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We verified the hypothesis that changes in the endogenous GM1 ganglioside density in the environment of TrkB, receptor of brain-derived neurotrophic factor, can affect receptor activity, and focused on rat cerebellar granule cells expressing both GM1 and TrkB. Changes of the amount of GM1 associated to immunoprecipitated TrkB and of receptor tyrosine phosphorylation were evaluated after treatment with phorbol-12-myristate-13-acetate (1 μM, 7 min), reported to affect the plasma membrane distribution of endogenous gangliosides in the same cells. After treatment, the amount of GM1 associated to receptor and TrkB phosphorylation decreased by about 40%. The amount of associated GM1 decreased by about 33% also after concomitant treatment with phorbol ester and brain-derived neurotrophic factor, but in this case the neurotrophin was unable to enhance receptor tyrosine phosphorylation. These results for the first time suggest that changes in the amount of endogenous GM1 in the environment of TrkB can modulate receptor activity, and offer new clues for a better understanding of physiological and pathological events of the nervous system.

Only limited therapeutic measures are currently available for the treatment of spinal cord injury. This review describes the pathologic mechanisms of trauma-induced spinal cord injury in rats, which will contribute to new understanding of the pathologic process leading to spinal cord injury and to further development of new therapeutic strategies. Spinal cord injury induced by trauma is a consequence of an initial physical insult and a subsequent progressive injury process that involves various pathochemical events leading to tissue destruction; the latter process should therefore be a target of pharmacological treatment. Recently, activated neutrophils have been shown to be implicated in the latter process of the spinal cord injury in rats. Activated neutrophils damage the endothelial cells by releasing inflammatory mediators such as neutrophil elastase and oxygen free radicals. Adhesion of activated neutrophils to the endothelial cell could also play a role in endothelial cell injury. This endothelial cell injury could in turn induce microcirculatory disturbances leading to spinal cord ischemia. We have found that some therapeutic agents that inhibit neutrophil activation alleviate the motor disturbances observed in the rat model of spinal cord injury. Methylprednisolone (MPS) and GM1 ganglioside, which are the only two pharmacological agents currently clinically available for treatment of acute spinal cord injury, do not inhibit neutrophil activation in this rat model. Taken together, these observations raise a possibility that other pharmacological agents that inhibit neutrophil activation used in conjunction with MPS or GM1 ganglioside may have a synergistic effect in the treatment of traumatic spinal cord injury in humans.

The purpose of this article is to review recent findings regarding the mechanisms by which GM1 may mimic or potentiate certain actions of neurotrophic factors, including promotion of neuronal survival. It is proposed that the neuroprotective activity of GM1 is due, at least in part, to its ability to favor the dimerization of neurotrophic factor receptor tyrosine kinases and thereby mimicking the action of their corresponding ligands. This may manifest both in the absence of ligand (thereby triggering a subset of neurotrophic-factor responses such as prevention of apoptosis) and in the presence of ligand (thereby potentiating responses to neurotrophic factors).

Low affinity anti-GM1 IgM-antibodies are part of the normal repertoire of human plasma antibodies (Mizutamari et al.: J Neuroimmunol 50:215–220, 1994), a fact that is against the pathological role proposed for them in autoimmune diseases. Here we present evidence that these low affinity IgM-antibodies are devoid of complement-mediated lytic activity to GM1-liposomes, suggesting that they should not be considered harmful. In contrast to the absence in normal individuals, in the plasma of a patient with sensory polyneuropathy we detected high affinity anti-GM1 IgM-antibodies. Concomitant with the presence of these high affinity anti-GM1 IgM-antibodies, the patient plasma is capable of producing complement-mediated lysis of GM1-liposomes. These results suggest that an increase in the affinity of the naturally existing anti-GM1 antibodies could be the trigger that switches them from non-harmful to pathological. J. Neurosci. Res. 51:237–242, 1998. © 1998 Wiley-Liss, Inc.

Survival of cerebellar granule cells (CGC) in culture was significantly improved in the presence of cholera toxin B subunit (Ctx B), a ligand which binds to GM1 with specificity and high affinity. This trophic effect was linked to elevation of intracellular calcium ([Ca2+]i), and was additive to that of high K+. Survival was optimized when Ctx B was present for several days during the early culture period. 45Ca2+ and cell survival studies indicated the mechanism to involve enhanced influx of Ca2+ through L-type voltage-sensitive channels, since the trophic effect was blocked by antagonists specific for that channel type. Inhibitors of N-methyl-D-aspartate receptor/channels were without effect. During the early stage of culture Ctx B, together with 25 mM K+, caused [Ca2+]i to rise to 0.2-0.7 microM in a higher proportion of cells than 25 mM K+ alone. A significant change in the nature of GM1 modulation of Ca2+ flux occurred after 7 days in culture, at which time Ctx B ceased to elevate and instead reduced [Ca2+]i below the level attained with 25 mM K+. GM1 thus appears to serve as intrinsic inhibitor of one or more L-type Ca2+ channels during the first 7 days in vitro, and then as intrinsic activator of (possibly other) L-type channels after that period. This is the first demonstration of a modulatory role for GM1 ganglioside affecting Ca2+ homeostasis in cultured neurons of the CNS.

The present single center, double-blind, delayed start study was conducted to examine possible symptomatic and disease-modifying effects of GM1 ganglioside in Parkinson's disease (PD). Seventy-seven subjects with PD were randomly assigned to receive GM1 for 120 weeks (early-start group) or placebo for 24 weeks followed by GM1 for 96 weeks (delayed-start group). Washout evaluations occurred at 1 and 2 years after the end of treatment. Seventeen additional subjects who received standard-of-care were followed for comparative information about disease progression. Primary outcome was change from baseline Unified Parkinson's Disease Rating Scale (UPDRS) motor scores. At week 24, the early-start group had significant improvement in UPDRS motor scores vs. a significant worsening of scores in the delayed-start group. The early-start group also showed a sustained benefit vs. the delayed-start group at week 72 and at week 120. Both groups had significant symptom worsening during washout. This study provides evidence that GM1 use for 24 weeks was superior to placebo for improving motor symptoms and that extended GM1 use (up to 120 weeks) resulted in a lower than expected rate of symptom progression. The data from this small study suggest that GM1 may have symptomatic and potentially disease modifying effects on PD.

The effect of ganglioside GM1 on isoproterenol-induced cAMP accumulation was studied in insect Sf9 cells expressing the human beta 1-adrenergic receptor by infection with recombinant baculovirus. When such Sf9 cells were treated with isoproterenol plus IBMX, intracellular cAMP formation increased approximately 10-fold over the basal level. Preincubation of the baculovirus-infected cells with GM1 for 1 h caused a concentration-dependent inhibition of the isoproterenol-induced cAMP accumulation. Phosphatidylserine, GM3, GT1b and a bovine brain ganglioside preparation lacking GM1 did not cause significant inhibition. Forskolin-induced cAMP accumulation was not affected by the GM1 treatment. Inhibition of isoproterenol-induced cAMP formation by GM1 was not observed in Sf9 cells expressing beta 2-adrenergic receptor instead of the beta 1-adrenergic receptor. Binding studies with (-)-[3H]CGP12177 showed that preincubation with GM1 significantly reduced the affinity of antagonist binding to the beta 1-adrenergic receptor. These results suggest that GM1 or related ganglioside structure(s) may function as natural modulator(s) of the beta 1-adrenergic receptor.

The effects of topical GM1 ganglioside on crushed rat sciatic nerve regeneration were studied in this presentation. Thirty-four rats, with 68 bilateral sciatic nerves, were divided into seven groups: one group of four rats for measurement of normal motor nerve conduction velocity (MNCV), three as controls, and another three in the GM1-treated groups. Sciatic nerves were exposed and crushed at a site 6 mm distal to the sciatic notch by the standard technique. In this manner, 3 mm wide crush injuries were created. Then 2.1 microliters of normal saline was injected into the crush site in the control groups and an equal volume of GM1 solution (containing 10 micrograms GM1) was injected into the GM1-treated groups. Electrophysiological, histological, and morphometric evaluations were carried out at 12, 28, and 56 days. A significantly higher muscle action potential (MAP) rate was found in the GM1-treated group (70%) vs. the controls (none) at 12 days (P < 0.005), and increased MNCV was found in the GM1-treated groups at both 28 and 56 days, especially at 56 days, when it was 39.59 +/- 9.23 m/sec vs. 31.42 +/- 4.07 m/sec in controls (P < 0.05). Morphometrically, there were more regenerated myelinated fibers (RMFs) at 12 days, and larger diameter of RMFs were observed at 12, 28, and 56 days in the GM1-treated groups.

Contents Preface Overview 1. Galectins in Disease and Potential Therapeutic Approaches Anatole A. Klyosov and Peter G. Traber Galectin and Galectin Inhibitors: Structural Aspects 2. Low-Molecular Weight Inhibitors of Galectins Hakon Leffler and Ulf J. Nilsson 3. From Carbohydrate to Peptidomimetic Inhibitors of Galectins Kevin H. Mayo Galectin Extra- and Intra-Cellular Functions and Their Therapeutic Implications 4. Intracellular Galectins: Platforms for Assembly of Macromolecular Complexes John L. Wang, Kevin C. Haudek, Patricia G. Voss, Ronald J. Patterson, and Eric J. Arnoys 5. Galectins as Novel Regulators of Platelet Signaling and Function: Therapeutic Implications Gabriel A. Rabinovich and Mirta Schattner 6. Galectin-1 Cross-Linking of GM1 Ganglioside in Autoimmune Suppression Robert W. Ledeen, Gusheng Wu, David Bleich, Zi-Hua Lu, and Hans-Joachim Gabius 7. How To Build "Lean and Mean" Anti-Tumor T Cells: A Strategic View into the Anti-Carbohydrate Action of Fluorinated Glucosamine Analogs Charles J. Dimitroff 8. Post-Translational Modification of Galectin-3 and Its Role in Biological Function James C. Byrd, Nachman Mazurek, and Robert S. Bresalier Galectin Mechanisms and Therapeutic Approaches in Cancer 9. The Role of Galectin-3 in Malignant Melanoma Gordana Radosavljevic, Ivan Jovanovic, Jelena Pantic, Nada Pejnovic, Nebojsa Arsenijevic, Daniel K. Hsu, and Miodrag L. Lukic 10. Galectins as Novel Targets for the Treatment of Malignant Gliomas Herwig M. Strik and Matthias Ocker 11. Dynamic Tuning of Galectins and Their Binding Sites During Mammary Tumor Progression and Metastasis Joana T. de Oliveira and Fatima Gartner 12. Galectin-3C: Human Lectin for Treatment of Cancer Gary A. Jarvis, Leonardo Mirandola, Yu Yuefei, Everardo Cobos, Maurizio Chiriva-Internati, and Constance M. John 13. Angiostatic Cancer Therapy by Targeting Galectins in the Tumor Vasculature Iris A. Schulkens, Arjan W. Griffioen, and Victor L. Thijssen 14. Galectins and Pathologies: Role of Galectin-3 in the Communication between Leukemia Cells and the Microenvironment Nora Heisterkamp, Fei Fei, and John Groffen 15. Translational Rational for the Clinical Development of OTX-008: A Novel Drug That Inhibits Galectin-1 Expression in Human Cancer Models Eric Raymond, Lucile Astrorgue-Xerri, Maria Serova, Maria Eugenia Riveiro, and Sandrine Faivre 16. Improving the Clinical Efficacy of Cancer Vaccines by Targeting Immune Suppression in Human Tumors Nathalie Demotte, Aristotelis Antonopoulos, Jean-Francois Baurain, Gregoire Wieers, Nicolas Van Baren, and Pierre van der Bruggen 17. Targeting Galectin-3 Unveils the Complexity of Multiple Myeloma: A Sweet Context Leonardo Mirandola, Yuefei Yu, Constance M. John, Marjorie Jenkins, Everardo Cobos, and Maurizio Chiriva-Internati 18. Galectins in the Blood Circulation: Potential Therapeutic Targets of Cancer Metastasis Carrie A. Duckworth and Lu-Gang Yu Galectin Mechanisms and Therapeutic Approaches in Inflammation and Fibrosis 19. A Therapeutic Role for Galectins in Acute Inflammation? Dianne Cooper 20. Galectins in Immune and Inflammatory Diseases: Insights from Experiments with Galectin Deficient Mice Daniel K. Hsu, Ri-Yao Yang, Agnes Fermin, and Fu-Tong Liu 21. Autoimmune Disorders in Galectin-3 Deficient Mice Vladislav Volarevic and Miodrag L. Lukic 22. Galectin-3: A Central Regulator of Chronic Inflammation and Tissue Fibrosis Neil C. Henderson, Alison C. Mackinnon, Claire Rooney, and Tariq Sethi 23. The Role of Galectin-3 in Stellate Cell Activation and Liver Fibrosis Joy X. Jiang, Xiangling Chen, Hiroo Fukada, Dan K. Hsu, Fu-tong Liu, and Natalie J. Torok 24. Galectin-3 Mediated Cardiovascular Fibrogenesis: An Important Cause of Heart Failure and Cardiovascular Mortality Wouter C. Meijers and Rudolf A. de Boer 25. Mucins and Galectin-3 in Ocular Surface Health and Disease Jerome Mauris and Pablo Argueso 26. Role of Galectins in Wound Healing Noorjahan Panjwani, Ph.D. Editors' Biographies Indexes Author Index Subject Index

During a study evaluating GM1 ganglioside as a possible treatment for Alzheimer's disease, two patients suffered immune responses that appeared to be limited to localized inflammation at the sites of the intramuscular GM1 injections. We determined that one patient's anti-GM1 IgM antibody titer rose from 1:400 to 1:3200 and her anti-GM1 IgG titer from < 1:50 to 1:400,000 during the immune response. The second patient's titer rose from < 1:50 to 1:3200 IgM and from 1:3200 to 1:400,000 IgG. These findings document that patients may experience acute rises in their anti-GM1 antibody levels in response to GM1 and that such rises may not necessarily cause significant acute clinical neuronal injury.

After De’s pivotal demonstration in 1959 of a diarrhoeogenic exo-enterotoxin in cell-free culture filtrates from Vibrio cholerae (of classical biotype), much insight has been gained about cholera toxin (CT), which is arguably now the best known of all microbial toxins. The subunit structure and function of CT, its receptor (the GM1 ganglioside), and its effects on the cyclic AMP system and on intestinal secretion were defined in the 1970s, and the essential aspects of the genetic organization in the 1980s. Recent findings have generated additional perspectives. The 3D-crystal structure of CT has been established, the CT-encoding operon has been shown to be carried by a non-lytic bacteriophage, and in depth knowledge has been gained on how the bacterium controls CT gene expression in response to cell density and various environmental signals. The mode of entry into target cells and the intracellular transport of CT are becoming clearer. CT has become the prototype enterotoxin and a widely used tool for elucidating important aspects of cell biology and physiology, e.g., cell membrane receptors, the cyclic AMP system, G proteins, as well as normal and pathological ion transport mechanisms. In immunology, CT has emerged as a potent, widely used experimental adjuvant, and the strong oral-mucosal immunogenicity of the non-toxic B-subunit (CTB) has led to the use of CTB as a protective antigen together with killed vibrios in a widely licensed oral cholera vaccine. CTB has also been shown to promote immunological tolerance against certain types of mucosally co-administered antigens, preferably tissue antigens linked to the CTB molecule; this has stimulated research and development to use CTB in this context for treatment of autoimmune and allergic diseases. In summary, in the 50 years after De’s discovery of CT, this molecule has emerged from being the cholera patient’s “foe” to also becoming a highly useful scientist’s “friend”.

These experiments tested the effectiveness of parenterally administered gangliosides and amphetamine as treatments for spatial learning deficits caused by bilateral lesions of the neostriatum. In Expt. 1, rats were tested postsurgically for 30 days on a shock-avoidance, spatial reversal task. Treatments of gangliosides (GM1 at 30 mg/kg, and AGF2 at 20 mg/kg and 30 mg/kg) and d -amphetamine (2 mg/kg) significantly decreased lesion-induced learning deficits on this task, while treatments of 10 mg/kg AGF2 and the combination of GM1 (30 mg/kg) and d -amphetamine (2 mg/kg) were ineffective. In Expt. 2, rats were given bilateral neostriatal lesions and treated with GM1 (30 mg/kg), AGF2 (20 mg/kg) or d -amphetamine (2 mg/kg) and tested postsurgically for 5 days on a place learning task in the Morris water maze. Only the GM1-treated rats showed a reduction in lesion-induced place learning deficits on this task. Since in both experiments, cell counts near the area of the lesion revealed no differences among any of the brain-damaged groups, it was suggested that the treatments exert their behavioral effects by biochemically activating spared neurons, independent of any ultimate effects they may have on neuronal survival.

In conventional latex-particle agglutination tests, latex beads are either coated with antibody and clump if antigen is present in a sample or are coated with antigen and clump if an antibody is present in a sample. Ligands other than antigen and antibody have not been used previously for latex-particle agglutination tests. We report here a new variation, a sandwich latex-particle agglutination test in which interactions between GM1 gangliosides, antigen (cholera toxin) and anticholera antibody are used to affect agglutination. the principles that are described can be applied to develop tests for the rapid detection of other small ligands.

Glutamate significantly increased intracellular calcium concentration, enhanced45Ca2+ entry, and activated Na+/Ca2+ exchanger in synaptosomes from rat cerebral cortex. Preincubation with GM1 ganglioside reduced the glutamate-induced increase in intracellular calcium and45Ca2+ entry. Gangliosides and glutamate stimulated Na+/Ca2+ exchanger showing additive effects.

The accumulation of amyloid beta (Abeta) protein in the brain reflects the cognitive impairment noted in Alzheimer's disease. Recent studies have shown that brain Abeta disappeared and cognitive improvement occurred as a result of passive or active Abeta immunization. Peripheral administration of nonimmunization substances, such as GM1 ganglioside, also reduced brain Abeta. Therefore, we hypothesized that the rapid removal of Abeta from the blood by an extracorporeal system may act as a peripheral Abeta sink from the brain. In the present study, we investigated the Abeta removal activity of medical materials as a first step toward the design of an Abeta removal system. First, the removal activities of six materials were studied for Abeta(1-40) and Abeta(1-42) by batch analysis in albumin solution or in human plasma for 1-16 h. Two of the six materials reduced the Abeta concentrations by 90-99% within 1 h. Next, the two effective materials, hexadecyl-alkylated cellulose particles (HDC) and charcoal, were analyzed in a continuous single-pass system with minicolumns. Both materials showed around 81-90% removal activity for more than 2 h, which corresponded to over 4 l of plasma treatment in humans. In a human extracorporeal system, HDC also removed both Abeta(1-40) and Abeta(1-42) from whole blood circulation. In conclusion, biomedical materials were found that could remove Abeta(1-40) and Abeta(1-42) effectively in an extracorporeal system. It is now conceivable that further studies can be undertaken to reduce Abeta concentrations in the brain to improve cognitive function.

A long molecular dynamic simulation of a fully hydrated DOPC bilayer, containing one GM1 ganglioside molecule embedded in each of the two leaflets, has been performed. The location and conformation of the GM1 molecules as well as their effect on the properties of the membrane are investigated in detail. The simulation results reveal that the GM1 molecules are present in two equilibrium arrangements, differing in the orientation of one of their two headgroup branches. The existence of these two equilibrium arrangements of GM1 in the membrane is clearly demonstrated, although their relative population, and hence their free energy difference, cannot be inferred from the present results. A condensing effect on the membrane due to the presence of the GM1 molecules is observed, and the local changes in surface density are analyzed using Voronoi polygons. Although the DOPC molecules are packed more closely in proximity of the gangliosides, the analysis of the deuterium order parameter shows that the DOPC tails are less ordered when close to a GM1.

One month intact C57BL/6 mice were treated with GM1 ganglioside for 3 consecutive weeks. At 2 months of age, treated and control mice were observed in the open-field situation and tested for spatial learning in a radial eight-arm maze. The results showed that, in the open-field, treated mice displayed less freezing but more rearing behavior than control animals. In the radial maze, GM1-treated mice made more correct path choices before the first error within each trial than control mice. However, this improvement was limited to the first stage of training. These results suggest an early stimulating effect of the GM1 ganglioside treatment which could facilitate adaptive reactions to new situations.

New fluorophore-labelled G(M1) gangliosides have been synthesised and spectroscopically characterised. Spectroscopically different BODIPY groups were covalently linked, specifically to either the polar or the hydrophobic part of the ganglioside molecule. The absorption and fluorescence spectroscopic properties are reported for 564/571-BODIPY- and 581/591-BODIPY-labelled G(M1). Each of the different BODIPY groups is highly fluorescent and depolarisation experiments provide molecular information about the spatial distribution in lipid bilayers, as well as order and dynamics. From experiments performed on two spectroscopically different BODIPY:s, specific interactions can be revealed by monitoring the rate/efficiency of donor-acceptor electronic energy transfer. Systems of particular interest for applying these probes are e.g. mixtures of lipids, and peptides/proteins interacting with lipid membranes.

GM1 gangliosidosis is one of the inherited metabolic lysosomal storage disorders characterized by neurological symptoms caused by beta-galactosidase deficiency and consequent accumulation of GM1 ganglioside in neuronal cells. Shiba dogs affected with GM1 gangliosidosis have been found to suffer from corneal opacity. In our morphological analysis, keratocyte enlargement was induced by abnormal intracellular accumulation of neutral carbohydrates, resulting in the loss of normal arrangement of collagen fibrils in the opaque cornea was found to be associated with the disorder. We therefore conclude that corneal opacity in this Shiba dog with GM1 gangliosidosis may be caused by neutral carbohydrate accumulation in lysosomes, swelling and dysfunction of keratocytes, and subsequent irregular arrangement of collagen fibrils in the corneal proper substance.

The deposition of amyloid beta-protein (Abeta) is an invariable feature of Alzheimer's disease (AD); however, the biological mechanism underlying Abeta assembly into fibrils in the brain remains unclear. Here, we show that a high-density cluster of GM1 ganglioside (GM1), which was detected by the specific binding of a novel peptide (p3), appeared selectively on synaptosomes prepared from aged mouse brains. Notably, the synaptosomes bearing the high-density GM1 cluster showed extraordinary potency to induce Abeta assembly, which was suppressed by an antibody specific to GM1-bound Abeta, an endogenous seed for AD amyloid. Together with evidence that Abeta deposition starts at presynaptic terminals in the AD brain and that GM1 levels significantly increase in amyloid-positive synaptosomes prepared from the AD brain, our results suggest that the age-dependent high-density GM1 clustering at presynaptic neuritic terminals is a critical step for Abeta deposition in AD.

Chronic administration of GM1 ganglioside to C57BL/6 mice during development improved passive avoidance retention. A significant weight increase was also evident in the treated animals in comparison with the control group. The results are discussed in terms of the possible effects exerted by GM1 upon the cholinergic mechanisms of this inbred strain.

We report a case of partially treated brucellosis that developed quadriparesis, sixth and seventh cranial nerve palsy, and apnea. Electrodiagnostic studies were in favor of acute axonal poly-radiculoneuropathy. Crossreactive immunological responses due to molecular mimicry between Brucella lipooligosaccharide and GM1 ganglioside may justify the development of acute axonal polyradiculoneuropathy after brucellosis.

Autoimmune neuropathies including Guillain-Barre syndrome are frequently associated with anti-GM1 ganglioside antibodies. These are believed to play a pathogenic role and their clearance from the circulation would be predicted to produce therapeutic benefit. This study examines the conditions required for effective immunoadsorption of anti-GM1 antibodies using glycan-conjugated Sepharose as a matrix. In solution inhibition studies using a range of GM1-like saccharides in conjunction with mouse and human anti-GM1 antibodies, the whole GM1 pentasaccharide beta-Gal-(1-3)-beta-GalNAc-(1-4)-[alpha-Neu5Ac-(2-3)]-beta-Gal-(1-4)-beta-Glc was the favored ligand for maximal inhibiton of antibody-GM1 interactions in comparison with monosaccharides, Gal-(1-3)-beta-GalNAc-beta OMe, and synthetic GM1 mimetics. Immunoadsorption studies comparing binding of mouse monoclonal anti-GM1 antibodies to GM1-Sepharose and beta-Gal-(1-3)-beta-GalNAc-Sepharose confirmed the preference seen in solution inhibition studies. GM1-Sepharose columns were then used to adsorb anti-GM1 immunoglobulin G and immunoglobulin M antibodies from human neuropathy sera. Anti-GM1 antibodies subsequently eluted from the columns often showed a striking monoclonal or oligoclonal pattern, indicating that the immune response to GM1 is restricted to a limited number of B-cell clones, even in the absence of a detectable serum paraprotein. These data support the view that immunoadsorption plasmapheresis could potentially be developed for the acute depletion of serum anti-GM1 antibodies in patients with neuropathic disease, and also provide purified human anti-GM1 antibodies for analytical studies.

C-Galactosides have been used as scaffolds to design a library of non-hydrolysable inhibitors of cholera toxin (CT). Test elements from the library were synthesized and found to inhibit CT binding to an asialofetuin-coated SPR chip with micromolar affinity. Preliminary results are reported. © 2007 Elsevier Ltd. All rights reserved.

The assembly and deposition of amyloid s-protein (As) in the brain are fundamental pathological events in Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). However, it remains to be determined how a nontoxic, monomeric As converts to its assembled toxic form.. We identified a unique As species that tightly binds to GM1 ganglioside and appears during the early pathological changes of AD. Based on the molecular characteristics of GM1 ganglioside-bound As (GAs), we hypothesized that As adopts an altered conformation through binding to GM1 ganglioside and acts as a seed for A8 aggregation. We confirmed GAs generation in the brain using a novel monoclonal antibody against purified GAs. While, the specific mechanism of GAB generation in the brain remains to be clarified, results from animal models suggest that GM1 expression and distribution are altered in AD brains. Furthermore, our recent finding shows that specific, selectively expressed gangliosides preferentially facilitate assembly of some hereditary variations of As that can lead to accumulation. The pivotal roles of gangliosides in the induction of As assembly and deposition of As in the brain are discussed.

A fundamental question about the pathogenesis of Alzheimer's disease (AD) is how monomeric, nontoxic amyloid beta-protein (Abeta) is converted to its toxic aggregates in the brain. The author previously identified a unique Abeta species in the AD brain, which is characterized by its binding to GM1 ganglioside (GM1). On the basis of the molecular characteristics of GM1-bound Abeta (GAbeta), the author hypothesized that GM1 plays a critical role in the process. The author recently examined this possibility using a novel monoclonal antibody raised against purified GAbeta and validated that GAbeta is endogenously generated in the brain and accelerates Abeta assembly by acting as a seed. Furthermore, the author provided a possibility that aging and the expression of apolipoprotein E4 facilitate Abeta assembly in the brain through an increase in the GM1 content in the neuronal membranes, which likely induces GAbeta generation. The author's results imply a mechanism underlying the onset of AD and also provide a new insight into development of novel therapeutic strategy.

Purpose: To report four patients with otherwise unexplained ophthalmoplegia who were found to have elevated levels of anti-GM1 antibodies. Methods: Retrospective chart evaluation of 50 consecutive patients with otherwise unexplained ophthalmoparesis. All patients were tested for anti-GM1 antibodies. Results: Six out of 50 cases (12%) were found to have elevated anti-GM1 antibodies, far greater than the 2.7% found in the general population. Four of the subjects with elevated anti-GM1 antibodies are reported. Conclusion: Although the mechanism and relationship between the neural antibodies and ophthalmoparesis is not understood, it is proposed that the presence of anti-GM1 antibodies should be considered in cases of otherwise unexplained ophthalmoplegia.