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Alzheimer’s in Cell Culture?

While we’re talking about cell culture, there’s some potentially significant news in Alzheimer’s. The Tanzi lab at Mass General is reporting in Nature that they’ve been able to grow 3D neuronal cultures that actually reproduce the plaque-and-tangle symptoms of Alzheimer’s. That’s quite a surprise – neurons are notoriously badly behaved in vitro, and Alzheimer’s has been a beast to model in any system at all. You can’t even get neurons from human Alzheimer’s patients to behave like that when you culture them (at least, I’ve never heard of it being done).
These new cultures apparently respond to secretase inhibitors, which on one level is good news – since you’d expect those compounds to have an effect on them. On the other hand, such compounds have been quite ineffective in human trials, so there’s a disconnect here. Is there more to Alzheimer’s that these cell cultures don’t pick up, or are the compounds much less better-behaved in vivo (or both)?
This new system, if validated, would seem to open up a whole new avenue for phenotypic screening, which until now has been a lost cause where Alzheimer’s is concerned. It’s going to be quite interesting to see how this develops, and to see what it can teach us about the real disease. Nothing in this area has come easy, and a break would be welcome. The tricky part will be whether compounds that come out of such a screen will be telling us something about Alzheimer’s, or just telling us something about the model. That’s always the tricky part.
Update: FierceBiotech notes that Tanzi’s “previous insights about Alzheimer’s have run into some serious setbacks.”

29 comments on “Alzheimer’s in Cell Culture?”

  1. Anonzy says:

    Interesting work, although it’s worth remembering that Tanzi was the one who said in 2000 that we should be able to lick AD in about ten years.

  2. Wavefunction says:

    “We have successfully recapitulated amyloid-β and tau pathology in a single 3D human neural cell culture system.”
    Definitely interesting (and quite a technical achievement), but does that mean we still believe that amyloid beta and tau are the main causative culprits?

  3. Anonymous says:

    And what about peroxyzzzzzzzzzzzzz

  4. Lane Simonian says:

    Yes and what about peroxyzzzzzzzzzzzzz? I am so glad that you asked.
    Here is why gamma secretase inhibitors not only failed to work in Alzheimer’s disease but make things worse.
    J Neurochem. 2004 Aug;90(4):800-6.
    Presenilin-directed inhibitors of gamma-secretase trigger caspase 3 activation in presenilin-expressing and presenilin-deficient cells.
    Alves da Costa C1, Ayral E, Hernandez JF, St George-Hyslop P, Checler F.
    The amyloid beta peptide (Abeta) is generated by subsequent cleavages by beta- and gamma-secretases. Therefore, these two enzymes are putative therapeutic targets to prevent Abeta production, and hopefully to slow down or even stop the Alzheimer’s disease (AD) neurodegenerative process. Several studies have revealed that gamma-secretase hydrolyses other important substrates besides beta-amyloid precursor protein (betaAPP) thus adding another level of complexity to designing fully AD-specific interfering drugs. Here we demonstrate that three distinct presenilin-directed gamma-secretase inhibitors as well as JLK compounds indirectly potentiate caspase 3 activity, the effector caspase of the apoptotic cascade. Thus, inhibitors were shown to drastically stimulate caspase 3 activity in wild-type mice blastocyst-derived and fibroblast cells. Interestingly, some of these inhibitors known to interact with presenilins also trigger caspase activation in presenilin-deficient cells. However, inhibitors do not affect recombinant caspase 3 activity, indicating that the effect on this enzyme was indirect. Furthermore, we established that caspase 3 activation was not due to an effect of gamma-secretase inhibitors on calpains, a family of proteolytic enzymes able to modulate caspase 3 activity. Altogether, our data demonstrate that presenilin-directed gamma-secretase inhibitors affect caspase 3 activity in a presenilin-independent manner. Therefore, as presenilin-dependent gamma-secretase activity is not specific for betaAPP and because its inhibitors clearly affect other vital cell functions, care should be taken in considering ‘gamma-secretase’ inhibitors as putative therapeutic tools to interfere with AD pathology.
    Gamma secretase inhibitors result in higher levels of the c-terminal fragment of the amyloid precursor protein which via g proteins increase the production of peroxynitrites which increases the activation of caspases which increases the activation of the beta secretase.
    J Neurochem. 2001 Jul;78(1):109-20.
    C-terminal fragment of amyloid precursor protein induces astrocytosis.
    Bach JH1, Chae HS, Rah JC, Lee MW, Park CH, Choi SH, Choi JK, Lee SH, Kim YS, Kim KY, Lee WB, Suh YH, Kim SS
    Furthermore, conditioned media derived from CT105-treated astrocytes enhanced neurotoxicity and pretreatment with NO and peroxynitrite scavengers attenuated its toxicity. These suggest that CT-APP may participate in Alzheimer’s pathogenesis through MAPKs- and NF-kappaB-dependent astrocytosis and iNOS induction.
    If you inhibit beta secretase inhibitors by inhibiting caspases or peroxynitrite formation, you have a shot at effectively treating Alzheimer’s disease. There are rumors that Merck’s beta secretase inhibitor is a curcumin analog which would do this. Otherwise, beta secretase inhibitors would only slow down the early progression of Alzheimer’s disease.

  5. Lane Simonian says:

    To continue with the progression of Alzheimer’s disease. The overactivation of tyrosine receptor kinases and/or g protein-coupled receptors (often coupled with high levels of myo-inositol or the inhibition of the phosphatidylinostiol 3-kinase)is what leads to the formation of peroxynitrites, amyloid, and hyperphosphorylated tau. The peroxynitrite-mediated nitration of cytochrome c adds to the release of intracellular calcium and the calpain activation of the gamma secretase. This leads to the formation of amyloid oligomers. Peroxynitrite dependent and independent nitration of amyloid oligomers leads to the formation of amyloid plaques.
    The formation of amyloid is an adaptive response. The c-terminal fragment which increases the formation of peroxynitrites is more toxic than amyloid oligomers (which increases the formation of hydrogen peroxide) is more toxic that amyloid plaques (which reduces the formation of hydrogen peroxide and has no effect on peroxynitrites). If amyloid oligomers are the appropriate target in Alzheimer’s disease why does the disease continue to progress once most of oligomers have been converted into plaques? And why do some people have oligomers and plaques in their brain and not have Alzheimer’s disease?
    The key to neuronal cell death in Alzheimer’s disease is via peroxynitrites, caspases, and PARP. This cell death can be inhibited as follows.
    J Neurosci. 1998 Jan 15;18(2):687-97.
    Mitochondrial manganese superoxide dismutase prevents neural apoptosis and reduces ischemic brain injury: suppression of peroxynitrite production, lipid peroxidation, and mitochondrial dysfunction.
    Keller JN1, Kindy MS, Holtsberg FW, St Clair DK, Yen HC, Germeyer A, Steiner SM, Bruce-Keller AJ, Hutchins JB, Mattson MP.
    Author information
    Oxidative stress is implicated in neuronal apoptosis that occurs in physiological settings and in neurodegenerative disorders. Superoxide anion radical, produced during mitochondrial respiration, is involved in the generation of several potentially damaging reactive oxygen species including peroxynitrite. To examine directly the role of superoxide and peroxynitrite in neuronal apoptosis, we generated neural cell lines and transgenic mice that overexpress human mitochondrial manganese superoxide dismutase (MnSOD). In cultured pheochromocytoma PC6 cells, overexpression of mitochondria-localized MnSOD prevented apoptosis induced by Fe2+, amyloid beta-peptide (Abeta), and nitric oxide-generating agents. Accumulations of peroxynitrite, nitrated proteins, and the membrane lipid peroxidation product 4-hydroxynonenal (HNE) after exposure to the apoptotic insults were markedly attenuated in cells expressing MnSOD. Glutathione peroxidase activity levels were increased in cells overexpressing MnSOD, suggesting a compensatory response to increased H2O2 levels. The peroxynitrite scavenger uric acid and the antioxidants propyl gallate and glutathione prevented apoptosis induced by each apoptotic insult, suggesting central roles for peroxynitrite and membrane lipid peroxidation in oxidative stress-induced apoptosis. Apoptotic insults decreased mitochondrial transmembrane potential and energy charge in control cells but not in cells overexpressing MnSOD, and cyclosporin A and caspase inhibitors protected cells against apoptosis, demonstrating roles for mitochondrial alterations and caspase activation in the apoptotic process. Membrane lipid peroxidation, protein nitration, and neuronal death after focal cerebral ischemia were significantly reduced in transgenic mice overexpressing human MnSOD. The data suggest that mitochondrial superoxide accumulation and consequent peroxynitrite production and mitochondrial dysfunction play pivotal roles in neuronal apoptosis induced by diverse insults in cell culture and in vivo.
    And in regards to tau hyperphosphorylation:
    FASEB J. 2006 Jul;20(9):1431-42.
    Peroxynitrite induces Alzheimer-like tau modifications and accumulation in rat brain and its underlying mechanisms.
    Zhang YJ1, Xu YF, Liu YH, Yin J, Li HL, Wang Q, Wang JZ.
    To investigate the upstream effector that led to tau hyperphosphorylation, nitration, and accumulation as seen in Alzheimer’s disease brain, and the underlying mechanisms, we bilaterally injected SIN-1, a recognized peroxynitrite donor, into the hippocampus of rat brain. We observed that the level of nitrated and hyperphosphorylated tau was markedly increased in rat hippocampus 24 h after drug administration, and these alterations were prevented by preinjection of uric acid, a natural scavenger of peroxynitrite. Concomitantly, we detected a significant activation in glycogen synthase kinase-3beta (GSK-3beta) and p38 MAPKs, including p38alpha, p38beta, and p38delta, but no obvious change was measured in the activity of p38gamma, ERK, and c-Jun amino-terminal kinase (JNK). Both nitrated tau and hyperphosphorylated tau were aggregated in the hippocampus, in which the activity of 20S proteasome was significantly arrested in SIN-1-injected rats. Further studies demonstrated that the hyperphosphorylated tau was degraded as efficiently as normal tau by 20S proteasome, but the nitrated tau with an unorderly secondary structure became more resistant to the proteolysis. These results provide the first in vivo evidence showing that peroxynitrite simultaneously induces tau hyperphosphorylation, nitration, and accumulation, and that activation of GSK-3beta, p38alpha, p38beta, p38delta isoforms and the inhibition of proteasome activity are respectively responsible for the peroxynitrite-induced tau hyperphosphorylation and accumulation. Our findings reveal a common upstream stimulator and a potential therapeutic target for Alzheimer-like neurodegeneration.
    Tanzi and many others have been stuck on the amyloid/tau hypotheses for Alzheimer’s disease for more than a decade (although Tanzi had added the transition metal wrinkle). But the real cause of Alzheimer’s disease is peroxynitrite. All the symptoms of Alzheimer’s disease can be tied directly or indirectly to peroxynitrites, all the risk factors for Alzheimer’s disease can be tied to peroxynitrites, all the successful human clinical trials on Alzheimer’s disease have involved peroxynitrite scavengers. The only question remaining is whether the most powerful peroxynitrite scavengers can do any more than partially reverse the disease.

  6. Lane Simonian says:

    Methoxyphenols (eugenol, vanillic acid, syringic acid, sinapic acid, curcumin, etc.) are the best peroxynitrite scavengers because the methoxy group donates electrons and increases the hydrogen donating capacity of the phenol group or groups.
    ONOO- + 2H+ + 2e-= H20 + NO2-.
    Water is a de-nitrating agent and de-nitration of tyrosine helps improve cognitive function.
    Tyrosine-NO2 + H20= Tyrosine-H + H+ + N03-.
    Nitrite is potentially a problem because it combines with hydrogen peroxide to reform peroxynitrites:
    H202 + NO2-= ONOO- + H20 or in the presence of transition metals can form NO2. Partly for this reason a peroxynitrite scavenging strategy cannot be suspended or a person will revert rather quickly.
    More importantly, it is time to start assaying thousands of plants to determine their peroxynitrite scavenging capacities and at what concentrations they may be safe and effective. Here is one example of a little known plant that may help treat Alzheimer’s disease.
    Zhongguo Zhong Yao Za Zhi. 2010 May;35(10):1261-71.
    [Chemical constituents of stems and branches of Adina polycephala].
    [Article in Chinese]
    Zhang Y1, Gan M, Li S, Wang S, Zhu C, Yang Y, Hu J, Chen N, Shi J.
    To investigate chemical constituents of the stems and branches of Adina polycephala and their pharmacological activities.
    The constituents were isolated by a combination of various chromatographic techniques including column chromatography on silica gel, Sephadex LH-20, and C-18, as well as reversed-phase HPLC. Structures of the isolates were identified by spectroscopic data analysis. In vitro cytotoxic, anti-inflammatory, anti-oxidant, anti-HIV, neuroprotective and anti-diabetic activities were screened by using cell-based models.
    Twenty-eight constituents were isolated. Their structures were identified as clemochinenoside B (1), kelampayoside A (2), osmanthuside H (3), 4-hydroxy-3-methoxyphenol-beta-D-[6-O-(4-hydroxy-3,5-dimethoxylbenzoate)]-glucopyranoside (4), and syringic acid beta-D-glucopyranosyl ester (5). Ten iridoidal glycosides: geniposidic acid (6), geniposide (7), 6beta-hydroxygeniposide (8), 6beta-hydroxygeniposide (9), ixoside (10), ixoside 11-methyl ester (11), 11-methyl forsythide (12), 7beta-hydroxysplendoside (13), gardoside (14) and mussaenosidic acid (15), (+) -pinoresinol (16), (+) -medioresinol (17), (+) -syringaresinol (18), (-)-lariciresinol (19), evofolin-B (20), alpha-hydroxyacetovaillone (21), syringic acid (22), vanillin (23), 3, 4, 5-trimethoxyphenol (24), and 2,6-dimethoxy-1, 4-benzoquinone (25), beta-sitosterol (26), mannitol (27), and daucosterol (28). At a concentration of 1.0 x 10(-5) mol x L(-1), these compounds were inactive in the assays, including cytotoxicity against human tumor cell lines (HCT-8, Bel-7402, BGC-823, A549 and A2780), anti-inflammatory activity against the release of beta-glucuronidase in rat polymorphonuclear leukocytes (PMNs) induced by platelet-activating factor (PAF), antioxidant activity in Fe(2+)-cystine-induced rat liver microsomal lipid peroxidation, anti-HIV activity against HIV-1 replication, neuroprotective activity against serum deprivation or glutamate induced neurotoxicity in cultures of PC12 cells, and the inhibitory activity against protein tyrosine phosphatase 1B (PTP1B).
    Compounds 1-20 were obtained from the genus Adina for the first time. The 13C-NMR data of compounds 10 and 11 were reassigned. A further evaluation of pharmacological activity of these compounds is expected.
    We are not far away from developing more effective treatments for Alzheimer’s disease.

  7. Anonymous says:


  8. Anchor says:

    @ 3-You had it coming! The Simonian wrath. Please don’t wake up the giant, hereafter!

  9. Barry says:

    Usually, the chronology is different. First there’s a cell-based model, then there’s a small molecule effort, then we learn that the drug candidates that worked in the model aren’t (or are) efficacious in vivo.
    In this case it’s given to us. Secretase inhibitors that are known to be inefficacious in the clinic light up this model. So why would we trust it?

  10. Anonymous says:

    @9: Just to make sure we destroy even more value, as Pharma R&D isn’t destroying enough already.

  11. biomicro says:

    I don’t have access to Nature at the moment. Does anyone know if they’ve tried any of the drugs that have gone through clinical trials?
    Also, I know that none of the trials have been successful, but have any of them actually decreased plaque formation? It could be that this model system will provide the definitive proof that the obvious irregularities such as plaque deposition and tangle formation aren’t causatively related to symptoms.
    Certainly Tanzi is, shall we say, optimistic. He says “we can test hundreds of thousands of drugs in a matter of months.” I think for that to be true you would have to have a large, purpose-built factory, given the time and labor involved with culturing a slow-growing cell type, and assays such as microscopy.

  12. Proteus says:

    So they have validated a system based their hypothesis to test their hypothesis. What could go wrogn?

  13. molecular architect says:

    I agree with other commenters about the validity of the model. It can only be proven valid by testing known compounds which have shown some efficacy through the beta-amyloid mechanism in the clinic. But are there any? Otherwise using the model to find new clinical candidates may become a giant money (and time) wasting exercise.

  14. steve says:

    Pretty rampant cynicism. I’m not in the Alzheimer’s field though I know that there have been many false leads and lots of wasted money. But it seems to me to be a huge advance if you can reproduce the pathology in a dish. The paper shows that you can get plaques and tangles from just beta amyloid and that if you block beta amyloid with β- or γ-secretase inhibitors you get rid of the tangles as well. Seems to me to be a rather major advance confirming amyloid as the central causative agent. Whether that’s the whole story remains to be seen but it’s still a major advance.

  15. Anonymous says:

    “Seems to me to be a rather major advance confirming amyloid as the central causative agent.”
    Causative agent? I don’t think I’d draw that conclusion yet. Could just be one of many down stream effects.
    It’s still a tangled mess (see what I did there?).

  16. John Wayne says:

    I’m of the opinion that nobody has performed a good experiment in the clinic, so the jury on gamma secretase is still out. We are almost certainly bucketing patients with dementia based on phenotypes that are not related by biochemical cause. The secretases have strong genomic signatures in a few unfortunate families, and are important in some way. We don’t know if those mutations are sufficient for the disease for everybody. Gamma secretase inhibitors should at least help families with profound early onset Alzheimer’s disease; if they don’t, that would be something to know.
    My guess is that the first useful therapeutic will be discovered to work in a subset of patients with dementia, then we will retroactively learn a mechanism of action and importance of the disease.

  17. Hap says:

    I don’t know, but I wouldn’t think that the observed behavior would confirm the role of amyloid in Alzheimer’s. You don’t know if the damage seen is because of the amyloid deposits themselves, a smaller fragment of amyloid (correlated perhaps with amyloid deposition but not necessarily), or caused by something that also creates the amyloid (in which case removing the amyloid shouldn’t have much effect). In addition, if you have agents that are supposed to remove amyloid but don’t have clinical effect, you are getting something in that you know that the compounds clear amyloid, but you aren’t getting evidence that amyloid is causative – if you can show you’re removing amyloid with a compound, and the compound doesn’t work against Alzheimer’s pathology in vivo, then it seems that either amyloid isn’t causing the pathology or the damage is irreversible after amyloid deposition (in which case you have to administer agents before the start of deposition to have clinical effects). You know a little more than you did, but not much.

  18. Peter says:

    I thought this TED Talk discussed an interesting theory about Alzheimer’s disease.

  19. bank says:

    I would have to concur with steve.
    The paper makes some remarkable claims for the field. They claim to show that by over-expressing mutated forms of APP and presenilin in their system they manage to reproduce a range of Alzheimer-specific biochemical features related to both amyloid and tau, and further that they can reverse this effect using either inhibitors of BACE, g-secretase or GSK3. This would be the first time, to my current knowledge, that reversal of tauopathy using BACE or g-secretase inhibitors has been shown.
    The reason such a reversal has not previously been shown is that expressing mutated APP or presenilin in mice does not cause tauopathy unless human tau is also over-expressed. Also, clinical trials targeting g-secretase have failed to modify disease.
    So… does their 3D system truly replicate AD pathology. Fingers crossed. However, I would say that some of their claims rest on a generous interpretation of the underlying data, for example supplementary figure 6, which shows their FACS sorting of transfected cells, they have used only the top 1-2% of transfected cells in their subsequent studies.

  20. Anonymous says:

    Alzheimer’ disease is a death of neurons, right? In the model, do neurons die faster than controls ? If they indeed do, does gamma or better secretase inhibitors help ? Could not find anything in the paper. Does it mean amyloid deposition and tau tangles do not cause Alzheimer ?

  21. Harrison says:

    @Proteus: Ding, Ding, Ding! We have a winner! Tanzi is so deep into the amyloid hypothesis, it’s almost impossible to disconnect anything he does from it. This work is just self-fulfilling prophecy.

  22. steve says:

    #19, thanks. It seems to me that there are a great many comments from people who have not actually read the paper.

  23. bank says:

    Reading the paper helps!
    I would address another implication of the work. Since this is the first instance demonstrating that modifying Abeta generation also modifies tau pathology, and specifically neurofibrillary tangles, the question arises as to what is specifically unique about this model.
    To me, it seems as if the 3D aspect of their system is not a sufficient explanation, since numerous animal models do not replicate the pathology of AD as well as they claim their system does.
    So could it instead be that the use of human (induced) neurons is key? That seems possible, and subject to confirmation their system would would be a route to identifying the human-specific cell and molecular interactions necessary to produce the full range of AD phenotypes.
    Personally, however, I think that there are too many imponderables in the presented work for one to state that it represents an accurate model of AD.

  24. Lane Simonian says:

    This is probably the best explanation for the death of neurons in Alzheimer’s disease.
    The mechanisms of peroxynitrite-induced apoptosis are not fully understood. We report here that peroxynitrite-induced apoptosis of PC12 cells requires the simultaneous activation of p38 and JNK MAP kinase, which in turn activates the intrinsic apoptotic pathway, as evidenced by Bax translocation to the mitochondria, cytochrome c release to the cytoplasm and activation of caspases, leading to cell death. Peroxynitrite induces inactivation of the Akt pathway. Furthermore, overexpression of constitutively active Akt inhibits both peroxynitrite-induced Bax translocation and cell death. Peroxynitrite-induced death was prevented by overexpression of Bcl-2 and by cyclosporin A, implicating the involvement of the intrinsic apoptotic pathway. Selective inhibition of mixed lineage kinase (MLK), p38 or JNK does not attenuate the decrease in Akt phosphorylation showing that inactivation of the Akt pathway occurs independently of the MLK/MAPK pathway. Together, these results reveal that peroxynitrite-induced activation of the intrinsic apoptotic pathway involves interactions with the MLK/MAPK and Akt signaling pathways.
    This pathway is also cut off by presenilin gene mutations.
    The Akt pathway leads to an increased blood flow in the brain, the regeneration of neurons in the hippocampus, and the inactivation of GSK-3 (which partially protects against the hyperphosphorylation of tau proteins).
    Peroxynitrites activate the beta secretase (via caspases), contribute to the activation of the gamma secretase (via cytochrome c activation of inositol 1,4,5 receptors and the subsequent release of calcium), and contribute to the formation of amyloid plaques (via nitration). Under conditions of moderate oxidative stress or high oxidative stress with peroxynitrite scavengers you can have amyloid oligomers with relatively little damage to the brain (the classical study was with children in Mexico City exposed to high levels of pollution; many had plaques and tangles in their brain with subtle cognitive deficits; which was partially corrected after being fed real cocoa–a peroxynitrite scavenger).
    Air pollution exposures are linked to systemic inflammation, cardiovascular and respiratory morbidity and mortality, neuroinflammation and neuropathology in young urbanites. In particular, most Mexico City Metropolitan Area (MCMA) children exhibit subtle cognitive deficits, and neuropathology studies show 40% of them exhibiting frontal tau hyperphosphorylation and 51% amyloid-β diffuse plaques (compared to 0% in low pollution control children). We assessed whether a short cocoa intervention can be effective in decreasing plasma endothelin 1 (ET-1) and/or inflammatory mediators in MCMA children. Thirty gram of dark cocoa with 680 mg of total flavonols were given daily for 10.11 ± 3.4 days (range 9–24 days) to 18 children (10.55 years, SD = 1.45; 11F/7M). Key metabolite ratios in frontal white matter and in hippocampus pre and during cocoa intervention were quantified by magnetic resonance spectroscopy. ET-1 significantly decreased after cocoa treatment (p = 0.0002). Fifteen children (83%) showed a marginally significant individual improvement in one or both of the applied simple short memory tasks. Endothelial dysfunction is a key feature of exposure to particulate matter (PM) and decreased endothelin-1 bioavailability is likely useful for brain function in the context of air pollution. Our findings suggest that cocoa interventions may be critical for early implementation of neuroprotection of highly exposed urban children. Multi-domain nutraceutical interventions could limit the risk for endothelial dysfunction, cerebral hypoperfusion, neuroinflammation, cognitive deficits, structural volumetric detrimental brain effects, and the early development of the neuropathological hallmarks of Alzheimer’s and Parkinson’s diseases.
    The inflammatory mediator peroxynitrite, when generated in excess, may damage cells by oxidizing and nitrating cellular components. Defense against this reactive species may be at the level of prevention of the formation of peroxynitrite, at the level of interception, or at the level of repair of damage caused by peroxynitrite. Several
    selenocompounds serve this purpose and include selenoproteins such as glutathione peroxidase (GPx), selenoprotein P and thioredoxin reductase, or low-molecular-weight substances such as ebselen. Further, flavonoids, such as (/)-epicatechin, which occurs in green tea or cocoa as monomer or in the form of oligomers, can contribute to cellular defense against peroxynitrite.
    Now compare this with the results of a study using heat-processed ginseng to treat Alzheimer’s disease.
    J Med Food. 2009 Feb;12(1):124-30. doi: 10.1089/jmf.2007.0646.
    Evaluation of the peroxynitrite scavenging activity of heat-processed ginseng.
    Kang KS1, Tanaka T, Cho EJ, Yokozawa T.
    Author information
    To ascertain the principal active peroxynitrite (ONOO(-)) scavenging components of heat-processed Panax ginseng C.A. Meyer (sun ginseng [SG]), the ONOO(-) scavenging activities of fractions and components of SG were compared. The results demonstrated that the ONOO(-) scavenging ability of SG was due to its ether fraction containing phenolic compounds. High-performance liquid chromatography analysis and ONOO(-) scavenging activity tests of the phenolic acids contained in SG identified vanillic acid, ferulic acid, p-coumaric acid, syringic acid, and maltol as the main active ONOO(-) scavenging components of SG. The ONOO(-) scavenging activities of phenolic acids and maltol were dependent on the degrees of their proton donating ability.
    Nutr Neurosci. 2012 Jul 9. [Epub ahead of print]
    Heat-processed ginseng enhances the cognitive function in patients with moderately severe Alzheimer’s disease.
    Heo JH, Lee ST, Chu K, Oh MJ, Park HJ, Shim JY, Kim M.
    Ginseng has been reported to improve cognitive function in animals and in healthy and cognitively impaired individuals. In this study, we investigated the efficacy of a heat-processed form of ginseng that contains more potent ginsenosides than raw ginseng in the treatment of cognitive impairment in patients with moderately severe Alzheimer’s disease (AD).
    Forty patients with AD were randomized into one of three different dose groups or the control group as follows: 1.5 g/day (n = 10), 3 g/day (n = 10), and 4.5 g/day (n = 10) groups, or control (n = 10). The Alzheimer’s Disease Assessment Scale (ADAS) and Mini-Mental State Examination (MMSE) were used to assess cognitive function for 24 weeks.
    The treatment groups showed significant improvement on the MMSE and ADAS. Patients with higher dose group (4.5 g/day) showed improvements in ADAS cognitive, ADAS non-cognitive, and MMSE score as early as at 12 weeks, which sustained for 24-week follow-up.
    These results demonstrate the potential efficacy of a heat-processed form of ginseng on cognitive function and behavioral symptoms in patients with moderately severe AD.
    All you need for Alzheimer’s disease is peroxynitrites, caspases, the beta secretase and the c-terminal fragment of the amyloid precursor protein.
    Inhibition of the gamma secretase preventing the conversion of the c-terminal fragment into amyloid oligomers only makes the situation worse, as the c-terminal fragment is more toxic than the oligomers.
    Tanzi has captured a process without understanding what drives that process. Don’t study thousands of drugs that may be beta or gamma secretase inhibitors, starting screening plants for their peroxynitrite scavenging capacities.

  25. Harrison says:

    Another thing to consider are that the cultures in the paper are based on the e3 allele of APOE. By basing their work on FAD mutations, it represents 5% of AD cases AT BEST. Despite similar end results (amyloid plaques), the understanding of the relationship between Familial AD and Sporadic AD is quite limited. If they could show these effects with APOE4, it would be much more relevant to the sporadic, late-onset disease.

  26. Lane Simonian says:

    Just to put it together as simply as possible:
    The alternate hypothesis is that Aβ simply represents a bystander or a protector rather than the causative factor of disease (Smith et al., 2002; Lee et al., 2003, 2004b). Notably, all therapeutic studies that have an effect on Aβ levels in cells or animals have shown extremely poor or no efficacy in subsequent clinical trials. This includes indomethacin (Weggen et al., 2001), ibuprofen (Lim et al., 2000), sulindac sulfide (Weggen et al., 2001), a nitric oxide-releasing nonsterodial anti-inflammatory drug (Jantzen et al., 2002), and estrogen (Zheng et al., 2002). Clearly, the alternate hypothesis points to greater therapeutic efficacy by directing efforts to the upstream metabolic and oxidative abnormalities that are what led to Aβ.
    [Clinical trials with over-the-counter supplements have concentrated either on items which suppress inflammation or on antioxidants which scavenger oxygen derived free radicals. Most of these items have proved to be worthless in the treatment of Alzheimer’s disease. Similarly most drugs used to treat Alzheimer’s disease do little to slow the deterioration, but instead offer a mild temporary symptom relief. However, evidence has been accumulating that the primary driver of Alzheimer’s disease is a nitrogen derived free radical called peroxynitrites which may mediate both amyloid and tau accumulation as well as their toxicity. Excellent results have been obtained with peroxynitrite scavengers, with reversals of Alzheimer’s disease being repeatedly demonstrated. IMHO, the only thing which may be preventing the abolition of Alzheimer’s disease is the mental inertia of scientists as well as the bureaucrats who fund them. Unfortunately, most bureaucrats keep throwing money into repeatedly testing discredited interventions, while ignoring successful ones. Common sense is anything but…]
    It does not take a genius to figure out the cause and effective treatments for Alzheimer’s disease, only the ability of people to question the hardened orthodoxy that amyloid and tau tangles are the cause of Alzheimer’s disease.

  27. Proteus says:

    @ #21 Harrison “We have a winner”
    My prize may be the rampant cynicism referred to above. The biology of Tanzi’s new findings is likely interesting, but should be tempered by the spent patients, scientists and resources that a decade of “swarm mentality” spent unproductively trying to address a disease (or class of diseases–as discussed above) that will have no simple answer.

  28. Proteus says:

    I’m guessing most readers here are good with using PubMed.
    Thus, you don’t have to post entire abstracts.
    Speaking for myself, a concise summary with a reference is more likely to be thoughtfully read.
    That being said, keep fighting the power.

  29. Anonymous says:

    Really makes you wonder why anyone these days continues to use 2-D topologies to do cell work. Sure it may seem easier, faster, and cheaper, but in the grand scheme of things, is screening in 2-D really cheaper or faster if it leads you down a wrong development path?

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