Next, they found that the axons branching within the CA1 contacted pyramidal cell dendrites (see image below), and patch clamp recording from longitudinal hippocampal slices indicated that these synapses were functional. Further electrophysiological tests suggested that these excitatory connections strengthen in response to stimuli. Together, the findings imply that CA1 neurons in the hippocampus talk amongst themselves, the authors wrote.
    The authors used high-powered techniques to demonstrate the existence of these connections, as well as reveal their anatomy, functionality, and plasticity,” said Howard Eichenbaum of Boston University. “This tells us there are powerful connections along the longitudinal axis, and we need to find out what those connections are doing.”

    The longitudinal connections might explain how the hippocampus encodes temporal sequences, Tang said. “A chain of nearly identical neurons could transform a time sequence into a spatial one,” he told Alzforum. Such short-term “memory buffers” are essential for correctly interpreting information, such as the order of words in a sentence. The brain cannot function if it does not have such buffers to store the information in the correct temporal order, he said. Tang next plans to study how these connections work in animals receiving a sequence of inputs.

  • ALZforum
    Rethinking the Hippocampus
    24 Sep 2014

    The hippocampus contains some of the best-studied neural circuits in the brain. It also plays a crucial role in learning and memory, and it is compromised in people with Alzheimer’s disease. How well do neuroscientists know their favorite seahorse? A trio of recent studies suggests that its connections and morphology are more complex than textbooks describe. In the September 2 Proceedings of the National Academy of Sciences, researchers report that axons run lengthwise along the hippocampus, forming a potentially important cadre of synapses—this in addition to the well-described transverse projections that researchers study in hippocampal slices. A paper in the August 31 Nature Neuroscience describes how hippocampal neurons transmit signals backward through those transverse projections. And in the September 17 Neuron, researchers report that a large number of hippocampal axons sprout directly from dendrites, rather than neuronal bodies. Together, the papers highlight features of the hippocampus that have flown under the radar.

    “Understanding how the hippocampus encodes and relays information is fundamental to understanding memory,” said Cha-Min Tang, University of Maryland School of Medicine, Baltimore, the senior author on the PNAS paper.

    The prevailing notion about excitatory connections in the hippocampus is that they start in the dentate gyrus, project to the CA3, then on to CA1 and the subiculum (see image at left and Andersen et al., 1971). This “lamellar” hypothesis, which posits that neurons communicate between these areas and less so within them, led scientists to rely principally on cross-sectional or transverse slices for electrophysiological experiments of the hippocampus.

  • Well said tb. I also think there is a very good chance we will see 2yr zero loss of cognition in the MMSE cognition test they are using.

    Sentiment: Strong Buy

  • (cont)
    The findings suggested that increased hippocampal functional connectivity and volumes may be biomarkers for ECT response.

  • Yes, great reading. Like I said, the science matters. Others might see it as a roulette spin, but I find it hard to believe that the treatment for AD, HD, PD and other neuro-degenerative diseases will not involve managing the metals to some extent. Metals are too integral to the proper functioning of neurons to NOT be part of the disease and aging process.

    In AD, I think the body of evidence is getting very hard to ignore. Open label or not, the Extension results will likely add to that evidence. It's unlikely that we will ever see a 10 billion dollar ten year study that confirms a preventative treatment like PBT2 for AD. Ain't gonna happen. In the meantime, we're just ticking off the latest billion dollar failure, one after the next.

    AD is not just another nut that's proving very difficult to crack, it's a ticking time-b**b for Western societies, and yeah, they get AD in China too. Given that, I would put a much higher value on the Extension than some do. The playbook for getting an effective treatment for AD may look a little different than what we've seen in the past. Tanzi has given us a pretty good idea of what it might look like. AD, like AIDS a generation ago, is more and more becoming a political issue.

    Abeta buildup is required to get AD, although everybody with excessive abeta doesn't get AD. Prevent abeta accumulation and you prevent AD. If the Extension, with all its limitations, clearly shows that PBT2 safely reduces abeta in the trial participants, then Prana is holding a golden ticket. How many billion dollar failures does it take before the MPAC approach becomes the best approach? Not many more. Not many more.

  • Excellent! Thanks for posting, itm.

  • Judging from your usual 4 thumbs down he must still be around.

    Sentiment: Strong Buy

  • Reply to

    Tau

    by kadaicher1 Dec 19, 2014 10:13 AM

    It will be interesting to see how they incorporate the neural tube theory into all this as they are just getting started on looking at it.

  • Reply to

    Tau

    by kadaicher1 Dec 19, 2014 10:13 AM

    I meant to type gamma secretase modulator (as in Tanzi's GSM) not GSK. I do agree that PBT2 aids in GSK modulation... "This results in PBT2 forming a neutral complex with metal ions that is capable of crossing cellular membranes. Consistent with this, the data in Fig. 1c and Figure S2 show that PBT2 can transport Zn and Cu ions into the cell. Once inside cells the moderate affinity that PBT2 has for Cu and Zn means that the metals become bioavailable (i.e. able to dissociate from the PBT2), and this is supported by data in Figs 2d and 4d that shows PBT2 increases labile Zn within the cell. The increase in bioavailable metal initiates a signaling cascade including inhibitory phosphorylation of GSK3 (Figs 1, 2 and 4). There is a rapidly growing body of literature to support GSK3 inhibition as a valid therapeutic target in AD (Martinez and Perez 2008)."

    As I understand it cognition as an endpoint is not required though and signals we have seen in the HD and the AD trials relating to cognition have not been strong enough likely in part due to the inadequacy of the assessment methods and the powering of the trials.

    Monitoring tau in addition to amyloid reduction would be helpful in proving MOA. I like your comments that to date the the best results we have seen are in the later stages. I wholeheartedly agree with that based on the IMAGINE data, as you know.

  • Reply to

    Tau

    by kadaicher1 Dec 19, 2014 10:13 AM

    ITM, as I understand it GSK modulation is happening continuously through competing modulators. GSK dependent tau phosphorylation is happening all the time as microtubulins are deconstructed and reconstructed. One of the competing compounds for GSK modulation is insulin, zinc is another and there are others. One effect of PBT2 is that it corrects any zinc imbalance(shortage), when free matals are available. When GSK is not under control hyperphosphorylation is possible. PBT2 just restores the normal metal levels used in this natural process. Lindquist hinted that MPACs may have more benefit from how they move metals around inside the cell, rather than metals taken from outside the cell.
    PBT2 can prevent the hell out of tau and Ab formation in the model, but now the technology exists, it would be great to see the results in a clinical trial.
    All the above is just an opinion formed from papers I have seen, so don't hesitate to correct anything you see is wrong.

    Sentiment: Strong Buy

  • Reply to

    Tau

    by kadaicher1 Dec 19, 2014 10:13 AM

    I agree and know they have shown that PBT2 does all that. I sort of wondered about the safety issues around the GSK modulators and feel that there will be a bit of a path there to prove its safe. Certainly that path is well worn by PBT2.

    Prevention of tau is very important I agree as well as amyloid. I think PBT2 has certainly shown that it is capable of that. There was also a more recent paper on communication longitudinally within the hippocampus that was previously unnoticed looking at 2D slices perpendicular to the longitudinal axis. I can send that paper up to the top and I wouldn't mind hearing your thoughts on that one as well.

  • Reply to

    Tau

    by kadaicher1 Dec 19, 2014 10:13 AM

    ITM, Prana long ago demonstrated that by an indirect metal dependent modulation of GSK 3 PBT2 could prevent hyperphosphorylation of the microtubulins that form the tau tangles. They have also demonstrated in the animal model PBT2 can remove the tau tangles from the neurons in the model.
    They have also demonstrated clearance of HTT in the Huntington's model. All are metal dependent processes.
    I personally can't see secretes modulators working. Reason, secretase modulated APP production is a reaction to a sick cell condition. As the cell is dying trophic factor is cut off, APP goes into a secretase modulated hyper expulsion of amyloid from the cell before triggering the death receptor. I don't see good from keeping that cell on life support by shutting down or reducing secretase. Also Tanzi himself with Moir demonstrated amyloid to be a powerful antimicrobial peptide. If the brain is under a pathogen attack and one of its guns is kept at bay by secretase modulation I can see that not ending well. Amyloid bunches around brain injuries.
    The Chinese have done some research on a gerbil AD model and as cells were cleansed, the secretase levels naturally backed off.
    No argument that MACs can get into the metal imbalances and correct the condition before AD starts, but the best results so far have been on the more advanced patients. So it can work at various stages of the disease. Tau is just one of its many functions, and the prevention of tau tangles by modulation of GKK3 is at the very start of the process, and is just one of the arms of the MPAC MOA.
    What I would most like to stress is that the PBT2 MOA is nothing like Gante.

    Sentiment: Strong Buy

  • Zinc and neurodegenerative disease
    Alzheimer’s disease. One of the pathological hallmarks of Alzheimer’s disease is the marked accumulation of amyloid-β (Aβ) protein, in the form of senile plaques and cerebrovascular amyloid deposits180–182. There is considerable evidence that free zinc in the extracellular fluid induces amyloid deposition183,184 (FIGS 4 and 5), and early-phase clinical trials indicate that zinc chelation inhibits Aβ-plaque deposition185,186.
    The Aβ peptide is produced from the proteolytic cleavage of amyloid precursor protein (APP)182. A specific
    and saturable binding site for zinc (KD = 750 nM) has been reported in the cysteine-rich region on the ectodomain of APP187,188. This site has homology to all known members of the APP superfamily and
    the amyloid precursor-like proteins 1 and 2 (APLP1 and APLP2)187, which indicates that zinc interaction
    might have an important, evolutionarily conserved role in APP function and metabolism. Many observations
    indicate a role for zinc in sustaining the adhesiveness of APP during cell–cell and cell–matrix interactions189,190.
    Aβ40 specifically and saturably binds zinc, manifesting higher-affinity binding (KD = 107 nM) with a 1:1 (zinc:Aβ) stoichiometry and lower-affinity binding (KD = 5.2 μM) with a 2:1 stoichiometry.

    Sentiment: Strong Buy

  • Reply to

    Tau

    by kadaicher1 Dec 19, 2014 10:13 AM

    I agree Kad but the removal of tau tangles is not necessarily tied to measureable improvement in cognition yet in humans as far as I know. Tanzi has shown that tau in AD is an even further end pathology than amyloid and whether or not the removal of tau tangles, once the disease has progressed that far, is not necessarily going to improve matters since neuronal death has already occurred. Tanzi talks about the right drug at the right time and while tau tangles formation is certainly a bad thing the focus should be on inhibiting the formation not monitoring their removal necessary so that neuronal death can be avoided in the first place. That's why he's focusing his efforts on gamma-secretase modulators to get at the process before amyloid and before tau tangles. I believe that PBT2 works earlier in the process before amyloid formation and therefore before tau tangles and thats what the 2A showed.

  • Reply to

    Science Matters Here

    by tb00tb00a Oct 9, 2014 10:22 AM

    I view Prana as a sort of inverse roulette wheel, where the odds are tilted slightly in the gambler's favor as opposed to the standard roulette wheel, where the odds are tilted slightly in the house's favor. Prana is a sort of intelligent gamble where the science seems to indicate that there may be something of value here, with the emphasis on "may". But the elephant in the room is clinical results. No matter how compelling the non-clinical research may be, it can't substitute for clinical results. And the clinical results thus far have been few and weak and far between. I'm excited to see the IMAGINE extension results, even though they won't count for much from a clinical standpoint because it's an open-label study. The best possible scenario would be that the extension results cause enough excitement to raise the share price high enough that Prana can use its ATM facility to raise $50 million without excessive dilution, thereby enabling them to finance a new AD clinical trial. Whether such a scenario will pan out is, needless to say, completely unpredictable. But If the extension results push the share price above $3, I'll start selling off my remaining shares.

    Sentiment: Buy

  • This is a very interesting paper I thought maybe some may not have seen. For one it shows some very interesting photos of zinc in the brain and lists concentrations of zinc, copper and iron in AD brains v. healthy.

    THE NEUROBIOLOGY OF ZINC IN HEALTH AND DISEASE
    Christopher J. Frederickson*‡, Jae-Young Koh§ and Ashley I. Bush||¶
    Abstract
    The use of zinc in medicinal skin cream was mentioned in Egyptian papyri from 2000 BC (for example, the Smith Papyrus1), and zinc has apparently been used fairly steadily throughout Roman2 and modern times (for example, as the American lotion named for its zinc ore, ‘Calamine’). It is, therefore, somewhat ironic that zinc is a relatively late addition to the pantheon of signal ions in biology and medicine. However, the number of biological functions, health implications and pharmacological targets that are emerging for zinc indicate that it might turn out to be ‘the calcium of the twenty-first century’.

    Sentiment: Strong Buy

  • Reply to

    Tau

    by kadaicher1 Dec 19, 2014 10:13 AM

    Conclusion
    In summary, we present evidence that human wild type tau phosphorylation can be modulated by copper, and a copper-modulating strategy suitable for human use is effective in an animal model of tau expression. Translation to human subjects is consequently possible, but justification for such a trial depends on the demonstration that this intervention is functionally important for brain neurons, and will require careful monitoring to avoid adverse effects from copper deficiency.

    So, if Tanzi can prove that PBT2 can modulate cooper and in such way to decrease tau phosphorylation level in human brains Big Pharma will be interesting in collaboration with Prana. Measuring of pTau in CSF (CSF-PHFtau) is possible and Prana must include it in next AD trial.
    HD is caused by aggregation of HTT mutant forms that create intranuclear inclusions bodies and cytoplasmic aggregates in neurons. There is a big difference with AD where tau protein is not mutated (if mutated it's not AD but tauopathy). The cure for HD might some selective inhibitors that reduce the aggregation and toxicity of HTT.
    Again Prana scientist must show that PBT2 is an inhibitor of HTT aggregation.

PRAN
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