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A Adem

Publications and source records attributed to A Adem.

At least 55 records · Page 3Linked to original sources
PubMed1997

Differential regulation of adenylyl cyclase in fibroblasts from sporadic and familial Alzheimer's disease cases with PS1 and APP mutations.

beta-Adrenoceptor- and forskolin-stimulated adenylyl cyclase activities were determined in primary skin fibroblasts established from patients with sporadic Alzheimer's disease (AD) and from individuals with familial APP KM670/671NL, PS1 M146V and PS1 H163Y mutations. Our data showed a significantly decreased beta-adrenoceptor-stimulated adenylyl cyclase activity in fibroblasts from sporadic AD compared with age-matched controls (p < 0.001, Student's unpaired t-test). In contrast, both beta-adrenoceptor- and forskolin-stimulated adenylyl cyclase activities were significantly increased in fibroblasts bearing PS1 M146V and PS1 H163Y mutations compared with controls (p < 0.01 and p < 0.05, respectively). No differences were seen between cell lines with and without the Swedish APP KM670/671NL double mutation. We suggest that various gene mutations associated with AD have different consequences for the regulation of adenylyl cyclase signal transduction in this disorder.

Adenylyl Cyclases↗
PubMed1997

Expression of MHC class II CD4+ and ED1 molecules in association with selective hippocampal neuronal degeneration after long-term adrenalectomy.

The neuroendocrine and the immune systems are interconnected. Monoclonal antibodies against major histocompatibility complex (MHC) class I, class II, CD4, CD8, pan T cells, and macrophages were used for immunostaining brains from adrenalectomized (ADX) and shamoperated rats to investigate the potential involvement of the immune/inflammatory mechanisms in the neurodegeneration of hippocampus after ADX. Our results demonstrate upregulation of MHC class II, CD4 antigens and activated microglial marker-ED1 expression selectively in the hippocampus after ADX. The absence of CD5 reactivity precludes that these activated cells were T lymphocytes. The activated microglial cells may either be instrumental in the hippocampal neuronal loss or activated secondarily to the neuronal degeneration after long-term adrenalectomy.

Adrenalectomy↗
PubMed1997

Muscarinic receptor subtype selective toxins.

The muscarinic acetylcholine receptors are monomeric proteins with seven hydrophobic, membrane spanning helices, and share a common evolutionary origin with the other members of the superfamily of membrane proteins known as seven-helix receptors. The amino acid sequences of five different muscarinic acetylcholine receptors, called m1, m2, m3, m4 and m5 have been determined. The five subtypes are expressed to different extent in different tissues. A large number of low molecular ligands for muscarinic receptors are known, but they bind to all five subtypes of receptors and only a few of them have a slightly higher (five-six fold) affinity for one of the subtypes, e.g. pirenzepine for M1 (1) and tripitramine for M2 receptors (2). Several neurotoxins have been isolated from snake venoms and used as pharmacological tools. Mambas, African snakes of genus Dendroaspis, have toxins that recognize muscrinic receptors and some of these muscarinic toxins are the most selective ligands for M1 and M4 receptors known to date.

Amino Acid Sequence↗
PubMed1997

Localization of M1 muscarinic receptors in rat brain using selective muscarinic toxin-1.

Mambas, African snakes of the genus Dendroaspis, produce several types of toxins that are of pharmacological interest. The novel muscarinic toxin-1 (MT-1), from the green mamba Dendroaspis angusticeps, binds specifically to muscarinic M1 receptors in homogenates of rat cerebral cortex. Iodination of the toxin, 125I-muscarinic toxin-1 (125I-MT-1), renders the toxin selective for M1 muscarinic receptors. Quantitative measurement of 125I-MT-1 autoradiography in rat brain sections indicated highest labeling in the nucleus accumbens, striatum, and dentate gyrus. High densities of 125I-MT-1 binding sites were located in the CA1 region of the hippocampus, frontal, and parietal cortices. Moderate densities of binding sites were seen in temporal cortex, and hippocampal subregions CA2, CA3, and CA4, whereas low labeling was observed in the cerebellum and spinal cord.

Amino Acid Sequence↗
PubMed1997

Growth hormone stimulates production of interferon-gamma by human peripheral mononuclear cells.

There is substantial evidence for interactions between the immune and endocrine systems at different levels. In the present study we investigated whether human growth hormone (hGH) could stimulate proliferation of interferon-gamma-secreting cells (IFN-gamma-SC), and production of IFN-gamma. Human peripheral blood mononuclear cells (PBMC) taken from 15 normal subjects were incubated with varying doses (200,400,600 and 800 ng/ml) of recombinant hGH. Samples of cells were also incubated with PBS buffer (without hGH) to serve as controls. Effects of hGH were studied by enumerating IFN-gamma-SC and by measuring the concentration of IFN-gamma using an Immunospot assay and an enzyme-linked immunosorbent assay, respectively. The results showed that hGH significantly increased both the number of IFN-gamma-SC and the concentration of IFN-gamma in a dose-dependent manner. The maximum effects were obtained in the presence of (400 ng/ml) hGH (15 +/- .5 IFN-gamma-SC/10(6) PBMC and 300 +/- 55 U/ml IFN-gamma) compared to controls (4 +/- 2 IFN-gamma-SC/10(6) PBMC and 50 +/- 10 U/ml IFN-gamma). The results of the present study suggest that hGH might influence the immune system by stimulating the proliferation of IFN-gamma-SC and the production of IFN-gamma.

Human Growth Hormone↗
PubMed1997

Apolipoprotein E polymorphism in elderly east Africans.

Current advances have shown the apolipoprotein E (APOE)-epsilon 4 allele to be highly associated with late-onset familial and sporadic Alzheimer's disease (AD) in Western populations. The association of APOE allele frequencies and dementia remain unknown in populations from developing countries. We recently initiated a project to examine APOE frequencies in non-demented and demented elderly East Africans. Blood DNA collected from two hospital-based populations showed that the APOE allele frequencies in a group of non-demented 67 Tanzanians over the age of 65 years were found to be 14% for epsilon 2, 61% for epsilon 3 and 25% for epsilon 4. By comparison, the frequency of APOE-epsilon 4 in an age-matched demented group was also 25%. Assessment of APOE genotypes in the group of elderly Kenyan subjects from Nairobi also revealed high frequencies of the epsilon 4 allele with no clear difference in frequency between demented and non-demented subjects. Our preliminary observations suggest that elderly East Africans with no apparent clinical AD possess relatively high APOE-epsilon 4 allele frequencies compared to normal ageing subjects from Western countries including African-Americans. These results appear similar to those reported in a recent study in Nigerian Africans where a lack of correlation between APOE-epsilon 4 allele frequency and Alzheimer type of dementia was noted, and imply that APOE-epsilon 4 allele may not necessarily be a risk factor in some populations of Africa.

Aged↗
PubMed1996

Abundance of the longer A beta 42 in neocortical and cerebrovascular amyloid beta deposits in Swedish familial Alzheimer's disease and Down's syndrome.

Recent studies have demonstrated the deposition of amyloid beta (A beta) protein with carboxyl- and aminoterminal heterogeneity in cortical and cerebrovascular deposits of Alzheimer's disease (AD). Using carboxyl end-terminal specific antibodies to A beta peptides, we examined the immunocytochemical distribution of A beta 40 and A beta 42 species in brain tissue from a Swedish subject with familial AD (FAD) bearing the double mutation at codons 670/671 in the amyloid beta precursor protein (A beta PP), and from subjects with Down's syndrome and sporadic AD. In the Swedish subject, we found profound parenchymal A beta deposits and cerebral amyloid angiopathy in all four cortical lobes and cerebellum. A beta 42 was evident in almost all parenchymal deposits as well as many vascular deposits. Although A beta 40 was present in meningeal and intraparenchymal vessels, deposits containing this shorter peptide reactivity were sparse. Surprisingly, our observations in Swedish FAD showing a remarkable abundance of A beta 42 in both parenchymal and vascular deposits were qualitatively similar to the Down's syndrome and most sporadic AD cases, and to previously published A beta PP717 FAD. While previous transfection studies in different cell cultures indicate substantially increased soluble A beta production and A beta 40 species to be predominant, it would appear that the double A beta PP mutations in Swedish FAD largely result in the deposition of the longer A beta 42 in vivo.

Adult↗
PubMed1996

Rat striatal muscarinic receptors coupled to the inhibition of adenylyl cyclase activity: potent block by the selective m4 ligand muscarinic toxin 3 (MT3).

1. In rat striatal membranes, muscarinic toxin 3 (MT3), a selective ligand of the cloned m4 receptor subtype, antagonized the acetylcholine (ACh) inhibition of forskolin- and dopamine D1 receptor-stimulated adenylyl cyclase activities with pA2 values of 8.09 and 8.15, respectively. 2. In radioligand binding experiments, MT3 increased the Kd but did not change the Bmax value of [3H]-N-methylscopolamine (3H]-NMS) binding to rat striatal muscarinic receptors. The toxin displaced the major portion of the [3H]-NMS binding sites with a Ki of 8.0 nM. 3. In rat myocardium, MT3 antagonized the ACh inhibition of adenylyl cyclase with a Ki value of 860 nM. 4. In rat cerebral cortical membranes prelabelled with [3H]-myo-inositol, MT3 counteracted the methacholine stimulation of [3H]-inositol phosphates formation with a Ki value of 113 nM. 5. The present study shows that MT3 is a potent antagonist of the striatal muscarinic receptors coupled to inhibition of adenylyl cyclase activity. This finding provides strong evidence for the classification of these receptors as pharmacologically equivalent to the m4 gene product (M4). On the other hand, the weaker potencies of MT3 in antagonizing the muscarinic responses in cerebral cortex and in the heart are consistent with the reported lower affinities of the toxin for the cloned m1 and m2 receptor subtypes, respectively.

Acetylcholine↗
PubMed1995

Muscarinic toxins from the black mamba Dendroaspis polylepis.

Three new toxins acting on muscarinic receptors were isolated from the venom of the black mamba Dendroaspis polylepis. They were called muscarinic toxins alpha, beta, and gamma (MT alpha, MT beta, and MT gamma). All of the toxins have four disulphide bonds and 65 or 66 amino acids. The sequences of MT alpha and MT beta were determined. The muscarinic toxins, of which about 12 have been isolated from venoms of green and black mambas, have 60-98% sequence identity with each other, and are similar to many (about 180) other snake venom components, such as alpha-neurotoxins, cardiotoxins, and fasciculins. In contrast to the alpha-neurotoxins, muscarinic toxins do not bind to nicotinic acetylcholine receptors. The binding constants of MT alpha and MT beta were determined for human muscarinic receptors of subtypes m1-m5 stably expressed in Chinese hamster ovary cells. The toxins are less selective than the earlier discovered muscarinic toxins from the green mamba Dendroaspis angusticeps. MT alpha and the muscarinic toxin MT4 from D. angusticeps differ only in a region of three amino acids (residues 31-33), which are Leu-Asn-His in MT alpha and Ile-Val-Pro in MT4. This difference causes a pronounced shift in subtype selectivity. MT alpha has high affinity to all subtypes, with Ki (inhibition constant) values of 23 nM (m1; pKi = 7.64 +/- 0.10), 44 nM (m2; pKi = 7.36 +/- 0.06), 3 nM (m3; pKi = 8.46 +/- 0.14), 5 nM (m4; pKi = 8.32 +/- 0.07), and 8 nM (m5; pKi = 8.09 +/- 0.07). MT4 has high affinity only to m1 (Ki = 62 nM) and m4 (87 nM) receptors, and low (Ki > 1 microM) affinity to m2, m3, and m5. The region at positions 31-33 evidently plays an important role in the toxin-receptor interaction. MT beta has low affinity for m1 and m2 receptors (Ki > 1 microM) and intermediate affinity for m3 (140 nM; pKi = 6.85 +/- 0.03), m4 (120 nM; pKi = 6.90 +/- 0.06), and m5 (350 nM; pKi = 6.46 +/- 0.01). The low affinity of MT beta may reflect a tendency for spontaneous inactivation.

Amino Acid Sequence↗
PubMed1995

Prolactin binding sites in rat brain and liver: effects of long-term ovariectomy and ovarian steroids.

The effects of long-term ovariectomy on the levels of brain and liver lactogenic binding sites as well as plasma and liver prolactin (PRL) have been investigated in sham-operated and ovariectomized rats receiving either 17 beta estradiol (OVX-E), progesterone (OVX-P), or vehicle (OVX-V). The levels of lactogenic binding sites in the parietal and piriform cortices, amygdala, thalamus, hypothalamus, as well as in the liver were significantly decreased after long-term ovariectomy. Moreover, the levels of plasma and liver PRL were also significantly decreased. Exogenous estradiol and progesterone replacement restored the levels of lactogenic binding sites in the parietal cortex and hypothalamus as well as in the liver. However, plasma and liver PRL levels were significantly increased by estradiol but only restored by progesterone. These results suggest that ovarian steroids influence the levels of lactogenic binding sites and prolactin.

Animals↗
PubMed1995

Effects of long-term ovariectomy and ovarian steroids on somatogenic binding sites in rat brain and liver.

The effects of long-term ovariectomy and replacement with ovarian steroids on the levels of brain and liver somatogenic binding sites as well as plasma and liver growth hormone (GH) were studied in sham-operated (Sham) and ovariectomized female rats receiving either, 17 beta-estradiol (OVX-E), progesterone (OVX-P), or vehicle (OVX). Long-term ovariectomy decreased the levels of somatogenic binding sites in the choroid plexus and liver as well as GH in plasma and liver. The levels of these sites in the choroid plexus were partially restored only by estradiol replacement. Moreover, exogenous estradiol but not progesterone restored the levels of plasma and liver GH as well as liver somatogenic binding sites. Our results suggest that estrogens regulate the levels of somatogenic binding sites in the liver and choroid plexus.

Animals↗
PubMed1995

Behavioural deficits in adult rats following long-term adrenalectomy.

Long-term adrenalectomy results in loss of neurones in the hippocampal formation of the adult rat. The effects of long-term adrenalectomy on spatial learning and exploratory behaviour in adrenalectomized (ADX), adrenalectomized normal weight gain (ADXNW), sham operated and naive control male Sprague-Dawley rats were investigated in this study. The ADX rats had significantly longer latencies in the Morris maze task compared to the other groups. In the open-field situation, as a novel finding, the ADX rats showed significantly lower rearing scores compared to other groups. These data indicate that long-term adrenalectomy causes impairment in spatial learning and explorative behaviour in the rat.

Adrenalectomy↗
PubMed1995

Preservation of acetylcholine muscarinic M2 receptor G-protein interactions in the neocortex of patients with Alzheimer's disease.

The efficacy of acetylcholine muscarinic M2 receptor-G protein coupling was investigated in Alzheimer's disease and control neocortical membranes by measuring the effects of MgCl2 and 5'-guanylylimidodiphosphate (Gpp[NH]p) on high-affinity [3H]oxotremorine-M ([3H]OXO-M) binding. MgCl2 gave similar enhancements of [3H]OXO-M binding in Alzheimer's disease and control occipital cortex. In contrast, MgCl2 enhanced [3H]OXO-M binding was significantly higher in Alzheimer's disease superior temporal cortex, compared to controls. MgCl2 enhanced [3H]OXO-M binding in both the occipital and temporal cortices of the Alzheimer's disease cases was reversed to control levels by Gpp[NH]p. It is concluded that the number of high-affinity muscarinic M2 sites is increased in Alzheimer's disease superior temporal, but not occipital, cortex and that M2 sites in both regions maintain an efficient G-protein coupling.

Aged↗
PubMed1995

Characterization of muscarinic acetylcholine receptors in cultured adult skin fibroblasts: effects of the Swedish Alzheimer's disease APP 670/671 mutation on binding levels.

We have characterised the muscarinic receptor subtypes found in human skin fibroblasts and compared binding levels in cell lines from members of the Alzheimer's disease family with the Swedish amyloid precursor protein (APP) 670/671 mutation. Binding studies with [3H] quinuclidinyl benzilate ([3H]QNB) and the M2/M4 selective antagonist [3H] (+/-)-5,11-dihydro-11-([(2-[(di-propylamino)methyl]-1- piperidinyl]ethyl)amino]carbonyl)-6H-pyrido(2,3-b)(1,4)benzodiazepine-6- one ([3H]AF-DX 384) revealed the presence of a single population of muscarinic receptors on lysed fibroblast membranes. [3H]QNB binding was displaced by a number of selective muscarinic ligands with a rank order of potency: atropine > himbacine > methoctramine > (+/-)-p-fluoro-hexahydro-sila-difenidol hydrochloride > pirenzepine > muscarinic-toxin-3. APP 670/671 mutation carrying cell lines showed 25-35% lower levels of muscarinic receptors labelled with [3H]QNB, [3H]N-methyl scopolamine and [3H]AF-DX 384, compared to controls. This difference was not statistically significant due to large individual variation. It is concluded that muscarinic receptors on adult skin fibroblasts are predominantly of the M2 subtype. Since these cells do not possess M1 and M3 receptor subtypes, they are unlikely to provide a good model for studying muscarinic receptor regulation of APP processing.

Aged↗
PubMed1995

A snake toxin against muscarinic acetylcholine receptors: amino acid sequence, subtype specificity and effect on guinea-pig ileum.

The sequence of muscarinic toxin 1 (MT1) from Dendroaspis angusticeps (green mamba) was determined (66 amino acids, M(r) 7509). The central part, peptide 25-40, is rich in hydrophobic amino acids, which is a characteristic of muscarinic toxins. MT1 started to inhibit [3H]-NMS (N-methylscopolamine) binding to synaptosomal membranes of porcine brain (contains all five receptor subtypes) at about 1 nM and to membranes from pig heart muscle (only subtype m2) at about 1 microM. Binding of [3H]-AF-DX 384 to heart was inhibited with an IC50 of 14 microM and to brain in two steps. In the first step (IC50 = 32 nM) binding decreased by 37%, indicating that the toxin acted on m1 or m4 receptors, each accounting for about 40% of total receptor content. The second step was similar to the effect on heart. Pirenzepine inhibited binding of [125I]-MT1 to brain receptors with an IC50 of 6.5 nM, corresponding to a Ki of about 6 nM. Literature values of Ki for pirenzepine are 16-18 nM for m1 and > or = 120 mM for other subtypes. This indicates binding to m1 receptors. mM for other subtypes. This indicates binding to m1 receptors. [125I]-MT1 bound to brain with a Kd of 20 nM and a Hill coefficient of 1.0, i.e. one toxin molecule per receptor. In guinea-pig ileum, MT1 (670 nM) produced a rapid contraction, reversible by atropine. The toxin may be an agonist, but might also cause contraction by inducing acetylcholine release by a different mechanism.

Amino Acid Sequence↗
PubMed1995

Vascular permeability to growth hormone in the rat central nervous system after focal spinal cord injury. Influence of a new anti-oxidant H 290/51 and age.

Vascular permeability to the growth hormone (GH) across the blood-brain barrier (BBB) is unknown. This investigation was undertaken to examine vascular permeability to 125I-labelled rat growth hormone (rGH) in the central nervous system (CNS) of normal animals. Since age and spinal cord injury influences the metabolism of GH, these factors were also included. No statistically significant difference was seen regarding rGH permeability between young (aged 19-21 weeks) and old (age 38-42 weeks) animals. A focal trauma to the cord, produced by an incision into the right dorsal horn of the T10-11 segments in young animals, increased rGH permeability in several spinal cord segments at 0.5-5.0 h after injury. This permeability increase progressed over time. Similar trauma to old rats resulted in a significantly less increase in rGH permeability in the spinal cord 5 h after the trauma. This indicates that trauma-induced increased permeability of rGH is age-dependent. Pretreatment of normal young animals with a new antioxidant (H 290/51) did not influence the rGH permeability. However the drug prevented the trauma-induced increase of rGH permeability at 5 h after injury. This indicates that inhibition of lipid peroxidation has some protective effect on trauma-induced increase in rGH permeability.

Aging↗
PubMed1994

Loss of neurones after long-term adrenalectomy in the adult rat hippocampal formation.

The effects of long-term adrenalectomy (ADX) on hippocampal neurones were investigated 5 months after surgery in male Sprague-Dawley rats. Cells in Nissl-stained sections from ADX rats were counted and compared with those in sections from sham-operated rats. The ADX rats had a significantly reduced number of dentate granule cells. A novel finding was a significant reduction in the number of pyramidal cells in CA1, CA2, CA3 and CA4 regions of the hippocampus. Thus long-term adrenalectomy causes loss of dentate granule cells and pyramidal neurones of the hippocampus.

Adrenalectomy↗