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PubMed1991

Glutamic acid decarboxylase (GAD)-immunoreactive structures in the adult human lateral geniculate nucleus.

The distribution of glutamic acid decarboxylase (GAD)-like immunoreactivity in the lateral geniculate nucleus (LGN) of the human adult was studied in vibratome sections (50-60 microns thick) using the avidinbiotin-peroxidase method. The tissue was obtained at autopsy from five individuals without any known neurological disorders. Only few GAD-immunoreactive neurons were present in the layers of the LGN, even less in the interlaminar zones. The numerical density of GAD-immunoreactive neurons and puncta (probably synaptic boutons and or cross sectioned cell processes) in the magnocellular layers was larger than in the parvocellular layers. Furthermore, no striking differences between the individual parvocellular layers were noted. The immunoreactive somata were polygonal or triangular, occasionally pear-shaped, and ranged in size from 15 to 25 microns. They gave off two to four short, thick, straight primary dendrites. A preferred orientation of dendrites was not recognized. After bleaching the chromogen 4-chloro-1-naphthol and staining for lipofuscin pigment granules and basophilic material, 254 unequivocally relocated GAD-immunoreactive nerve cells could be classified as belonging to the lipofuscin pigment granules-containing class of interneurons.

Adult↗

PubMed1998

Peptide specificity of high-titer anti-glutamic acid decarboxylase (GAD)65 autoantibodies.

To study systematically the linear epitope specificity of anti-glutamic acid decarboxylase (GAD) autoantibodies associated with insulin-dependent diabetes mellitus (IDDM), we produced 93 overlapping 12-residue synthetic peptides derived from the sequence of the human GAD65 protein and covering the entire length of the protein. These peptides were used as antigens in an enzyme immunoassay to screen the sera from 10 IDDM patients, all of which contained at high level autoantibodies directed against GAD65. Three out of ten (30%) IDDM patients had antibodies that reacted with one or more of the synthetic peptides. Two of the peptide-reactive IDDM sera, which also bound denatured recombinant GAD65 on western blots, had the highest titers of anti-GAD antibodies in ELISA assay. Moreover, the anti-GAD antibodies-GAD complexes formed with these sera were characterized by low dissociation rates, indicative of their good stability. A fine specificity analysis, using analogs of antigen peptide 1 (residues 1-12), allowed us to identify the residues at positions 5-9 (GSGFW) as critical for antibody recognition.

Antibody Specificity↗

PubMed1977

Neurotransmitter enzyme abnormalities in senile dementia. Choline acetyltransferase and glutamic acid decarboxylase activities in necropsy brain tissue.

Reductions in 2 neurotransmitter synthesizing enzymes in brain, glutamic acid decarboxylase (GAD) and choline acetyltransferase (CAT), have been found in dementias of different origins, including senile dementia (Alzheimer type). Significant reductions in cerebral GAD have also been found in depression (unipolar). The GAD reductions did not generally appear to be localised in any specific region of the brain examined. However, the reduction of CAT in the hippocampus, relative to reductions in other areas examined, was substantially greater in the brains with Alzheimer-type changes. GAD and CAT activities in normal brains were examined for the effects of some variable factors inherent in necropsy biochemical measurements. These factors included: (i) age; (ii) agonal status; (iii) time of death, and (iv) delay in tissue sampling; and GAD was found to be significantly influenced by (ii), (iii) and (iv) and CAT by (i), (iii) and (iv). None of these factors accounted for the total alterations in the enzyme activities of the mentally abnormal brains. The results indicate that reductions in cerebral GAD require to be interpreted with caution in view of the sensitivity of this enzyme to premortem status but that reductions in cerebral CAT may be a more reliable index of pathological change in senile (Alzheimer-type) dementia.

Age Factors↗

PubMed1994

Evaluation of islet-specific autoantibodies in Japanese patients with insulin-dependent diabetes mellitus: a comparison between autoantibodies to glutamic acid decarboxylase, autoantibodies to 64 kDa islet cell protein and islet cell antibodies.

Autoantibodies to glutamic acid decarboxylase (GAD), autoantibodies to 64 kDa islet cell protein and islet cell antibodies (ICA) were measured in 79 Japanese patients with insulin-dependent diabetes mellitus (IDDM). The overall prevalences of GAD antibodies, 64K antibodies, and ICA in these patients were 69.6% (55/79), 48.1% (38/79), and 46.8% (37/79), respectively. However, in a subset of these patients with recent onset IDDM (< 1 year) the prevalences of GAD antibodies, 64K antibodies, and ICA were 78.8% (26/33), 66.7% (22/33), and 78.8% (26/33), respectively. Furthermore, the prevalences of GAD antibodies, 64K antibodies, and ICA were significantly decreased in patients with long standing diabetes at 60.9% (28/46), 34.8% (16/46), and 23.9% (11/46), respectively. However, when these patients were divided into two groups by the presence or absence of organ-specific autoimmune disease (OSAD), the mean levels of GAD antibodies and ICA in the patients who gave a positive result were significantly higher in patients with OSAD (397 units and 98 JDF units, respectively) than in patients without OSAD (74 units and 39 JDF units, respectively). These results demonstrate that it is important to evaluate the prevalences and levels of islet-specific autoantibodies when considering disease duration and co-existence of autoimmune disease in patients with IDDM.

Adolescent↗

PubMed1996

Comparison of the islet cell antibody pattern of monoclonal glutamic acid decarboxylase antibodies recognizing linear and conformational epitopes.

In order to compare the reactivity of glutamic acid decarboxylase (GAD) antibodies recognizing linear and conformational epitopes as islet cell cytoplasmic antibodies (ICA), monoclonal antibodies were generated. An ELISA displacement test using two biotinylated monoclonals recognizing a linear (M61/7E11) or a conformational GAD65 epitope (M65/6B12) was performed to identify epitope regions recognized by monoclonal GAD antibodies. The GAD binding by monoclonal GAD antibodies was tested by immunofluorescence on fixed and unfixed pancreatic sections of human, rat, and mouse, and by Dot-blot experiments. 16/23 (69.6%) of the monoclonals were specifically reactive with GAD65 and 7/23 (30.4%) were reactive with both GAD isoforms. 8/16 (50%) of monoclonal GAD65 antibodies recognized a linear GAD epitope located at the N-terminus (pattern 1). 5/16 (31.3%) displaced M65/6B12, indicating the recognition of a conformational GAD epitope (pattern 2). Monoclonals belonging to patterns 1 and 2 showed strong ICA binding. 3/16 (18.8%) of monoclonals specific for GAD65 with weak or no immunostaining of pancreatic islets (pattern 3) did not inhibit the binding of both biotinylated antibodies in the displacement test, indicating other epitope specificities. In conclusion, GAD antibodies recognizing both conformational and linear epitopes of the GAD65 molecule are involved in ICA binding with strong reactivity. Furthermore, results obtained with monoclonals of pattern 3 suggest the occurrence of GAD65 epitopes partly inaccessible on cryosections, which may result in an ICA-negative test of GAD65 autoantibody positive sera.

Animals↗

PubMed1986

Glutamic acid decarboxylase immunoreactivity in sector CA1 of the human Ammon's horn.

The distribution of glutamic acid decarboxylase (GAD) immunoreactive neurons, fibres and punctae in sector CA 1 of the adult human Ammon's horn was studied in Vibratome sections (40 micron thick) of tissue obtained at surgery and autopsy. On light microscopical examination, the material did not show pathological changes. The antibody was visualized by the unlabelled antibody enzyme method. GAD-immunoreactive neurons, fibres and punctae were present in all layers. Most immunoreactive neurons were located in the stratum pyramidale and stratum lacunosum. Their size ranged from 8 microns in the stratum lacunosum to about 50 microns in the stratum oriens. The somata offered a wide range of shapes, multiform to fusiform with the long axis aligned parallel or vertically to the alveus. All somata belonged to the heterogeneous group of non-pyramidal neurons. The dendrites either radiated in all directions or tended to run in two opposite directions. After bleaching the chromogen and staining for lipofuscin pigment granules and basophilic material, it turned out that within the stratum pyramidale all formerly GAD-immunoreactive neurons belonged to the group of lipofuscin-laden non-pyramidal neurons. Within the other layers, a few formerly GAD-immunoreactive neurons were devoid of lipofuscin pigment. The highest density of GAD-immunoreactive punctae was found in the stratum lacunosum. In addition to numerous GAD-immunoreactive punctae in the pyramidal layer and in the stratum radiatum there were thin GAD-immunoreactive fibres of varying length extending into various directions.

Adult↗

PubMed1988

Distribution of glutamic acid decarboxylase and gamma-aminobutyric acid in the hypoglossal nucleus in the rat.

Immunocytochemistry was used to investigate the distribution of glutamic acid decarboxylase (GAD) and gamma-aminobutyric acid (GABA) in the hypoglossal nucleus (XII) of the adult rat. The distribution of GAD and GABA was found to be co-extensive throughout XII. Although immunoreactivity was moderately dense in all regions, the intensity of staining was greatest in the ventral district of XII particularly ventromedially in the caudal half of the nucleus. Immunoreactive terminal-like profiles were observed around motoneuron somata and dendrites. There also was evidence of sparse mediolaterally-oriented densities of immunoreactivity at the junction of XII and the dorsal vagal nucleus and between dorsal and ventral districts of XII. In addition, neurons staining positive for GABA were found scattered within XII laterally and immediately outside of XII in and around the Nucleus of Roller. These observations suggest a complex, differential distribution of GABA in XII and are discussed in relation to tongue motor behavior.

Animals↗

PubMed1996

A new biological glue from gelatin and poly (L-glutamic acid).

This study describes the potentiality of hydrogels composed of gelatin and poly(L-glutamic acid) (PLGA) as a biological glue for soft tissues and compares its effectiveness with that of a conventional fibrin glue. Water-soluble carbodiimides (WSC) were used to crosslink the aqueous mixture of gelatin and PLGA. The mixed aqueous solution of gelatin and PLGA set to a hydrogel by use of WSC as rapidly as BOLHEAL fibrin glue. An addition of PLGA to gelatin aqueous solution reduced not only its gelation time but also the WSC concentration necessary for hydrogel formation. The cured hydrogel exhibited firm adhesion to the mouse skin and other soft tissues with a higher bonding strength than BOLHEAL fibrin glue. Cohesive failure in the hydrogel was observed when the gel-tissue bond was broken, in contrast to BOLHEAL fibrin glue. The bonding strength of the gelatin-PLGA hydrogel became higher with the increasing PLGA concentration. The inflammatory reaction around the gelatin-PLGA hydrogel subcutaneously implanted in mice was mild, and the hydrogel was gradually absorbed with time in vivo. A toxicity test demonstrated that the concentration of WSC necessary as a biological glue was low enough not to induce its toxicity.

Adhesives↗

PubMed1983

Effects of the glutamic acid decarboxylase inhibitor 3-mercaptopropionic acid on the synthesis of brain GABA in vivo and postmortally.

The effects of the glutamic acid decarboxylase inhibitor 3-mercaptopropionic acid (MPA) on the concentration of GABA in the mouse brain were studied. MPA completely inhibited the postmortem increase in GABA. This effect was used in order to achieve a maximal inhibition of the GABA synthesis in vivo during 67.5 minutes before killing by giving the drug repeatedly (50 mg/kg + 6 X 10 mg/kg i.p.) to mice pretreated with chloral hydrate (100 mg/kg i.p., 65 min before killing). Such a treatment with MPA markedly reduced the accumulation of GABA following inhibition of the GABA transaminase by aminooxyacetic acid but it did not change the endogenous concentration of GABA. This discrepancy might be due to inhibition of the impulse--evoked release of GABA following MPA.

3-Mercaptopropionic Acid↗

PubMed1989

Conformational transition of poly(alpha-L-glutamic acid). A polyelectrolytic approach.

The charge-induced conformational transition of poly(alpha-L-glutamic acid) (PLGA) is considered in this paper from the point of view of proton dissociation. Equations for the excess electrostatic Gibbs energy of dissociation (i.e., delta pKa) are derived as a function of the degree of ionization, alpha. These analytical equations are used to describe some experimental dissociation curves at different polymer and salt concentrations. The dependence of the calculated delta pKa with respect to the ionic strength for the two conformational states, alpha-helical and extended coil, respectively, is rather satisfactorily explained. Even more interesting are the predictions which are derived from this approach for the transition point, alpha tr which is found to be ionic-strength dependent, in full agreement with the experimental results.

Kinetics↗

PubMedDate not supplied

Multivalent conjugates of poly-gamma-D-glutamic acid from Bacillus licheniformis with antibody F(ab') and glycopeptide ligands.

Poly-gamma-D-glutamic acid from Bacillus licheniformis is a water-soluble, nontoxic, nonimmunogenic exopolymer. Using synthetic linkers, the alpha-carboxylate side chains of PGA were conjugated to an exposed thiol side chain of an antibody F(ab') fragment, Mc109F4. Analysis of the PGA-Mc109F4 conjugate by gel filtration HPLC revealed a mixture of multivalent conjugates. The PGA-Mc109F4 conjugate retained biological activity, but showed a lower binding affinity to target BCL3B3 cells than free Mc109F4 F(ab')(2) by flow cytometry, and a lower efficacy for BCL3B3 growth inhibition than free Mc109F4 F(ab')(2). PGA was also conjugated with the free amino group of glycopeptide antibiotic vancomycin. The PGA-vancomycin conjugate showed slightly lower antibacterial activity than free vancomycin versus susceptible Bacillus subtilis, but slightly higher activity versus intrinsically resistant Leuconostoc mesenteroides.

Antibodies, Neoplasm↗

PubMedDate not supplied

Novel functional biodegradable polymer II: fibroblast growth factor-2 activities of poly(gamma-glutamic acid)-sulfonate.

Basic fibroblast growth factor (FGF-2) mitogenic activities of sulfonated poly(gamma-glutamic acid) (gamma-PGA-S) were investigated with chlorate-treated L929 fibroblast culture tests. When 72% of the carboxyl groups in gamma-PGA were sulfonated (gamma-PGA-S72), cell numbers reached a maximum. The activity of gamma-PGA-S72 was higher than that of gamma-PGA and synthetic heparinoids and was almost comparable to that of heparin. Cytotoxicity of gamma-PGA-S72 was not observed, regardless of the degree of sulfonation. FGF-2-protective effects of gamma-PGA-S72 against acid and thermal inactivation were also evaluated, and gamma-PGA-S72 showed higher FGF-2-protective effects in comparison to nonsulfonated gamma-PGA. The steric structures of various sulfonated gamma-PGA-Ss were analyzed by molecular modeling (molecular orbital method (MOPAC)) and indicated that gamma-PGA-Ss are helical in vacuo. Results from MOPAC and the molecular mechanics method (MM2) demonstrated that electrostatic interactions can take place between sulfonic and carboxyl groups of gamma-PGA-S and basic amino acid residues in FGF-2. gamma-PGA-S72 can interact with FGF-2 strongly.

Animals↗

PubMed1990

Effect of opioids on acetylcholine release evoked by K+ or glutamic acid from rat neostriatal slices.

Endogenous acetylcholine (ACh) release from rat striatal slices was measured by a chemiluminescent method. Several opiate agents were tested for their ability to modulate ACh release evoked by potassium ions (K+) or glutamic acid (GLU). Morphine, [D-Ala2,Gly(0l)5]-enkephalin (DAGO), [D-Ala2,D-Leu5]-enkephalin (DADLE) and [D-Pen2-D-Pen5]-enkephalin (DPDPE) were found to have an inhibitory effect on K(+)- or GLU-evoked ACh release. This effect was completely blocked by naloxone, but this antagonist by itself had no effect on ACh release. The action of mu-opiate agonists (morphine and DAGO) on ACh release evoked by K+ was sensitive to tetrodotoxin (TTX), but that of delta-opiate agonists (DADLE and DPDPE) was insensitive. The release evoked by GLU was abolished in the presence of TTX. The activation of kappa-opiate receptor by dynorphin-(1-13) had no effect on K(+)- or GLU-evoked ACh release. It is concluded that mu- and delta-opiate agonists, but not kappa, exert an inhibitory control on striatal cholinergic interneurons, but with a different mechanism of action of localization of the receptors. Corticostriatal glutamatergic neurons have an important role in the interaction of the ACh-opioid systems.

Acetylcholine↗

PubMed2003

Enhancement of neuronal protection from oxidative stress by glutamic acid decarboxylase delivery with a defective herpes simplex virus vector.

We have developed defective herpes simplex virus 1 (HSV-1) vectors, based on amplicon plasmids with a replication-deficient mutant, as helper for the transfer of the glutamic acid decarboxylase (GAD67) or beta-galactosidase (beta-gal) gene as control directed by HCMV promoter into neuronal-like cells (PC12) and primary neurons. GAD67 protein was detected immunochemically, while GAD67 activity in virus-producing and nonproducing cell lines was detected enzymatically or by GABA release. Infection with GAD67-expressing amplicon vectors enhanced the resistance of PC12 cells to H(2)O(2). This protection was related to increased energy metabolism, as shown by MTT reduction and ATP level, and involved the GABA shunt, as shown by the reduction in ATP level seen in the presence of gamma-vinyl GABA (GVG), a specific GABA transaminase inhibitor. Level of glutathione (GSH), which requires ATP for its synthesis, was increased by the GAD67 transgene. The activity of glucose-6-phosphate dehydrogenase involved in the maintenance of the NADPH that can be used for the regeneration of the GSH pool, was increased by infection with amplicon vectors. Thus, replication-deficient HSV-1 and the GAD67 transgene have complementary neuroprotective effects and infection with GAD67-expressing amplicon vectors was able to protect nondifferentiated cortical neurons from glutamate toxicity mediated by oxidative stress. Such defective GAD67-expressing HSV-1, as neurotropic vector, should be helpful in neurodegenerative diseases implicating alterations of energy metabolism and oxidative stress in neuronal cells expressing GABA transaminase.

Adenosine Triphosphate↗

PubMed1995

Similar peptides from two beta cell autoantigens, proinsulin and glutamic acid decarboxylase, stimulate T cells of individuals at risk for insulin-dependent diabetes.

BACKGROUND: Insulin (1) and glutamic acid decarboxylase (GAD) (2) are both autoantigens in insulin-dependent diabetes mellitus (IDDM), but no molecular mechanism has been proposed for their association. We have identified a 13 amino acid peptide of proinsulin (amino acids 24-36) that bears marked similarity to a peptide of GAD65 (amino acids 506-518) (G. Rudy, unpublished). In order to test the hypothesis that this region of similarity is implicated in the pathogenesis of IDDM, we assayed T cell reactivity to these two peptides in subjects at risk for IDDM. MATERIALS AND METHODS: Subjects at risk for IDDM were islet cell antibody (ICA)-positive, first degree relatives of people with insulin-dependent diabetes. Peripheral blood mononuclear cells from 10 pairs of at-risk and HLA-DR matched control subjects were tested in an in vitro proliferation assay. RESULTS: Reactivity to both proinsulin and GAD peptides was significantly greater among at-risk subjects than controls (proinsulin; p < 0.008; GAD; p < 0.018). In contrast to reactivity to the GAD peptide, reactivity to the proinsulin peptide was almost entirely confined to the at-risk subjects. CONCLUSIONS: This is the first demonstration of T cell reactivity to a proinsulin-specific peptide. In addition, it is the first example of reactivity to a minimal peptide region shared between two human autoimmune disease-associated self antigens. Mimicry between these similar peptides may provide a molecular basis for the conjoint autoantigenicity of proinsulin and GAD in IDDM.

Adolescent↗

PubMed2002

Effects of antisense glutamic acid decarboxylase oligodeoxynucleotide on epileptic rats induced by pentylenetetrazol.

OBJECTIVE: To investigate the effects of antisense glutamic acid decarboxylase (GAD(67)) oligodeoxynucleo-tide (ODN) on behavior, seizure threshold and EEG of hippocampus in the epileptic rats induced by pentylenetetrazol (PTZ). METHODS: A model of chronic epilepsy in rats was established by PTZ. The inhibition of GAD(67) mRNA expression in hippocampus was selectively induced by antisense oligodeoxynucleotide of GAD(67). The effect of antisense GAD(67) ODN on behavior, seizure threshold and EEG recording of kindled rats was examined. RESULTS: Antisense GAD(67) ODN could inhibit the expression of GAD(67) mRNA and the concentration of GABA. It also could significantly shorten the latencies of seizure and increase the level of seizure and the frequency of epileptiform discharges. CONCLUSION: The gene of GAD(67) may be an anti-seizure gene, which might inhibit epileptiform discharge. The treatment of epilepsy by GAD(67) gene will have a bright future.

Animals↗

PubMed1975

A new haemoglobin variant: haemoglobin Anantharaj alpha 11 (A9) lysine replaced by glutamic acid.

Four heterozygotes for a fast alpha-chain variant in a Thai family were detected on starch gel electrophoresis during a survey study on iron deficiency anaemia in a rural area not far from Bangkok. They were healthy and had normal haematological profiles except for the presence of around 44% abnormal pigment, quantitated by cellulose acetate electrophoresis. The structural characterization of the variant by globin chain separation, peptide mapping, and amino acid analyses of the abnormal peptides indicated that lysine residue 11 (A9) of alpha-chain was replaced by glutamic acid. This mutation has not been previously described and it is proposed that it be called Haemoglobin Anantharaj.

Amino Acid Sequence↗

PubMed1997

In vitro effects of arachidonic and L-glutamic acids on the high-affinity choline transport in rat hippocampus.

A second messenger role for arachidonic acid (AA) in the regulation of the high-affinity choline uptake (HACU) was suggested. It was reported that micromolar concentrations of AA applied in vitro decreased the HACU values and increased the specific binding of [3H]hemicholinium-3 ([3H]HCh-3). It was published that L-glutamic acid (GA) applied in vivo produced a fall in the HACU values. In addition, GA liberates free AA. In this study, an ability of GA to influence in vitro the activity of presynaptic cholinergic nerve terminals via its effect on the release of AA is investigated in hippocampal synaptosomes of young Wistar rats. Millimolar concentrations of GA decrease both the high- and low-affinity choline uptake, the specific as well as nonspecific binding of [3H]HCh-3 and the activity of Na+, K(+)-ATPase. Kinetic analysis (Lineweaver-Burk and Scatchard plots) reveals a change in Vmax and Bmax, but not in KM and KD. It appears very likely that under normal conditions GA applied in vitro is not able to change markedly the choline transport via its effect on the release of AA. Results confirm the hypothesis about an indirect inhibitory role for glutamatergic receptors on cholinergic cells.

Animals↗