Assignment of a familial Alzheimer's disease locus between D14S289 and D14S53.
Explore the source record for details and available documents.
Alleles↗
Biomedical subjects
T Tabira
Publications and source records attributed to T Tabira.
Insulin-like growth factor II promotes in vitro cholinergic development of mouse septal neurons: comparison with the effects of insulin-like growth factor I.
We investigated the effect of insulin-like growth factors II and I (IGFII and IGFI) on septal primary cultures from mouse embryonic day 15 brains. The addition of IGFII to septal cultures enhanced total choline acetyltransferase (ChAT) activity in a dose-dependent manner. Maximal stimulation of ChAT activity was observed at 10 ng/ml IGFII. The effect of IGFII on ChAT activity was completely blocked by anti-IGFII/M-6-P receptor antibodies, whereas the antisera alone had no effect on the enzyme activity. Double-labeled immunohistochemical studies revealed that most ChAT-positive neurons expressed IGFII/M-6-P receptor immunoreactivity. These results indicate that the trophic effect of IGFII results from the direct action of this molecule through the IGFII/M-6-P receptor in septal cholinergic neurons. IGFI also stimulated ChAT activity, but with less potency than IGFII. Antibodies against the IGFII/M-6-P receptor inhibited approximately 50% of the IGFI response, suggesting that the effect of IGFI is mediated in part by the IGFII/M-6-P receptor. Thus, it appears that IGFII and IGFI are potent trophic factors for central cholinergic neurons and could potentially play a significant role in the differentiation, maintenance and regeneration of these neurons.
Animals↗
Demonstration of amyloid beta-protein secretion in a mouse neuronal cell line.
We investigated the secretion of amyloid beta-protein (beta AP) in a mouse neuronal cell line SN49. SN49 cells stably transfected with mouse beta-amyloid precursor protein (APP) 695 cDNA released approximately three times greater amounts of a 4 kDa protein immunoreactive with anti-beta AP antibodies than untransfected and mock-transfected cells. This 4 kDa protein was further identified as mouse beta AP by direct amino acid sequence analysis. These results strongly suggest that the beta AP secretion occurs in mouse neuronal cells as in human cells.
Amino Acid Sequence↗
HSP72 induction by heat stress is not universal in mammalian neural cell lines.
Heat-induced expression of 72-kDa heat shock protein (HSP72) was investigated in a panel of neuronal and non-neuronal cell lines by immunoblotting and immunocytochemistry using monoclonal antibodies directed to HSP72. By immunoblotting, HSP72 expression was observed in most cell lines of mouse (SN6.1b, CL8c4.7, NSC34.6, B2A, C2C12), rat (PC12, C-6, L3), and human (NB-1, GOTO, IMR-32, HeLa) origin under the heat-stressed condition. The mouse neuroblastoma cell line N18TG2, however, did not express HSP72 under the heat-stressed condition. By immunocytochemistry, HSP72 was undetectable in the heat-stressed N18TG2 cells, while it was identified in the heat-stressed SN6.1b cells, a clonal hybrid neuron between N18TG2 and mouse septal cholinergic neuron. By exposure to a priming sublethal heat shock, SN6.1b cells but not N18TG2 cells acquired a significant level of tolerance to a subsequent lethal heat shock. These results suggest that heat-induced expression of HSP72 may contribute to acquisition of the thermotolerant state in SN6.1b cells.
Animals↗
Suppression of lymphocyte spontaneous proliferative response by proteolipid protein peptide in patients with HAM/TSP.
To understand the immune mechanism suggested in HTLV-I-associated myelopathy (HAM/TSP), we investigated T cell response to proteolipid protein (PLP). Because of high autologous proliferative response (APR) of peripheral blood mononuclear cells (PBMC) in culture, the lymphocyte proliferation assay was not useful in this disease. Unexpectedly, however, APR was profoundly (70-98%) suppressed in 6 of 9 cases when PLP peptide 105-124 was added in the culture. PLP peptide 85-104 or 145-159 also suppressed APR in a few cases. Time course study showed that the peptide-mediated suppression became apparent after day 4 in culture. The results can be interpreted as that suppressor cells recognizing the PLP peptides were present in the PBMC of HAM/TSP patients and suppressed the APR as the consequence of antigen specific response. This may indicate that a T cell response to certain PLP determinants is involved in the pathomechanism of HAM/TSP at least in part. Molecular mimicry between PLP and HTLV-I may account for the T cell sensitization to PLP in HAM/TSP.
Adult↗
Rapidly proliferating glial cells isolated from adult mouse brain have a differentiative capacity in response to cyclic AMP.
A glial cell line designated as B2 was generated from primary cultures of oligodendrocytes/astrocytes isolated from an adult BALB/c mouse brain and maintained for over 1 year. Phenotypic characteristics of B2 cells were investigated by immunolabeling with cell type-specific markers for oligodendrocytes (O4 and galactocerebroside (GalC)), astrocytes (glial fibrillary acidic protein (GFAP)), and immature neuroectodermal cells (vimentin). When cultured in a serum-containing medium, B2 cells exhibited a bipolar or a tripolar process-bearing morphology and proliferated with a 24-28 h doubling time, without requirement of exogenous growth factors. Under this culture condition, vimentin was identified in all of the B2 cells, GFAP in 7%, and O4 and GalC in less than 1% of the cells. When cultured in a serum-free medium containing 1 mM dibutyryl cyclic AMP (dbcAMP), B2 cells extended longer processes and 45% of the cells expressed cell type-specific markers for oligodendrocytes or astrocytes. GFAP was identified in 29% of B2 cells, O4 in 16%, and GalC in 6% of the cells, although, neither O4+GFAP+ nor GalC+GFAP+ cells were observed. B2 cells proliferated in response to phorbol 12-myristate 13-acetate (PMA), basic fibroblast growth factor (bFGF), insulin, insulin-like growth factor (IGF-I) and platelet-derived growth factor (PDGF), but not to dbcAMP, forskolin (FK), or retinoic acid (RA). These results indicate that B2 cells are distinct from typical oligodendrocytes and astrocytes with respect to their great proliferative potential, and suggest that B2 cells, with a capacity to differentiate into oligodendrocytes and astrocytes in response to cyclic AMP, may represent a population of glial precursor cells in the adult mouse central nervous system (CNS).
Animals↗
Analysis of T cell antigen receptors of myelin basic protein specific T cells in SJL/J mice demonstrates an alpha chain CDR3 motif associated with encephalitogenic T cells.
Experimental autoimmune encephalomyelitis (EAE) is an animal autoimmune disease mediated by CD4+ T cells. Analysis of TCR expression revealed that limited TCR elements (V beta 8.2, V alpha 2 or 4) were utilized by myelin basic protein (MBP) specific T cells in mice with H-2u haplotype and Lewis rats. The usage of a particular beta chain complementarity determining region 3 (CDR3) motif has also been shown. However, it remains unclear to what extent these observations can be extrapolated. Here we studied the TCR sequences of MBP 89-101/I-A(s) specific T cell clones derived from SJL/J mice, using the polymerase chain reaction on reverse transcribed mRNA. Although the V beta usage was less restricted than in H-2u mice, they predominantly utilized V beta 17a and expressed LGG or related motifs in the V beta-D beta-J beta junctions. Furthermore, a single alpha chain rearrangement between V alpha 1.1 and J alpha BBM142 with no N region diversity was preferentially used. Concordantly, immunization with a peptide corresponding to the alpha chain CDR3 was found to significantly alter the clinical course of EAE. Comparison of the published TCR junctional regions demonstrates that the CDR3 motifs (LGG in beta chain, CA*R*NY motif in alpha chains) are expressed by other encephalitogenic clones. Notably, the CA*R*NY was conserved in PL/J mice clones that recognize a distinct MBP-MHC determinant. It suggests that an antigen-independent mechanism may contribute to conserving the alpha chain motif. The implications of these observations are discussed.
Amino Acid Sequence↗
High expression on Kunitz-type protease inhibitor-containing substances in the cerebral vessels of patients with Down syndrome.
Down syndrome (DS) brains, from 19 gestational weeks to 50 years of age were studied by immunohistochemical methods with a polyclonal antibody against synthetic peptide comprising part of the Kunitz-type protease inhibitor (KPI) domain of Alzheimer disease amyloid precursor protein (APP), residues 301 to 323 of APP 770. In DS, positive KPI immunoreactivity was observed in early infancy and from child to adulthood on the tunica media of the arteries in the leptomeninges, cerebral cortex and white matter, but negative or little in controls. In DS with Alzheimer type dementia, KPI immunoreactivity in the arteries was reduced, but a gross granular reactivity was noted in neurons and glial cells. The high expression of KPI in DS vessels may be one of the predisposing factors to vascular diseases and amyloid deposition associated with DS.
Adolescent↗
The decrement of muscarinic receptor-mediated calcium influx by overexpression of APP in a mouse cholinergic cell line.
The effects of beta-amyloid precursor protein (APP) overexpressing on cell metabolisms of cholinergic neuronal hybridoma cell line (SN49) were examined. The cells stably overexpressing APP contained higher amount of GTP binding protein Go and cytosolic inactive protein kinase C epsilon, and showed less Ca2+ influx through muscarinic acetylcholine receptor ml compared to original and mock cells which had been transfected with a vector alone. The contents of sn-1, 2-diacylglycerol and cyclic AMP were also reduced in the APP transfectants, although the similar changes were observed in the mock cells. These findings strongly suggest that the overexpression of APP affect the transient receptor-mediated ion channel and calcium-related cell metabolisms in neuronal cells.
Acetylcholine↗
[Is a false image of the senile plaque in elderly Japanese with leprosy?--pathological findings on the immunohistology].
By the advance of chemotherapy and aging of the inpatients with leprosy (mean age: 75.7 years), geriatric disease are becoming major problems in Japanese National Leprosarium. Dementia is not diagnosed inpatient with leprosy. After autopsy Alzheimer fibrillary tangle and senile plaques in the brain of aged leprosy is not easy demonstrated by routine stains. However, these is easy demonstrable a different senile plaque with accretion to the Alzheimer fibrillary tangle, if it employed the specific immunohistochemical method on these brain. We employed both tau protein and the divided beta protein, and each of protein is able to divide dementia and non-dementia into aged groups in leprosy. Low prevalence in Japanese leprosy patients is demonstrable in dementia of what happened was accurate in alzheimer disease with subtype of senile plaque.
Aged↗
Decreased beta-amyloid and increased abnormal Tau deposition in the brain of aged patients with leprosy.
We examined the brains of 37 leprosy patients (mean age, 76.3 +/- 7.8 years), 5 patients with Alzheimer-type dementia (mean age, 79.0 +/- 9.5 years), and 23 age-matched non-dementia controls (mean age, 77.6 +/- 5.4 years). The frequency of beta-amyloid (A beta)-positive cases was lower (27.0%) in leprosy patients (n = 37) than in controls (47.8%; P = 0.05, Z = 1.49). When senile plaque subtypes were examined, type III (classical) plaques were significantly fewer (P < 0.05) in leprosy subjects compared with controls. Interestingly, neurofibrillary tangles in the temporal cortex were much more frequent in leprosy patients than in controls (P < 0.05). However, hippocampal CA3 pyramidal neurons in leprosy patients were well preserved. These data indicate that 1) leprosy patients have a low risk of A beta deposition but a high risk of abnormal tau deposition, 2) abnormal tau deposition is unrelated to A beta deposition in leprosy, and 3) neuronal loss is unrelated to abnormal tau deposition. It is not clear at present whether the result is related to the disease process itself, antileprosy treatment, environmental factors, or the genetic background in leprosy patients.
Aged↗
[Target antigens in neuroimmunological diseases].
Target antigens in neuroimmunological diseases were reviewed. These are; ple21 in limbic encephalitis; PCD17, CDR62, CDR34, and CZF in paraneoplastic cerebellar degeneration; one of the anion transporters band 3 in chorea-acanthocytosis; visinin-like substance in cancer-associated retinopathy (CAR syndrome); myelin basic protein (MBP) and proteolipid protein (PLP) in acute disseminated encephalomyelitis; MBP, PLP and myelin-oligodendrocyte glycoprotein (MOG) in multiple sclerosis; glutamic acid decarboxylase in stiff-man syndrome; GM1 ganglioside in amyotrophic lateral sclerosis; peripheral nerve K+ channel in Isaacs syndrome; synaptotagmin in Lambert-Eaton syndrome; acetylcholine receptor in myasthenia gravis; GM1 ganglioside in Guillain-Barré syndrome; GQ1b ganglioside in Fisher syndrome; myelin-associated glycoprotein in IgM paraproteinemic neuropathy; HuD in paraneoplastic sensory neuropathy; and tRNA and HSP65 in polymyositis.
Autoantigens↗
[Concentric sclerosis (Baló)].
Seventeen autopsy cases were collected in the Philippines. Mean age of onset 32.5 years, male/female ratio 1/2, no seasonal change, and the patients' occupation variable. A half had prodromal symptoms: mild fever, general malaise and headache. The disease was characterized by acute onset with behavioral changes, reticence, hemi- or quadriplegia with pyramidal signs, and incontinence. A quarter of patients had generalized seizure. There were no specific abnormalities in the routine blood examination, and CSF showed unexpectedly mild change. CT scan and MRI show diffuse or multifocal abnormalities in the centrum semiovale. They died of cerebral herniation or secondary infection. The brain was characterized by diffuse or multifocal necrotic and concentric demyelination in the cerebral white matter with marked gemistocytosis.
Adult↗
Functional erythropoietin receptor of the cells with neural characteristics. Comparison with receptor properties of erythroid cells.
Radioiodinated erythropoietin (Epo) was bound specifically to the cells of two non-erythroid clonal lines, PC12 and SN6, which expressed neuronal characteristics. The binding was time-, cell number-, and dose-dependent and was reversible. Although the cloned Epo receptor from PC12 cells (derived from rat adrenal medulla) was identical to that from rat erythroid cells, significant differences in the ligand binding properties between two cell lineages were found; 1) PC12 cells had a single class of binding sites with very low affinity (Kd = 16 nM), whereas erythroid cells had two classes of binding sites with different affinities (Kd = 95 pM for high affinity sites and 1.9 nM for low affinity sites), and 2) cross-linking experiments revealed one cross-linked product of 105 kDa for PC12 cells and two products of 140 and 120 kDa for erythroid cells. Taken together with additional results, the presence of a putative accessory protein(s) that may alter the ligand binding affinity through interaction with Epo receptor is discussed. The binding of Epo to PC12 cells caused a rapid increase in the cytosolic concentration of free calcium. The presence of EGTA had no effect on the Epo binding but completely inhibited the calcium increase, indicating that Epo stimulated the calcium influx from outside of the cells. The addition of Epo to the culture media of PC12 cells elevated the intracellular concentrations of monoamines.
Adrenal Medulla↗
Thioredoxin from activated macrophages as a trophic factor for central cholinergic neurons in vitro.
The conditioned medium from gamma-interferon-stimulated macrophages elevated the choline acetyltransferase activity in mouse septal neurons as well as in cholinergic hybrid cell lines SN6.10.2.2 in vitro. After purification and sequencing, the active fraction was identical to thioredoxin (TRX), and the neurotrophic activity of recombinant TRX was confirmed.
Amino Acid Sequence↗
Trophic effect of erythropoietin and other hematopoietic factors on central cholinergic neurons in vitro and in vivo.
In vitro granulocyte colony-stimulating factor (G-CSF), macrophage colony-stimulating factor (M-CSF), erythropoietin (EPO), and erythroid differentiation factor (EDF) augmented choline acetyltransferase (ChAT) activity in mouse embryonic primary septal neurons and in cholinergic hybridoma cell line, SN6.10.2.2. This is similar to the effects seen with interleukin-3 (IL-3) or granulocyte-macrophage colony-stimulating factor (GM-CSF). Moreover, in vivo GM-CSF and EPO promoted survival of septal cholinergic neurons in adult rats which had undergone fimbria-fornix transections. These results suggest that some of the hematopoietic factors act on cholinergic neurons as 'neurotrophic factors' to influence the differentiation, maintenance and regeneration of these neurons.
Animals↗
T lymphocyte lines and clones selected against synthetic myelin basic protein 82-102 peptide from Japanese multiple sclerosis patients.
As has been indicated in experimental autoimmune encephalomyelitis (EAE), the application of synthetic peptides for the selection of T cell lines may provide new insights into the pathogenesis of multiple sclerosis (MS). We report here on T cell lines/clones generated from peripheral blood of MS patients against an immunodominant myelin basic protein (MBP) peptide 82-102. This study demonstrates that the selection of T cell lines against the MBP peptide is much more efficient than against whole MBP in generating a large panel of T cell lines/clones, and therefore provides a powerful strategy for studying autoimmune T cell repertoire in individual subjects. The peptide-selected lines and clones recognized MBP 82-102, shorter peptides MBP 89-101, 89-100 and guinea pig whole MBP mainly in the context of HLA-DR, but did not cross-recognize virus-derived peptides homologous to MBP 82-102. Seven out of ten clones were found to recognize MBP 82-102 in the absence of autologous antigen presenting cells (APC), and in three of the seven clones, specificity for MBP 82-102 could be demonstrated only in the absence of APC because of their strong reactivity against autologous APC. Two-color flow cytometry revealed that the clones were heterogeneous with regard to expression of CD4 and CD8 molecules. Overall, the clones selected by the peptide were rather heterogeneous in phenotype and function compared with those selected by whole MBP.
Adult↗
Binding of an SJL T cell clone specific for myelin basic protein to SJL brain microvessel endothelial cells is inhibited by anti-VLA-4 or its ligand, anti-vascular cell adhesion molecule 1 antibody.
Adhesion molecules probably are required for the migration of T lymphocytes to inflamed tissues, but the roles of these molecules have yet to be understood in the pathogenesis of inflammatory diseases such as multiple sclerosis. The adhesion of an SJL murine T cell clone specific for myelin basic protein (MBP) to endothelial cells (ECs) from SJL newborn brain microvessels was examined. Sixty percent of the 2 x 10(4) T cell clones stimulated once every 2 weeks with MBP were bound to ECs, whereas less than 5% of the same number of lymphocytes from peripheral lymph nodes were bound. However, binding was not central nervous system (CNS)-specific. Monoclonal antibody to VLA-4 or VCAM-1 partially inhibited the binding of the T cell clone to ECs. Binding of the T cell clone to ECs increased when the latter were incubated with IL-1 or TNF, but was not inhibited by anti-VLA-4 or VCAM-1. We suggest that the VLA-4/VCAM-1 pathway functions in the binding of the T cell clone specific for MBP to brain ECs but that adhesion molecules other than VLA-4/VCAM-1 are involved because anti-VLA-4 and anti-VCAM-1 did not produce complete inhibition.
Animals↗