Aβ Busters and Other Ploys Show Promise for Treating Neurodegeneration

The news this week brings four papers describing different approaches to prevent or treat neurodegeneration. From an inhibitor of aggregation and a DNA vaccine targeted at amyloid-β (Aβ), to a kinase inhibitor for tau and a kinase target in Parkinson disease, there’s plenty to read and heed in these reports.

In the first, JoAnne McLaurin, Peter St. George-Hyslop, and colleagues at the University of Toronto show that certain orally delivered cyclohexanehexol (aka inositol) stereoisomers can block the accumulation of soluble Aβ oligomers in the brain of transgenic mice. The compounds reverse memory deficits (as measured by performance in the Morris water maze), reduce plaque load, and reverse other signs of Aβ pathology. The results strengthen the case that high-molecular-weight oligomers of Aβ (like Aβ*, see ARF related news story) play a major role in producing memory deficits in mice, and pave the way for the testing of these inositols to prevent or reverse Alzheimer disease in people. A phase I trial of their most effective compound, scyllo-inositol, has just been launched under the name AZD-103.

The in vivo work with inositol stereoisomers follows on first author McLaurin’s previous observations that Aβ oligomerization is enhanced by phosphatidylinositol lipids. She discovered that several isomers of inositol itself compete for the lipid binding and prevent Aβ oligomer formation in vitro and toxicity in cell culture (McLaurin et al., 1998 and McLaurin et al., 2000).

It’s important to note that inositol comes in eight possible stereoisomeric forms, of which three are found in brain. McLaurin’s earlier work indicated that myo-inositol, the common stereoisomer that makes up inositol phospholipids and is widely available as a nutritional supplement, has no effect on Aβ aggregation. The current paper also reiterates that myo-inositol does not affect pathology in the mouse model, so forget loading up on nutraceutical myo-inositol—it will have no benefit.

It is the other isomers that appear more promising. In a prophylactic treatment regimen, TgCRND8 mice were fed epi- or scyllo-inositol ad libitum beginning at 6 weeks old until they were 4 or 6 months old. A treatment regimen was also done which consisted of dosing 4-month-old mice for 1 month. In both cases, the mice that got scyllo-cyclohexanehexol showed a significant reduction in brain Aβ levels, with decreases in soluble or insoluble Aβ40 or Aβ42 ranging from 20 to 60 percent. These reductions correlated with improved performance in the water maze compared to untreated animals. In fact, the scyllo-treated mice navigated the water maze just as well as normal nontransgenic controls after several days of testing. Measurements of synaptic loss and glial inflammation also showed improvement, and there was a reduction in mortality in the scyllo treated mice. Overall, the epi-stereoisomer showed lower activity.

To confirm if the inositol isomers were inhibiting Aβ aggregation, McLaurin and colleagues measured soluble oligomeric Aβ in brain, using the oligomer-specific antibody from Charles Glabe’s lab (see ARF related news story). This antibody recognizes soluble Aβ assemblies larger than 40 kDa, and dot blots of brain homogenates showed that scyllo treatment decreased amount of brain Aβ it picked up. Western blotting confirmed that brain homogenates from the scyllo-treated mice had less of the high-molecular-weight Aβ species and increased lower-order species, particularly trimers. Finally, dose response studies demonstrated that scyllo-inositol caused progressive decline in the immunoreactive oligomers, which was accompanied by significant behavioral improvement in the water maze and a decrease in the number of plaques.

While it’s not clear if the Aβ oligomer that McLaurin observes corresponds to the Aβ* recently described by Karen Ashe and coworkers, the current work fits right in with that study’s conclusion that accumulation of soluble aggregated forms of Aβ could be responsible for memory impairment in AD.

Transition Therapeutics in Toronto has just started a phase 1 trial of scyllo-cyclohexanehexol (AZD-103), according to company CEO Tony Cruz. They are expediting development and expect to be in a large phase 2 trial in AD patients by early next year if all goes well. AZD-103 follows another aggregation inhibitor, 3-amino-1-propane sulfonic acid (Alzhemed) which is currently in phase 3 trials, with results expected in early 2007.

Another way to rid the brain of toxic Aβ plaques and oligomers is to let the immune system do the work. But since the unexpected toxicity of an Aβ peptide immunogen halted the Elan vaccine trial, researchers have been looking for a safer stimulant. Now, a paper from the lab of Yoh Matsumoto at the Tokyo Metropolitan Institute for Neuroscience, along with Matthias Staufenbiel at Novartis in Basel, Switzerland, presents data on a DNA vaccine that might fit the bill. In their paper, to be published online in PNAS, first author Yoshio Okura and colleagues describe a nonviral Aβ DNA vaccine which reduced Aβ load in APP23 mice even when the mice were vaccinated later in life. Importantly, the researchers found no inflammation or T cell response in either the APP23 mice or in wild-type mice given the vaccine.

The vaccines tested consisted of plasmids that that express Aβ1-42 alone, or with a leader sequenced attached to increase secretion, with or without an immunoglobulin Fc sequence to maintain stability. In cells, all three constructs produced Aβ, but only the latter two supported secretion. In a prophylactic trial, vaccine was administered by intramuscular injection starting at 3-4 months of age, before amyloid appears in the APP23 mice. In this mode, all three vaccines dramatically reduced amyloid in the frontal cortex of mice at 7 months to 15-30 percent of the levels of untreated mice. By one year, the two secretion-competent vaccines produced reductions of 30-50 percent in brain Aβ load, while the Aβ peptide construct had no effect. Reduction was long-lived, since it was still apparent at 18 months.

In a therapeutic scheme, the mice that got the vaccines when they were 1 year old showed decreased amyloid deposition in the cortex and hippocampus at 18 months. In fact, there was no significant difference between therapeutic and prophylactic protocols. Both paradigms also decreased intracellular Aβ deposition in cortical pyramidal neurons, an early event in AD.

The vaccines raised anti-Aβ antibody titers in both APP and normal mice by about two- to fourfold, much lower than the increase (up to 10,000-fold) seen after immunization with Aβ peptides. Yet even at these low levels, reduction of Aβ burden was significantly correlated with antibody titers. The researchers could detect no Aβ-responsive T cells or histological signs of brain inflammation in either normal or transgenic mice after DNA vaccination. They suggest that the fact that DNA vaccines do not require adjuvants may be an advantage over peptide immunization by giving more control over the strength of the immune response. The steady, low level of protein expression driven by the plasmid vaccine generates a “gentle and quiet” immune reaction, they say, but one that is nonetheless sufficient to drive down amyloid burden. Behavioral studies will be necessary to determine if this kinder, gentler approach is really tough enough to improve mental functioning.

Any successful treatment for AD may have to deal with tau hyperphosphorylation in addition to Aβ deposition. Treatment of pure tauopathies like frontotemporal dementia-17 will also require taming the aberrant phosphorylation of mutant tau that leads to neurodegeneration. In another paper this week in PNAS online, Hanno Roder, from Sirenade Pharmaceuticals in Martinsried, Germany, along with Michael Hutton and colleagues at the Mayo Clinic in Jacksonville, Florida, show that they can tackle tau phosphorylation head on with a new kinase inhibitor. The compound, a brain-permeable derivative of the natural product K252a, shuts down mutant tau phosphorylation and prevents the onset of motor impairments in transgenic mice expressing the P301L mutant human tau. At the same time, they show the treatment does not reduce the number of neurofibrillary tangles in the mice. The results join other recent studies pointing to tau hyperphosphorylation, leading to the formation of soluble aggregates as the pathogenic lesion in these mice (see ARF related news story, ARF news story, and Spires et al., 2006) and suggest the new inhibitor or related compounds may be useful for treating tauopathies.

Starting with K252a, first author Sylvie Le Corre and the team optimized the kinase inhibitor for oral availability and brain penetration. In its modified form, the new compound, SRN-003-556, inhibited a range of kinases including Erk, Cdc2, GSK3β, PKA, and PKC with about equivalent potency, and prevented phosphorylation of tau at multiple residues in cells. To look at in vivo effects, the researchers used JNPL3 transgenic mice, which develop neurofibrillary tangles, neuronal loss, and motor deficits as they age due to the human tau P301L transgene. Treating the mice at the first sign of motor deficits delayed the development of severe deficits as measured by a wire hang and a beam balance test.

In the brain and spinal cord of these animals, they found a 64 KDa form of soluble aggregated phospho-tau, and showed it was decreased in the treated animals. In both treated and untreated groups, the level of 64 KDa tau, and not the amount of neurofibrillary tangles, correlated with the stage of phenotypic disease for each mouse. The results echo those of the Aβ aggregation inhibitors in implicating soluble aggregates as the species of interest for therapeutic attack.

Kinase inhibitors could be useful in treating Parkinson disease as well, according to a paper from Mark Cookson and colleagues at the National Institute on Aging in Bethesda, Maryland, and collaborators in London. In a report online in the Neurobiology of Disease, Cookson and colleagues show that the kinase activity of the PD gene LRRK/dardarin is required for the mutant protein to form inclusion bodies and cause cell death.

The LRRK/dardarin gene, which accounts for up to 6 percent of inherited PD, encodes a large protein with multiple motifs, including a GTPase domain and a kinase domain. PD-causing mutations are found throughout the protein, but it is not clear how they work to produce disease.

To find out, first author Elisa Greggio expressed a number of dardarin mutants in cells, and replicated a previous finding (Smith et al., 2005) that the mutants formed inclusions at a much higher rate than wild-type protein, which rarely showed such aggregates. She then made kinase-inactive mutants of the PD proteins by introducing a triple alanine substitution in the active site. When these proteins were introduced into cells, they formed inclusion bodies less frequently than wild-type proteins. Similar results were obtained when they tested the ability of the mutants to kill SH-SY5Y or primary rat neurons: kinase dead versions of several dardarin PD mutants lost their ability to kill the cells as measured by TUNEL staining and morphological changes.

Using immunostaining, the researchers showed that dardarin is in fact present in cell bodies and processes in mid-brain melanized neurons in both normal and PD brain. These results suggest that their neuronal model may be relevant to disease, and that inhibitors of the dardarin kinase activity should be considered potential therapeutic agents for patients with LRRK2 mutations, and possibly also sporadic PD.—Pat McCaffrey

Comments

  1. The recent PNAS paper by Okura and colleagues provides interesting new data regarding a nonviral Aβ DNA vaccine. It is encouraging that testing with two of the three naked DNA plasmid vaccines (Aβ-Fc and IgL-Aβ) against Aβ1-42 significantly lowered cerebral Aβ in APP23 transgenic mice when given prior to Aβ deposition as well as later, when plaque deposition was well underway. As has been shown previously in 3xTg-AD mice by LaFerla's group, the authors in this paper showed clearance or prevention of intracellular Aβ in neurons in addition to extracellular plaques. Antibody titers were lower with the Aβ DNA vaccines than using full-length Aβ1-42/CFA (Complete Freund’s Adjuvant) but were enough to reduce CNS Aβ burden. T cells and macrophages were absent from the immunized mouse brains, indicating a lack of neuroinflammation; however, microglial and astrocytic labeling were apparently not investigated and would shed further light on the state of inflammation in the brains of immunized mice. Interestingly, T cells isolated from draining lymph nodes of APP23 mice immunized with either the Aβ DNA vaccines (without CFA but with bupivacaine, and adjuvant commonly used for DNA vaccines) or Aβ1-42 peptide with CFA did not proliferate in response to restimulation with Aβ1-42 peptide in vitro, whereas T cells from B6 wild-type mice responded strongly to immunization with Aβ1-42/CFA but not the Aβ DNA vaccines. The authors believe that tolerance to the high levels of human Aβ transgenic peptide may be responsible for the lack of Aβ recognition by T cells in APP23 mice. In particular, it is curious that immunization with Aβ1-42 and CFA did not cause T cell proliferation in the APP23 mice. This result contrasts with what we have found in 3x AD-like Tg mouse models (PSAPP, J20 APP, 3xTg-AD) using Aβ1-42 peptide and various routes of administration and adjuvants, including CFA (by intraperitoneal injection). In the Okura paper, the T cell studies were performed after 3 weeks of immunization, whereas our studies examined splenocytes after the full-term multi-month vaccine. It would be informative to examine T cells after the long-term Aβ DNA immunization, especially in older mice, although according to the paper, the results were the same after 5 months of immunization (data not shown). In addition, differences in Aβ peptide conformation, adjuvant, route of administration, and the genetic background of the mice examined may also influence the T cell reaction. The APP23 mice used here were on a C57BL/6 background, which may partially explain their somewhat suppressed immune response. However, 3xTg-AD mice are also on the same genetic background and show a strong proliferative response to immunization with full-length Aβ and CFA or a heat labile enterotoxin adjuvant called LT(R192G).

    In the future, it will be of interest to know if these nonviral Aβ DNA vaccines have any effect on cerebrovascular Aβ (including the induction of microhemorrhage), cerebral gliosis, and behavior. Immunoglobulin isotyping may help determine the extent of T helper cell contribution to the overall immune response. Unfortunately, because Aβ immunized mice do not show the same adverse events as humans in the AN1792 trial, it will be difficult to predict exactly how humans will respond to such a vaccine. However, these earlier studies are encouraging and may represent a safer, cost-efficient strategy for Aβ vaccination. Testing these Aβ DNA vaccines in APP Tg mouse models in which immunization with full-length Aβ and CFA results in a strong T cell proliferative response will help tease out the safety of the vaccine.

    View all comments by Cynthia Lemere

  2. Okura et al. demonstrated effectiveness of no viral Aβ DNA vaccine in reducing Aβ load in APP23 Tg mice. The vaccine was administered without an adjuvant and appears to elicit no cellular immunity. Therefore, it may be considered safer that AN1792, containing Aβ and QS-21 adjuvant, which caused exaggerated cellular response resulting in autoimmune encephalitis in 5 percent of study subjects. No signs of toxicity were observed in APP23 and wild-type mice which received the DNA vaccine from the age of 3 to 18 months. One has to remember, however, that in the original study of Aβ vaccination administered with Freund adjuvant, no toxicity was also observed in Tg mice and similarly no toxicity was observed in phase 1 of the human clinical trial. Although the safety concepts behind development of this nonviral DNA vaccine sound reasonable, they have not been fully evaluated. One way to evaluate long-term safety prior to clinical trials would be a study in aged primates. The risk of an autoimmune reaction is known to significantly increase with aging. Risks here would include the generation of anti-DNA antibodies and the genome integration risk associated with DNA vaccination, as well as the remaining risk of these vaccines, inducing cellular immunity in a small proportion of patients. So far, DNA vaccines have fared well in some model systems of disease; however, in human clinical trials the results have been disappointing. On the other hand, two DNA vaccines have recently been licensed in animals (horse and fish), highlighting the potential of this approach.

    View all comments by Thomas Wisniewski

  3. The PNAS paper by Okura et al. describes results regarding a DNA-based Alzheimer disease vaccine. Significant advantages of DNA immunization in comparison to other means include ease of vaccine development; high stability of preparation; capability of modifying genes encoding desired antigen(s); ability to target cellular localization of an antigen by means of adding or removing signal sequences or transmembrane domains; and the ability to selectively elicit the desired type of immune response (humoral or cellular).

    Three years ago we reported (Ghochikyan et al., 2003) that immunization of B6SJLF1 mice with a DNA vaccine encoding the human Aβ42 gene generated robust anti-Aβ42 antibodies of predominantly IgG1 and IgG2b isotypes, and that these antibodies were capable of binding to β-amyloid plaques in brain tissue from AD cases. Thus, we demonstrated for the first time that DNA immunization is capable of inducing therapeutically potent anti-Aβ42 antibodies in wild-type mice. However, later we reported (Cribbs, 2005) that this prototype vaccine induced only low titers of anti-Aβ antibody in APP/Tg 2576 mice. These results were not totally unexpected, because previously we, and others, observed that immune responses to Aβ in APP/Tg animals were significantly impaired even after protein immunizations with fAβ42 (Monsonego et al., 2001; Petrushina et al., 2003). Other groups also attempted to generate anti-Aβ antibodies using DNA vaccines encoding the Aβ42 peptide (Schultz et al., 2004; Qu et al., 2004; Kutzler et al., 2005). Schultz et al. demonstrated that DNA encoding human Aβ42 (pAβ42) was not capable of inducing anti-Aβ antibodies even in wild-type mice. Only pAβ42 mixed with aggregated Aβ42 peptide slightly increased antibody production. The second group (Kutzler et al., 2005) demonstrated that pAβ42 was capable of inducing T cell proliferation in mice of different immune haplotypes as well as HLA Class II transgenic mice; however, these authors did not report generation of anti-Aβ antibodies. The last group (Qu et al., 2004) induced in one out of three wild-type mice significant titers of anti-Aβ antibodies only after immunization with plasmid encoding the Aβ42 dimer gene. These results were expected, because DNA vaccination is generally known to induce relatively low levels of antibody production and/or cellular immune responses in mice, and it is not always successful in large animals and humans.

    Okura et al. are basically reporting in PNAS the same immunological data with DNA vaccine based on Aβ42, although they did not cite all these papers published and reported in different conferences within the last 4 years. More specifically, they are showing that multiple intramuscular immunizations (sometimes it is more than 20 injections) with DNA vaccines encoding the Aβ42 gene with signal peptide induced low titers of anti-Aβ antibodies (titers are 1,000-6,000). With these low titers of antibodies (exact concentration of antibodies, unfortunately, is not provided), it is not surprising that the authors did not detect immune lymph node (LN) cell proliferation specific to Aβ42 in APP/Tg mice. However, it should be mentioned that Aβ42 is a T-dependent antigen, because immunization of two types of nude mice with fibrillar Aβ42 peptide formulated in a strong conventional adjuvant did not induce any humoral responses (our unpublished data). Therefore, without CD4+T helper cell responses, APP23 mice couldn’t produce antibodies, so we still have to assume that DNA vaccine is inducing some anti-Aβ cellular responses that the authors likely did not detect because of the methodology they used (for example, incorporation of H3 thymidine was analyzed “after the first injection”; Stimulation Index is not reported at all; see also comments of Dr. Lemere about cellular responses).

    Data from the AN1792 clinical trial indicate that vaccinated patients with anti-Aβ titer of 1:1,000 had very low Aβ-plaques in postmortem brain (see Nicoll et al., 2003 and ARF related news story), and that all AD patients that showed significant improvement in cognitive functions and activities of daily living, had titers of anti-Aβ antibodies 1:2,200 at any time after injections (Hock et al., 2003; Gilman et al., 2005; Fox et al., 2005; Bayer et al., 2005). Recently, using our epitope peptide vaccine approach (Agadjanyan et al., 2005), we demonstrated that concentrations of anti-Aβ antibody from ~1.5 to ~250 mg/ml are sufficient for clearing/reducing of AD-like neuropathology in APP/Tg2576 mice (paper submitted and data presented in the last AD/PD conference in Italy). So it was not totally unexpected that Okura et al. showed that vaccination with DNA encoding secreted Aβ42 reduced Aβ burden in both prophylactic and therapeutic protocols and “there was significant correlation between the serum anti-Aβ antibody titer and the reduction of amyloid depositions at 7 months and 9 months of age.” What was unexpected was that therapeutic vaccination induced a more profound response than prophylactic vaccination. This was unexpected because previous reports by several investigators showed that clearance of pre-existing Aβ plaques is much more difficult than the prevention of Aβ accumulation. Another unexpected result was data with the DNA vaccine targeting the non-secreted form of Aβ42. The authors mentioned that this K-Aβ vaccine was also effective. However, because the authors did not analyze immune responses after vaccination with K-Aβ, it is not clear whether antibodies or some other mechanism(s) are involved in the significant reduction of Aβ burden (Fig 2E). While these questions could be clarified in the future, we would like to focus our discussion on the safety of the DNA vaccine based on Aβ42 peptide.

    As we mentioned above, and as shown by Okura et al., anti-Aβ antibody concentrations may be critical for clearance/reduction of AD-like neuropathology in the brains of AD patients. Thus, immunotherapy can only be effective if it will induce therapeutically relevant titers of anti-Aβ antibodies capable of removing toxic species of this peptide (oligomers, fibrils, monomers) from the brain of AD patients. The DNA vaccine generated by Okura et al. induced very low concentration of such antibodies in APP23 mice. Hence, it should be expected that the concentration of these antibodies will be even lower in AD patients, since it is well known that DNA vaccination is less immunogenic in humans. Thus, to enhance such humoral responses, authors will ultimately need to enhance anti-Aβ CD4+T helper cell responses in AD patients. I think that this is not only a difficult task, but also not a very safe one. Such an approach is not very safe because of the potential for T cell-mediated toxicity, as detected in AD patients immunized with AN1792 vaccine (Nicoll et al., 2003; Ferrer et al., 2004; Masliah, 2005). Unfortunately, the absence of neuroinflammation in the brains of DNA vaccinated APP23 mice is not a good argument that such a vaccine really is “highly secure and easily controllable,” because firstly, as the authors show vaccinated APP23 mice do not generate robust anti-Aβ42 T cell responses, and secondly, it is well known that the mouse model is a poor predictor of Aβ vaccination-induced adverse effects in humans. Thus, one needs to use an alternative approach to make a safe DNA vaccine. For example, one theoretical solution that circumvents the need for autoreactive T cells is to use a DNA epitope vaccine composed of the self-B cell antigenic determinant of Aβ42 and the non-self T cell antigenic determinant as we and others demonstrated with using a peptide-based approach (Agadjanyan et al., 2005; Maier et al., 2006). This strategy appears to eliminate the need for the stimulation of autoreactive T cells, while simultaneously allowing for potent Th2 support of B cell-mediated therapeutic anti-Aβ42 antibodies. Such an approach may avoid the generation of systemic inflammatory responses, which can be propagated to the CNS. This and other DNA vaccine approaches should be considered in the future to ensure the best possible strategy for the development of an AD vaccine.

    References:

    Ghochikyan A, Vasilevko V, Petrushina I, Movsesyan N, Babikyan D, Tian W, Sadzikava N, Ross TM, Head E, Cribbs DH, Agadjanyan MG. Generation and characterization of the humoral immune response to DNA immunization with a chimeric beta-amyloid-interleukin-4 minigene. Eur J Immunol. 2003 Dec;33(12):3232-41. PubMed.

    Cribbs DH, David H, Agadjanyan MG. Immunotherapy for Alzheimer's Disease: Potential Problems and Possible Solutions. Current Immunology Reviews. 2005 June 1;1(2):139-155.

    Monsonego A, Maron R, Zota V, Selkoe DJ, Weiner HL. Immune hyporesponsiveness to amyloid beta-peptide in amyloid precursor protein transgenic mice: implications for the pathogenesis and treatment of Alzheimer's disease. Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10273-8. PubMed.

    Petrushina I, Tran M, Sadzikava N, Ghochikyan A, Vasilevko V, Agadjanyan MG, Cribbs DH. Importance of IgG2c isotype in the immune response to beta-amyloid in amyloid precursor protein/transgenic mice. Neurosci Lett. 2003 Feb 20;338(1):5-8. PubMed.

    Schiltz JG, Salzer U, Mohajeri MH, Franke D, Heinrich J, Pavlovic J, Wollmer MA, Nitsch RM, Moelling K. Antibodies from a DNA peptide vaccination decrease the brain amyloid burden in a mouse model of Alzheimer's disease. J Mol Med (Berl). 2004 Oct;82(10):706-14. PubMed.

    Qu B, Rosenberg RN, Li L, Boyer PJ, Johnston SA. Gene vaccination to bias the immune response to amyloid-beta peptide as therapy for Alzheimer disease. Arch Neurol. 2004 Dec;61(12):1859-64. PubMed.

    Kutzler MA, Cao C, Bai Y, Dong H, Choe PY, Saulino V, McLaughlin L, Whelan A, Choo AY, Weiner DB, Ugen KE. Mapping of immune responses following wild-type and mutant ABeta42 plasmid or peptide vaccination in different mouse haplotypes and HLA Class II transgenic mice. Vaccine. 2006 May 22;24(21):4630-9. PubMed.

    Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med. 2003 Apr;9(4):448-52. PubMed.

    Hock C, Konietzko U, Streffer JR, Tracy J, Signorell A, Müller-Tillmanns B, Lemke U, Henke K, Moritz E, Garcia E, Wollmer MA, Umbricht D, de Quervain DJ, Hofmann M, Maddalena A, Papassotiropoulos A, Nitsch RM. Antibodies against beta-amyloid slow cognitive decline in Alzheimer's disease. Neuron. 2003 May 22;38(4):547-54. PubMed.

    Gilman S, Koller M, Black RS, Jenkins L, Griffith SG, Fox NC, Eisner L, Kirby L, Rovira MB, Forette F, Orgogozo JM, . Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology. 2005 May 10;64(9):1553-62. PubMed.

    Fox NC, Black RS, Gilman S, Rossor MN, Griffith SG, Jenkins L, Koller M. Effects of Abeta immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease. Neurology. 2005 May 10;64(9):1563-72. PubMed.

    Bayer AJ, Bullock R, Jones RW, Wilkinson D, Paterson KR, Jenkins L, Millais SB, Donoghue S. Evaluation of the safety and immunogenicity of synthetic Abeta42 (AN1792) in patients with AD. Neurology. 2005 Jan 11;64(1):94-101. PubMed.

    Agadjanyan MG, Ghochikyan A, Petrushina I, Vasilevko V, Movsesyan N, Mkrtichyan M, Saing T, Cribbs DH. Prototype Alzheimer's disease vaccine using the immunodominant B cell epitope from beta-amyloid and promiscuous T cell epitope pan HLA DR-binding peptide. J Immunol. 2005 Feb 1;174(3):1580-6. PubMed.

    Ferrer I, Boada Rovira M, Sánchez Guerra ML, Rey MJ, Costa-Jussá F. Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer's disease. Brain Pathol. 2004 Jan;14(1):11-20. PubMed.

    Masliah E, Hansen L, Adame A, Crews L, Bard F, Lee C, Seubert P, Games D, Kirby L, Schenk D. Abeta vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer disease. Neurology. 2005 Jan 11;64(1):129-31. PubMed.

    Maier M, Seabrook TJ, Lazo ND, Jiang L, Das P, Janus C, Lemere CA. Short amyloid-beta (Abeta) immunogens reduce cerebral Abeta load and learning deficits in an Alzheimer's disease mouse model in the absence of an Abeta-specific cellular immune response. J Neurosci. 2006 May 3;26(18):4717-28. PubMed.

    View all comments by Michael G. Agadjanyan

  4. Bravo.

    View all comments by Andre Delacourte

  5. Scyllo-inositol may limit or reverse Alzheimer disease because it appears to inhibit the uptake of myo-inositol in the brain and thus stops the overproduction of D-myo-inositol-1,4,5-triphosphate, a compound which plays a critical role in regulating calcium in the cytoplasm of nerve cells. If there is too much D-myo-inositol-1,4,5-triphosphate, calcium levels should rise. The enzyme which cleaves off the beta amyloid protein may be activated by high intracellular calcium levels. Thus, high levels of D-myo-inositol-1,4,5-triphosphate would likely lead to the aggregation of beta amyloid proteins.

    The high levels of myo-inositol in the pre-dementia phase of people with Down syndrome, and the high levels of myo-inositol monophosphatase (which converts myo-inositol monophosphates into myo-inositol) in post-mortem Alzheimer disease brains implicate myo-inositol in these two forms of dementia. High levels of myo-inositol also correlate with insulin-resistant diabetes, which may help explain the link between diabetes and Alzheimer disease as well as why insulin-like nerve growth factors also show promise against the disease. Myo-inositol monophosphate is produced from glucose-6-phosphate with the phosphate being added by ATP (when glucose enters into a cell it is converted into glucose-6-phosphate; the more glucose that enters into a cell the more glucose-6-phosphate is produced). ATP also probably plays an important role in the conversion process from there: myo-inositol/myo-inositol monophosphate, phosphatidyl-myo-inositol-4,5-biphosphate, myo-inositol-1,4,5-triphosphate. It is possible, however, that phosphates from other sources (phosphoric acids, aluminum phosphates, and biphosphates such as Fosamax) and phosphate analogs (such as aluminum fluoride and sodium fluoride) accelerate the creation of myo-inositol triphosphate and thus the onset of Alzheimer disease.

    Scyllo-inositol may not be as easily taken up into lipids as myo-inositol. "Scyllo-inositol biphosphate" may not be as easy to cleave off from lipids as myo-inositol biphosphates, or "scyllo-inositol triphosphate" may not work with calcium receptors as effectively as myo-inositol triphosphates. The end result should be lower levels of calcium and fewer beta amyloid proteins being generated. The slowing down in the processing of beta amyloid proteins may allow for some or all of those proteins to be moved out of the nerve cells or otherwise eliminated.

    View all comments by Lane Simonian

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References

News Citations

  1. Aβ Star is Born? Memory Loss in APP Mice Blamed on Oligomer
  2. Amyloid Oligomer Antibody—One Size Fits All?
  3. How Now, Phospho-tau? Sparing Synapses, Messing with Microtubules
  4. No Toxicity in Tau’s Tangles?

Paper Citations

  1. McLaurin J, Franklin T, Chakrabartty A, Fraser PE. Phosphatidylinositol and inositol involvement in Alzheimer amyloid-beta fibril growth and arrest. J Mol Biol. 1998 Apr 24;278(1):183-94. PubMed.
  2. McLaurin J, Golomb R, Jurewicz A, Antel JP, Fraser PE. Inositol stereoisomers stabilize an oligomeric aggregate of Alzheimer amyloid beta peptide and inhibit abeta -induced toxicity. J Biol Chem. 2000 Jun 16;275(24):18495-502. PubMed.
  3. Spires TL, Orne JD, Santacruz K, Pitstick R, Carlson GA, Ashe KH, Hyman BT. Region-specific dissociation of neuronal loss and neurofibrillary pathology in a mouse model of tauopathy. Am J Pathol. 2006 May;168(5):1598-607. PubMed.
  4. Smith WW, Pei Z, Jiang H, Moore DJ, Liang Y, West AB, Dawson VL, Dawson TM, Ross CA. Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18676-81. PubMed.

Further Reading

Primary Papers

  1. McLaurin J, Kierstead ME, Brown ME, Hawkes CA, Lambermon MH, Phinney AL, Darabie AA, Cousins JE, French JE, Lan MF, Chen F, Wong SS, Mount HT, Fraser PE, Westaway D, St George-Hyslop P. Cyclohexanehexol inhibitors of Abeta aggregation prevent and reverse Alzheimer phenotype in a mouse model. Nat Med. 2006 Jul;12(7):801-8. PubMed.
  2. Greggio E, Jain S, Kingsbury A, Bandopadhyay R, Lewis P, Kaganovich A, van der Brug MP, Beilina A, Blackinton J, Thomas KJ, Ahmad R, Miller DW, Kesavapany S, Singleton A, Lees A, Harvey RJ, Harvey K, Cookson MR. Kinase activity is required for the toxic effects of mutant LRRK2/dardarin. Neurobiol Dis. 2006 Aug;23(2):329-41. PubMed.
  3. Okura Y, Miyakoshi A, Kohyama K, Park IK, Staufenbiel M, Matsumoto Y. Nonviral Abeta DNA vaccine therapy against Alzheimer's disease: long-term effects and safety. Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9619-24. PubMed.
  4. Le Corre S, Klafki HW, Plesnila N, Hübinger G, Obermeier A, Sahagún H, Monse B, Seneci P, Lewis J, Eriksen J, Zehr C, Yue M, McGowan E, Dickson DW, Hutton M, Roder HM. An inhibitor of tau hyperphosphorylation prevents severe motor impairments in tau transgenic mice. Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9673-8. PubMed.

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