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pivalde 68 posts  |  Last Activity: Aug 28, 2015 2:55 AM Member since: Feb 15, 2001
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    PBT2 inhibits excitotoxity

    by pivalde Aug 27, 2015 1:55 PM
    pivalde pivalde Aug 28, 2015 2:55 AM Flag

    Clinically this is an old fact: survival and progress in rehabilitation after stroke and brain injury depends much on level of dementia level. This sounds as self clear to anybody but in this excitotoxity is a very important factor. Could we stop it, the results in rehab would be much better.

  • Very important paper, mentioned also in the annual report:

    Neurobiol Dis. 2015 Feb 17. pii: S0969-9961(15)00028-5. doi: 10.1016/j.nbd.2015.02.008. [Epub ahead of print]

    PBT2 inhibits glutamate-induced excitotoxicity in neurons through metal-mediated preconditioning.

    Johanssen T1, Suphantarida N2, Donnelly PS3, Liu XM4, Petrou S2, Hill AF5, Barnham KJ6.

    Abstract

    Excitotoxicity is the pathological process by which neuronal death occurs as a result of excessive stimulation of receptors at the excitatory synapse such as the NMDA receptor (NMDAR). Excitotoxicity has been implicated in the acute neurological damage from ischemia and traumatic brain injury and in the chronic neurodegeneration in Alzheimer's disease (AD) and Huntington's disease (HD). As a result NMDAR antagonists have become an attractive therapeutic strategy for the potential treatment of multiple neurodegenerative diseases. However NMDAR signaling is dichotomous in nature, with excessive increases in neuronal intracellular calcium through excessive NMDAR activity being lethal but moderate increases to intracellular calcium levels during normal synaptic function providing neuroprotection. Subsequently indiscriminant inhibition of this receptor is best avoided as was concluded from previous clinical trials of NMDAR antagonists. We show that the metal chaperone, PBT2, currently in clinical trials for HD, is able to protect against glutamate-induced excitotoxicity mediated through NMDARs. This was achieved by PBT2 inducing Zn2+-dependent increases in intracellular Ca2+ levels resulting in preconditioning of neurons and inhibition of Ca2+-induced neurotoxic signaling cascade involving calpain-activated cleavage of calcineurin. Our study demonstrates that modulating intracellular Ca2+ levels by a zinc ionophore is a valid therapeutic strategy to protect against the effects of excitotoxicity thought to underlie both acute and chronic neurodegenerative diseases.

  • The Relationship between Iron Dyshomeostasis and Amyloidogenesis in Alzheimer's Disease: Two Sides of the Same Coin.

    Peters DG1, Connor JR2,

    The dysregulation of iron metabolism in Alzheimer's disease is not accounted for in the current framework of the amyloid cascade hypothesis. Accumulating evidence suggests that impaired iron homeostasis is an early event in Alzheimer's disease progression. Iron dyshomeostasis leads to a loss of function in several enzymes requiring iron as a cofactor, the formation of toxic oxidative species, and the elevated production of beta-amyloid proteins. Several common genetic polymorphisms that cause increased iron levels and dyshomeostasis have been associated with Alzheimer's disease but the pathoetiology is not well understood. A full picture is necessary to explain how heterogeneous circumstances lead to iron loading and amyloid deposition. There is evidence to support a causative interplay between the concerted loss of iron homeostasis and amyloid plaque formation. We hypothesize that iron misregulation and beta-amyloid plaque pathology are synergistic in the process of neurodegeneration and ultimately cause a downward cascade of events that spiral into the manifestation of Alzheimer's disease. In this review, we amalgamate recent findings of brain iron metabolism in healthy versus Alzheimer's disease brains and consider unique mechanisms of iron transport in different brain cells as well as how disturbances in iron regulation lead to disease etiology and propagate Alzheimer's pathology.

    Copyright © 2015. Published by Elsevier Inc.

  • Now it is obvious that FDA did not make PCH to stop the next Ph2 study, but it's concern was IMO "what if PBT2 will be on sale in pharmacies", could we end up similar problems there was in Japan with clioquinol and which were reproduced later in experimental dog studies when trying to find the reason to SMON.
    SMON is a serious complication of uncontrolled usage of clioquinols. But this problem was solved in Prana years ago, when PBT2 was developed. Now the independent specialist group will give it's report with all the clinical information about PBT2. These facts will support that PBT2 is safe and they still increase safety controls in their future study.
    I would say that there would be no need to do any PCH if Prana would be doing only a new, perhaps longer study with double number of patients than earlier with the same dosage. It must be that an accelerated approval was asked. That was Prana's original plan. Now FDA must get evidence that PBT2 will not cause SMON at the level of planned dosage.
    Prana seems to make their responce very carefully. All it's MPACs are clioquinols ! IMO Prana's application will be approved in few months. Prana is sure that PBT2 does not cause SMON and they need to prove it to FDA. FDA cannot have a SMON epidemy in USA, but neither would Prana like it to happen.

  • pivalde pivalde Aug 26, 2015 3:35 PM Flag

    abakeraaa3, I think you ask about the annual report. IMO they told quite a lot and they are now admitting that the Imagine study was only a pilot study, numbers were too small for anything else. But for planning the next study these results are most likely important. That is why they now use AIBL population as a "control" when looking in what kind of population they perhaps could best demonstrate efficacy and with what kind of tools they perhaps should use. The Imagine study was not a efficacy study to start with but everybody was considering it as such. That is why they told that SUVR goes down with PBT2. And I think it is also important.
    Main effort in Prana seems to be now the next HD sudy and it was great to hear that the problem is most likely the DOG studies demonstrating clioquinol to cause eye problems. This is very comforting news because it should be easy to tell FDA that it is not the problem with PBT2. I think they solved the problem well and after they get their paper dlivered, I would expect the HD study will start.
    I got more than I expected from this report. It seems very evident that they will get ph2 study started for HD and they will also find the way how to study the efficacy of PBT2 in AD. I have waited PBT434 ph 1 studies perhaps too long and in spite 2016 is very close, I was a bit disappointed (again).

  • pivalde pivalde Aug 26, 2015 1:44 PM Flag

    This one SMON dog paper, not the best, however, but it tells the concern of FDA.but what Prana solved years ago :

    Neuropathology. 2000 Sep;20 Suppl:S20-4.

    Subacute myelo-optico-neuropathy: clioquinol intoxication in humans and animals.

    Tateishi J1.

    It remains a tragic event that some 10,000 individuals in Japan developed a unique neurologic disease, subacute myelo-optico-neuropathy (SMON). Many of the affected patients still suffer serious sequelae, such as dysesthesia and muscle weakness in the lower extremities, and loss or deficits in visual acuity. Neuropathologic studies on SMON patients and experimental reproduction of the disease in animals which had been administered clioquinol helped resolve the etiology of this disease. Common pathologic features seen in SMON patients and in dogs and cats chronically intoxicated with clioquinol were distal dominant axonopathy, mainly in the spinal long tracts and optic tracts. Particular abdominal symptoms present in patients after clioquinol ingestion could also be reproduced experimentally in dogs. SMON research in Japan may be worth reviewing for determining the etiology and preventing similar neurotoxic diseases in the future.

  • Here some of them :

    Modification of hippocampal excitability in brain slices pretreated with a low nanomolar concentration of Zn2.

    Takeda A, Shakushi Y, Tamano H.

    J Neurosci Res. 2015 Aug 13. doi: 10.1002/jnr.23629. [Epub ahead of print]

    PMID: 26268632

    Similar articles

    Select item 26204819
    2.

    Influx of extracellular Zn(2+) into the hippocampal CA1 neurons is required for cognitive performance via long-term potentiation.

    Takeda A, Suzuki M, Tempaku M, Ohashi K, Tamano H.

    Neuroscience. 2015 Sep 24;304:209-16. doi: 10.1016/j.neuroscience.2015.07.042. Epub 2015 Jul 21.

    PMID: 26204819

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    Select item 26044210
    3.

    Excess influx of Zn(2+) into dentate granule cells affects object recognition memory via attenuated LTP.

    Suzuki M, Fujise Y, Tsuchiya Y, Tamano H, Takeda A.

    Neurochem Int. 2015 Aug;87:60-5. doi: 10.1016/j.neuint.2015.05.006. Epub 2015 Jun 1.

    PMID: 26044210

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    Select item 25959547
    4.

    Is interaction of amyloid β-peptides with metals involved in cognitive activity?

    Tamano H, Takeda A.

    Metallomics. 2015 Aug 5;7(8):1205-12. doi: 10.1039/c5mt00076a.

    PMID: 25959547

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    Select item 25818846
    5.

    Regulation of extracellular Zn(2+) homeostasis in the hippocampus as a therapeutic target for Alzheimer's disease.

    Takeda A, Tamano H.

    Expert Opin Ther Targets. 2015 Aug;19(8):1051-8. doi: 10.1517/14728222.2015.1029454. Epub 2015 Mar 27.

    PMID: 25818846

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    Select item 25603776
    6.

    Blockade of intracellular Zn(2+) signaling in the dentate gyrus erases recognition memory via impairment of maintained LTP.

    Tamano H, Minamino T, Fujii H, Takada S, Nakamura M, Ando M, Takeda A.

    Hippocampus. 2015 Aug;25(8):952-62. doi: 10.1002/hipo.22418. Epub 2015 Feb 11.

  • Worth reading this 2 months old free paper again and look at the other papers the authors recommend.

    Front Aging Neurosci. 2015; 7: 116.

    Published online 2015 Jun 17. doi: 10.3389/fnagi.2015.00116

    Editorial: The molecular pathology of cognitive decline: focus on metals

  • pivalde pivalde Aug 25, 2015 11:28 AM Flag

    market_mania
    So these are comming and there is nothing yet on the web page. How do you know that these are comming? Could you explain a bit more, please.

  • Mol Neurobiol. 2015 Aug 23. [Epub ahead of print]

    Multiple Effect of APOE Genotype on Clinical and Neuroimaging Biomarkers Across Alzheimer's Disease Spectrum.

    Liu Y1, Tan L, Wang HF, Liu Y, Hao XK, Tan CC, Jiang T, Liu B, Zhang DQ, Yu JT; Alzheimer’s Disease Neuroimaging Initiative.

    The apolipoprotein E ε4 (APOE ε4) allele is the most important genetic risk factor for Alzheimer's disease (AD); however, the underlying mechanisms responsible for it remain controversial. We used the Alzheimer's Disease Neuroimaging Initiative (ADNI) database to examine the influence of APOE ε4 dose on clinical and neuroimaging biomarkers across the AD spectrum (from cognitive normal to AD patients with severe cognitive impairment). A total of 1718 participants from the ADNI cohort were selected, and we evaluated the impact of ε4 dose on cerebrospinal fluid (CSF) levels' Abeta1-42 (Aβ1-42), tau, and phosphorylated-tau (p-tau); cortical amyloid deposition (Florbetapir-PET-AV45); brain atrophy (MRI); brain metabolism (FDG-PET); hippocampal metabolism; and cognitive declines, through different cognitive subgroups. We found that (1) ε4 was associated with decreased CSF beta-amyloid (Aβ1-42) and increased cerebral Aβ deposition across the AD spectrum; (2) increased CSF tau, P-tau and cerebral hypometabolism, hippocampal atrophy, and cognition decline were all associated with APOE ε4 in prodromal AD stage; (3) increased CSF tau, P-tau and cerebral hypometabolism appear to begin earlier than hippocampal atrophy and cognitive decline. We hypothesized that APOE ε4 increases cerebral amyloid-β (Aβ) deposition in all the stages of AD development, and also influences Aβ-initiated cascade of downstream neurodegenerative effects, thereby increasing the risk of AD.

  • Mol Neurobiol. 2015 Aug 23. [Epub ahead of print]

    Multiple Effect of APOE Genotype on Clinical and Neuroimaging Biomarkers Across Alzheimer's Disease Spectrum.

    Liu Y1, Tan L, Wang HF, Liu Y, Hao XK, Tan CC, Jiang T, Liu B, Zhang DQ, Yu JT; Alzheimer’s Disease Neuroimaging Initiative.

    The apolipoprotein E ε4 (APOE ε4) allele is the most important genetic risk factor for Alzheimer's disease (AD); however, the underlying mechanisms responsible for it remain controversial. We used the Alzheimer's Disease Neuroimaging Initiative (ADNI) database to examine the influence of APOE ε4 dose on clinical and neuroimaging biomarkers across the AD spectrum (from cognitive normal to AD patients with severe cognitive impairment). A total of 1718 participants from the ADNI cohort were selected, and we evaluated the impact of ε4 dose on cerebrospinal fluid (CSF) levels' Abeta1-42 (Aβ1-42), tau, and phosphorylated-tau (p-tau); cortical amyloid deposition (Florbetapir-PET-AV45); brain atrophy (MRI); brain metabolism (FDG-PET); hippocampal metabolism; and cognitive declines, through different cognitive subgroups. We found that (1) ε4 was associated with decreased CSF beta-amyloid (Aβ1-42) and increased cerebral Aβ deposition across the AD spectrum; (2) increased CSF tau, P-tau and cerebral hypometabolism, hippocampal atrophy, and cognition decline were all associated with APOE ε4 in prodromal AD stage; (3) increased CSF tau, P-tau and cerebral hypometabolism appear to begin earlier than hippocampal atrophy and cognitive decline. We hypothesized that APOE ε4 increases cerebral amyloid-β (Aβ) deposition in all the stages of AD development, and also influences Aβ-initiated cascade of downstream neurodegenerative effects, thereby increasing the risk of AD.

  • pivalde pivalde Aug 24, 2015 2:05 PM Flag

    biotech....
    This is a result of Japanese- Canadian co-operation published in a very new online publication. This kind of a new paper can never have any high impact factor. I suggest you to write them and give them critics. I think they would like it because only then they will find that somebody is reading the paper. As you can see they have done a lot of work in a very difficult topics. I am sure they would be very happy to get your advice how to get published in more respected papers and even in improving their methods etc. .
    It may be BS, at least in your opinion, but I think you have seen some of it already earlier on this MB, not usually posted by those understanding at least some science but by those who have no understanding of it and report their ignorance here at least once in an hour.

  • pivalde pivalde Aug 24, 2015 2:23 AM Flag

    Thanks Kadaicher. Yes, PBT2 works both on the neurofibrillary tangeles and oligomers.

  • pivalde pivalde Aug 24, 2015 1:41 AM Flag

    Li X et al published the article below on 11th of Aug 2015 and IMO nothing is simple, however.

    Abstract

    The amyloid cascade hypothesis of Alzheimer's disease (AD) positions tau protein as a downstream mediator of β-amyloid (Aβ) toxicity This is largely based on genetic cross breeding, which showed that tau ablation in young (3-7-month-old) transgenic mice overexpressing mutant amyloid precursor protein (APP) abolished the phenotype of the APP AD model. This evidence is complicated by the uncertain impact of overexpressing mutant APP, rather than Aβ alone, and for potential interactions between tau and overexpressed APP. Cortical iron elevation is also implicated in AD, and tau promotes iron export by trafficking APP to the neuronal surface. Here, we utilized an alternative model of Aβ toxicity by directly injecting Aβ oligomers into the hippocampus of young and old wild-type and tau knockout mice. We found that ablation of tau protected against Aβ-induced cognitive impairment, hippocampal neuron loss, and iron accumulation. Despite injected human Aβ being eliminated after 5 weeks, enduring changes, including increased APP levels, tau reduction, tau phosphorylation, and iron accumulation, were observed. While the results from our study support the amyloid cascade hypothesis, they also suggest that downstream effectors of Aβ, which propagate toxicity after Aβ has been cleared, may be tractable therapeutic targets.

  • pivalde pivalde Aug 23, 2015 9:01 AM Flag

    Ryan et al reported in Feb 2015 how clioquinols neuralizes neurotoxic oligomers:

    The extracellular accumulation of amyloid β (Aβ) peptides is characteristic of Alzheimer's disease (AD). However, formation of diffusible, oligomeric forms of Aβ, both on and off pathways to amyloid fibrils, is thought to include neurotoxic species responsible for synaptic loss and neurodegeneration, rather than polymeric amyloid aggregates. The 8-hydroxyquinolines (8-HQ) clioquinol (CQ) and PBT2 were developed for their ability to inhibit metal-mediated generation of reactive oxygen species from Aβ:Cu complexes and have both undergone preclinical and Phase II clinical development for the treatment of AD. Their respective modes of action are not fully understood and may include both inhibition of Aβ fibrillar polymerization and direct depolymerization of existing Aβ fibrils. In the present study, we find that CQ and PBT2 can interact directly with Aβ and affect its propensity to aggregate. Using a combination of biophysical techniques, we demonstrate that, in the presence of these 8-HQs and in the absence of metal ions, Aβ associates with two 8-HQ molecules and forms a dimer. Furthermore, 8-HQ bind Aβ with an affinity of 1-10 μm and suppress the formation of large ( 30 kDa) oligomers. The stabilized low molecular weight species are nontoxic. Treatment with 8-HQs also reduces the levels of in vivo soluble oligomers in a Caenorhabditis elegans model of Aβ toxicity. We propose that 8-HQs possess an additional mechanism of action that neutralizes neurotoxic Aβ oligomer formation through stabilization of small (dimeric) nontoxic Aβ conformers.

  • Acta Neuropathol Commun. 2015 Aug 21;3(1):51. doi: 10.1186/s40478-015-0230-2.

    Intracellular amyloid β oligomers impair organelle transport and induce dendritic spine loss in primary neurons.

    Umeda T1,2, Ramser EM3, Yamashita M1, Nakajima K4, Mori H2,5, Silverman MA6, Tomiyama T7,8.

    INTRODUCTION:

    Synaptic dysfunction and intracellular transport defects are early events in Alzheimer's disease (AD). Extracellular amyloid β (Aβ) oligomers cause spine alterations and impede the transport of proteins and organelles such as brain-derived neurotrophic factor (BDNF) and mitochondria that are required for synaptic function. Meanwhile, intraneuronal accumulation of Aβ precedes its extracellular deposition and is also associated with synaptic dysfunction in AD. However, the links between intracellular Aβ, spine alteration, and mechanisms that support synaptic maintenance such as organelle trafficking are poorly understood.

    RESULTS:

    We compared the effects of wild-type and Osaka (E693Δ)-mutant amyloid precursor proteins: the former secretes Aβ into extracellular space and the latter accumulates Aβ oligomers within cells. First we investigated the effects of intracellular Aβ oligomers on dendritic spines in primary neurons and their tau-dependency using tau knockout neurons. We found that intracellular Aβ oligomers caused a reduction in mushroom, or mature spines, independently of tau. We also found that intracellular Aβ oligomers significantly impaired the intracellular transport of BDNF, mitochondria, and recycling endosomes: cargoes essential for synaptic maintenance. A reduction in BDNF transport by intracellular Aβ oligomers was also observed in tau knockout neurons.

    CONCLUSIONS:

    Our findings indicate that intracellular Aβ oligomers likely contribute to early synaptic pathology in AD and argue against the consensus that Aβ-induced spine loss and transport defects require tau.

  • pivalde by pivalde Aug 23, 2015 8:02 AM Flag

    J Neurol Neurosurg Psychiatry. 2015 Aug 20. pii: jnnp-2015-310548. doi: 10.1136/jnnp-2015-310548. [Epub ahead of print]

    Meta-analysis of modifiable risk factors for Alzheimer's disease.

    Xu W1, Tan L2, Wang HF3, Jiang T3, Tan MS1, Tan L4, Zhao QF1, Li JQ1, Wang J1, Yu JT5.

    Abstract

    BACKGROUND:

    The aetiology of Alzheimer's disease (AD) is believed to involve environmental exposure and genetic susceptibility. The aim of our present systematic review and meta-analysis was to roundly evaluate the association between AD and its modifiable risk factors.

    METHODS:

    We systematically searched PubMed and the Cochrane Database of Systematic Reviews from inception to July 2014, and the references of retrieved relevant articles. We included prospective cohort studies and retrospective case-control studies.

    RESULTS:

    16 906 articles were identified of which 323 with 93 factors met the inclusion criteria for meta-analysis. Among factors with relatively strong evidence (pooled population 5000) in our meta-analysis, we found grade I evidence for 4 medical exposures (oestrogen, statin, antihypertensive medications and non-steroidal anti-inflammatory drugs therapy) as well as 4 dietary exposures (folate, vitamin E/C and coffee) as protective factors of AD. We found grade I evidence showing that one biochemical exposure (hyperhomocysteine) and one psychological condition (depression) significantly increase risk of developing AD. We also found grade I evidence indicative of complex roles of pre-existing disease (frailty, carotid atherosclerosis, hypertension, low diastolic blood pressure, type 2 diabetes mellitus (Asian population) increasing risk whereas history of arthritis, heart disease, metabolic syndrome and cancer decreasing risk) and lifestyle (low education, high body mass index (BMI) in mid-life and low BMI increasing the risk whereas cognitive activity, current smoking (Western population), light-to-moderate drinking, stress, high

  • While waiting PBT434 studies, it good to read this, hope it is not posted earlier.

    Metallomics. 2015 Jul 8;7(7):1091-102. doi: 10.1039/c4mt00345d.

    Reactivity of copper-α-synuclein peptide complexes relevant to Parkinson's disease.

    Dell'Acqua S1, Pirota V, Anzani C, Rocco MM, Nicolis S, Valensin D, Monzani E, Casella L.

    Parkinson's disease (PD) is a neurodegenerative disorder characterized by the presence of abnormal α-synuclein (αSyn) deposits in the brain. Alterations in metal homeostasis and metal-induced oxidative stress may play a crucial role in the aggregation of αSyn and, consequently, in the pathogenesis of PD. We have therefore investigated the capability of copper-αSyn6 and copper-αSyn15 peptide complexes, with the 1-6 and 1-15 terminal fragments of the protein, to promote redox reactions that can be harmful to other cellular components. The pseudo-tyrosinase activity of copper-αSyn complexes against catecholic (di-tert-butylcatechol (DTBCH2), 4-methylcatechol (4-MC)) and phenolic (phenol) substrates is lower compared to that of free copper(ii). In particular, the rates (kcat) of DTBCH2 catalytic oxidation are 0.030 s(-1) and 0.009 s(-1) for the reaction promoted by free copper(ii) and [Cu(2+)-αSyn15], respectively. On the other hand, HPLC/ESI-MS analysis of solutions of αSyn15 incubated with copper(ii) and 4-MC showed that αSyn is competitively oxidized with remarkable formation of sulfoxide at Met1 and Met5 residues. Moreover, the sulfoxidation of methionine residues, which is related to the aggregation of αSyn, also occurs on peptides not directly bound to copper, indicating that external αSyn can also be oxidized by copper. Therefore, this study strengthens the hypothesis that copper plays an important role in oxidative damage of αSyn which is proposed to be strongly related to the etiology of PD.

  • This paper is already one month old and may be it was discussed here. It is a free paper and worth reading it again. Go and find it in pubmed.

    Editorial: Metals and neurodegeneration: restoring the balance

    Anthony R. White,1,* Katja M. Kanninen,2 and Peter J. Crouch1

PRAN
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