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T E Morgan

Publications and source records attributed to T E Morgan.

At least 19 recordsLinked to original sources
PubMed1997

Astrocytes and microglia respond to estrogen with increased apoE mRNA in vivo and in vitro.

This study examined the regulation of apolipoprotein E (apoE) by 17beta-estradiol (E2) in brain glia, using rats with regular ovulatory cycles as an in vivo model and cultured astrocytes and mixed glia as in vitro models. Two brain regions were examined which had demonstrated transient synaptic remodeling during the estrous cycle. In the hippocampal CA1 region and the hypothalamic arcuate nucleus, apoE mRNA was elevated at proestrus when plasma E2 was high and synaptic density was increasing. Both astrocytes and microglia contributed to this increase in apoE mRNA. In vitro, E2 treatment had no effect on apoE mRNA levels in monotypic cultures of either astrocytes or microglia. In contrast, mixed glial cultures responded to E2 with increased apoE mRNA and protein, suggesting that heterotypic cellular interactions are important in the brain response to estrogens. In situ hybridization in combination with cell-specific markers showed that E2 increased apoE mRNA levels in both astrocytes and microglia. These results, which are the first evidence of apoE mRNA localization to microglia in vivo and the control of apoE expression in brain cells by estrogens, are discussed in terms of the possible protective role of E2 in Alzheimer's disease and prior findings that emphasize the expression of apoE mRNA in astrocytes within the brain.

Animals↗
PubMed1997

Kainic acid and decorticating lesions stimulate the synthesis of C1q protein in adult rat brain.

The first component of the classic complement cascade, C1q, was increased in whole rat brain after lesioning by intraperitoneally injected kainic acid (KA) (20-fold, 3 days after KA) and in the striatum ipsilateral to unilateral decortication (fivefold, 10 days after decortication). C1q was measured after purification by chromatography and electrophoresis. De novo biosynthesis of C1q 3 days after KA was increased >10-fold, as measured by the incorporation of [35S]methionine into C1q after incubation of brain slices from KA-treated rats for 2 h. In parallel with these responses, KA induced fivefold increase of C1q bioactivity, as evaluated with C1q-dependent hemolysis. The contribution of C1q from entrapped cerebrovascular blood was evaluated by the effects of perfusion and was minor relative to the increases of C1q in response to KA lesioning. These findings support the hypothesis that the C1q protein detected by immunocytochemistry in senile plaques of Alzheimer brains and in the hippocampus after deafferenting lesions is synthesized by resident brain cells.

Animals↗
PubMed1996

Transcription supports age-related increases of GFAP gene expression in the male rat brain.

During aging, rodent and human brains show progressive increases in the levels of glial fibrillary acidic protein (GFAP) mRNA and protein. The role of transcription was investigated by in situ hybridization, using an intron-containing cRNA probe as a measure of primary GFAP transcripts. We found parallel age-related increases in GFAP intron RNA in the hippocampus, internal capsule, and corpus callosum of 3 versus 24 month old male F344 rats. We conclude that increased transcription supports the age-related increase of GFAP mRNA and protein. GFAP is a unique example of a gene that shows increased expression during aging in contrast to the decreased transcription of certain genes reported in non-neural tissues.

Aging↗
PubMed1996

Pituitary lactotrope expresses transforming growth factor beta (TGF beta) type II receptor mRNA and protein and contains 125I-TGF beta 1 binding sites.

Transforming growth factor beta 1 (TGF beta 1) has recently been shown to be produced in the prolactin (PRL)-secreting lactotropes of the pituitary gland. TGF beta 1 inhibits lactotropic secretion and proliferation, and the production of TGF beta 1 in lactotropes is reduced during lactotropic growth following estrogen treatment in ovariectomized rats. In many estrogen-responsive tissues, TGF beta 1 has been shown to exert its effect by binding to TGF beta 1 type II receptors (T beta R II) at the cell surface. In this study, we sought to ascertain whether T beta R II is involved in TGF beta 1 action on lactotropes by determining the changes of T beta R II mRNA and protein levels and specific 125I-TGF beta 1 binding sites on the lactotropes during estrogen-induced proliferation of lactotropes in Fischer 344 rats. Double immunohistochemical procedures were employed to identify immunoreactive T beta R II in PRL-reactive cells. The majority of T beta R II-reactive cells in the anterior pituitary were observed to be lactotropes. Dual immunohistochemistry and in situ hybridization procedures also indicated that lactotropes were the major cell types containing T beta R II mRNA hybrids. Both the levels of immunoreactive T beta R II protein and in situ T beta R II mRNA hybrids in the pituitary were significantly decreased in ovariectomized rats after 15 days of estrogen treatment. Determination of 125I-TGF beta 1 binding sites in lactotropes by double immunohistochemistry and receptor autoradiography also revealed specific binding sites of 125I-TGF beta 1 in lactotropes in the anterior pituitary. 125I-TGF beta 1 binding in the anterior pituitary was also reduced following estrogen treatment in ovariectomized rats. These data suggest that down-regulation of T beta R II may be an important mechanism of estrogen action on lactotropic cell growth and PRL secretion, and further support the notion that TGF beta 1 controls lactotropic function by autocrine/paracrine mechanisms.

Animals↗
PubMed1995

Clusterin (apoJ) alters the aggregation of amyloid beta-peptide (A beta 1-42) and forms slowly sedimenting A beta complexes that cause oxidative stress.

Clusterin (apoJ), a multifunctional apolipoprotein made by cells in the brain and many other locations, is associated with aggregated amyloid beta-peptide (A beta) in senile and diffuse plaques of Alzheimer's disease (AD). We observed that purified human serum clusterin partially blocked the aggregation of synthetic A beta 1-42, as shown by centrifugal assays (14,000g x 10 min) and by atomic force (scanning probe) microscopy. Slowly sedimenting A beta complexes were formed in the presence of clusterin, which included aggregates > 200 kDa that resist dissociation by low concentrations of SDS. Clusterin enhanced the oxidative stress caused by A beta, as assayed by oxidative stress in PC12 cells with MTT, which is widely used to estimate neurotoxicity. These indications of enhanced neurotoxicity by the MTT assay were observed in the highly aggregated rapidly sedimenting fraction, but also in more slowly sedimenting "soluble" forms. This novel activity of slowly sedimenting A beta may enhance the neurotoxicity of A beta deposits in AD brains, because soluble complexes have a potential for diffusing to damage distal neurons.

Alzheimer Disease↗
PubMed1995

Expression of vimentin increases in the hippocampus and cerebral cortex after entorhinal cortex lesioning and in response to transforming growth factor beta 1.

Entorhinal cortex lesions (ECL) that damage the perforant path to the dentate gyrus of the hippocampal formation were used to model the regulation of vimentin (VIM) mRNA. ECL increased VIM mRNA in the ipsilateral hippocampus and in the ipsilateral cortex including the wound cavity within 1 day. By in situ hybridization, at 4 days post-ECL, VIM mRNA increased two-fold in the molecular layer of the dentate gyrus. VIM protein was co-localized by immunocytochemistry to astrocytes and microglia/macrophages. Transforming growth factor-beta 1 (TGF-beta 1), which was previously shown to increase in microglia/macrophages of the molecular layer after hippocampal deafferentation by ECL, was investigated as a regulator of VIM expression. Infusions of TGF-beta 1 into the lateral ventricle induced VIM mRNA with dose-dependence, e.g. infusion of 100 ng TGF-beta 1 increased VIM mRNA three-fold. The increase in VIM mRNA was localized by in situ hybridization to astrocytes and microglia in the molecular layer of the dentate gyrus. These findings further implicate TGF-beta 1 as a regulator of cytoskeletal proteins during synaptic reorganization.

Animals↗
PubMed1995

Clusterin expression by astrocytes is influenced by transforming growth factor beta 1 and heterotypic cell interactions.

This study characterizes the effect of transforming growth factor (TGF) beta 1 on clusterin expression in rat brain cells. 24 h after an acute unilateral intracerebroventricular infusion of TGF-beta 1, clusterin mRNA prevalence was increased in astrocytes that contained immunoreactive (IR) glial fibrillary acidic protein (GFAP). TGF-beta 1 selectively induced clusterin mRNA in astrocytes, as no clusterin mRNA was detected in neurons, oligodendrocytes, or microglia. TGF-beta 1 induced a bilateral increase in clusterin mRNA per astrocyte. Astrocyte hypertrophy (GFAP-IR area) was only increased on the ipsilateral side. In pure astrocyte cultures, TGF-beta 1 (200 pM) decreased clusterin mRNA levels and the rate of clusterin RNA transcription. However, in cultures of astrocytes that contained microglia and oligodendrocytes (mixed glia cultures), TGF-beta 1 caused a dose-dependent increase in astrocytic clusterin mRNA levels. The astrocytes that responded to TGF-beta 1 included two GFAP-IR subtypes, type 1 and 2. TGF-beta 1 increased clusterin protein in the conditioned medium from cultured glia, in either monotypic or mixed glial cultures. Thus, TGF-beta 1 and heterotypic cell interactions influence clusterin expression by astrocytes and may be important to the role of clusterin in multiple sclerosis, AIDS, and Alzheimer's disease.

Animals↗
PubMed1994

Transforming growth factor-beta 1 induces neuronal and astrocyte genes: tubulin alpha 1, glial fibrillary acidic protein and clusterin.

Transforming growth factor-beta 1 was studied as a possible regulator of messenger RNAs in astrocytes and neurons that increase after hippocampal deafferentation by perforant path transection: tubulin alpha 1, clusterin and glial fibrillary acidic protein messenger RNA. Because transforming growth factor-beta 1 messenger RNA is increased after this lesion, we examined which messenger RNA lesion responses could be induced by transforming growth factor-beta 1 alone. Porcine transforming growth factor-beta 1 infused into the lateral ventricle elevated the messenger RNAs for tubulin alpha 1, clusterin and glial fibrillary acidic protein 24 h after infusion in the ipsilateral hippocampus. As assayed by nuclear run-on, the transcription of glial fibrillary acidic protein RNA was increased in the ipsilateral hippocampus after perforant path transection and in primary rat astrocyte cultures by transforming growth factor-beta 1. In contrast, transforming growth factor-beta 1 did not change apolipoprotein-E messenger RNA or transcription, or growth associated protein-43 messenger RNA levels. We conclude that transforming growth factor-beta 1 increases subsets of neuronal and astrocyte messenger RNAs coding for cytoskeletal proteins that are also elevated in response to experimental lesions and Alzheimer's disease. This suggests that transforming growth factor-beta 1 might be a local organizing factor of neuronal and astrocyte responses to brain injury.

Animals↗
PubMed1994

Selective expression of clusterin (SGP-2) and complement C1qB and C4 during responses to neurotoxins in vivo and in vitro.

This study concerns expression of the genes encoding three multifunctional proteins: clusterin and two complement cascade components, C1q and C4. Previous work from this and other laboratories has established that clusterin, Clq and C4 messenger RNAs are elevated during Alzheimer's disease, and in response to deafferenting and excitotoxic brain lesion. This study addresses hippocampal clusterin, ClqB and C4 expression in response to neurotoxins that caused selective neuron death. Kainate, which preferentially kills hippocampal CA3 pyramidal neurons but not dentate gyrus granule neurons induced clusterin immunoreactivity in CA1 and CA3 pyramidal neurons and adjacent astrocytes, but not in dentate gyrus granule neurons. In contrast, colchicine, which preferentially kills the dentate gyrus granule neurons, induced clusterin immunoreactivity in the local neuropil as punctate deposits, but not in the surviving or degenerating dentate gyrus granule neurons. Clusterin messenger RNA was increased in astrocytes. ClqB and C4 messenger RNAs increased within 48 h after kainate injections, particularly in the CA3 pyramidal layer, less in the dentate gyrus-CA4, and less in CA1. Clq immunoreactivity was detected in CA1 pyramidal neurons and also as small punctate deposits in the CA1 region at eight and 14 days after kainate. The increase of both clusterin and ClqB messenger RNAs after kainate injections was blocked by barbiturates that prevented seizures and neurodegeneration. In primary hippocampal neuronal cultures treated with glutamate, a subpopulation of cultured neurons that survived glutamate toxicity also had parallel elevations of clusterin and ClqB messenger RNA. In conclusion, cytotoxins that target selective hippocampal neurons increase the expression of both clusterin and ClqB in vivo and in vitro. These results show that elevations of clusterin messenger RNA or protein can be dissociated from each other and from cell death. These increased messenger RNAs were associated with immunoreactive deposits that differed by cell type and intra- versus extracellular locations. These results suggest that the complement system is involved in brain responses to injury.

Animals↗
PubMed1993

TGF-beta 1 is an organizer of responses to neurodegeneration.

TGF-beta 1 mRNA and protein were recently found to increase in animal brains after experimental lesions that cause local deafferentation or neuron death. Elevations of TGF-beta 1 mRNA after lesions are prominent in microglia but are also observed in neurons and astrocytes. Moreover, TGF-beta 1 mRNA autoinduces its own mRNA in the brain. These responses provide models for studying the increases of TGF-beta 1 protein observed in beta A/amyloid-containing extracellular plaques of Alzheimer's disease (AD) and Down's syndrome (DS) and in brain cells of AIDS victims. Involvement of TGF-beta 1 in these human brain disorders is discussed in relation to the potent effects of TGF-beta 1 on wound healing and inflammatory responses in peripheral tissues. We hypothesize that TGF-beta 1 and possibly other TGF-beta peptides have organizing roles in responses to neurodegeneration and brain injury that are similar to those observed in non-neural tissues. Work from many laboratories has shown that activities of TGF-beta peptides on brain cells include chemotaxis, modification of extracellular matrix, and regulation of cytoskeletal gene expression and of neurotrophins. Similar activities of the TGF-beta's are well established in other tissues.

Animals↗
PubMed1993

TGF-beta 1 mRNA increases in macrophage/microglial cells of the hippocampus in response to deafferentation and kainic acid-induced neurodegeneration.

This study examined TGF-beta 1 mRNA levels and cellular localization in the F344 rat hippocampus following deafferentation or kainic acid (KA)-induced neurodegeneration. By RNA solution hybridization, TGF-beta 1 transcripts were at low prevalence in intact adult rat hippocampus (0.02 pg/microgram total RNA). Four days after unilateral entorhinal cortex lesioning (ECL), TGF-beta 1 mRNA increased threefold in the ipsilateral hippocampus. This increase was localized to the outer molecular layer of the dentate gyrus, where gliosis, synapse loss, and synaptic reorganization occur. TGF-beta 1 mRNA also increased in the hippocampus after KA-induced limbic seizures, particularly in the areas of the hippocampus undergoing neurodegeneration. Microglia [OX-42 immunoreactive (IR) cells] responded to these two lesions with distinct morphological changes. Combined immunocytochemistry-in situ hybridization showed that TGF-beta 1 mRNA was localized to reactive microglia (OX-42-IR, with blunt processes), but not to resting ramified microglia (OX-42-IR, with numerous fine processes) or to astrocytes (GFAP-IR). After ECL, round macrophage-like cells (OX-42-IR with TGF-beta 1 mRNA) were seen at the wound site. Thus, brain macrophage/microglial cells produce TGF-beta 1 mRNA in the hippocampus in response to deafferentation and neurodegeneration.

Afferent Pathways↗
PubMed1993

Isolation and characterization of a regulated form of actin depolymerizing factor.

Actin depolymerizing factor (ADF) is an 18.5-kD protein with pH-dependent reciprocal F-actin binding and severing/depolymerizing activities. We previously showed developing muscle down-regulates ADF (J. R. Bamburg and D. Bray. 1987. J. Cell Biol. 105: 2817-2825). To further study this process, we examined ADF expression in chick myocytes cultured in vitro. Surprisingly, ADF immunoreactivity increases during the first 7-10 d in culture. This increase is due to the presence of a new ADF species with higher relative molecular weight which reacts identically to brain ADF with antisera raised against either brain ADF or recombinant ADF. We have purified both ADF isoforms from myocytes and have shown by peptide mapping and partial sequence analysis that the new isoform is structurally related to ADF. Immunoprecipitation of both isoforms from extracts of cells prelabeled with [32P]orthophosphate showed that the new isoform is radiolabeled, predominantly on a serine residue, and hence is called pADF. pADF can be converted into a form which comigrates with ADF on 1-D and 2-D gels by treatment with alkaline phosphatase. pADF has been quantified in a number of cells and tissues where it is present from approximately 18% to 150% of the amount of unphosphorylated ADF. pADF, unlike ADF, does not bind to G-actin, or affect the rate or extent of actin assembly. Four ubiquitous protein kinases failed to phosphorylate ADF in vitro suggesting that ADF phosphorylation in vivo is catalyzed by a more specific kinase. We conclude that the ability to regulate ADF activity is important to muscle development since myocytes have both pre- and posttranslational mechanisms for regulating ADF activity. The latter mechanism is apparently a general one for cell regulation of ADF activity.

Actin Depolymerizing Factors↗
PubMed1992

Complement C1qB and C4 mRNAs responses to lesioning in rat brain.

These data show the presence of mRNAs for two complement components (C) in the adult rat brain and describe their responses to experimental lesions. Cortical deafferentation caused elevations in striatal C1qB and C4 mRNAs that coincided temporally and overlapped anatomically with the course of degeneration of corticostriatal afferent fibers. By in situ hybridization, C1qB mRNA in the lesioned striatum was colocalized to cells immunoreactive for CR3, a complement receptor found on microglia-macrophages. The mRNA for SGP-2, a putative C inhibitor in rat, showed parallel changes. Similarly, in hippocampus and other brain regions, kainic acid lesions increased C1qB mRNA. The data suggest that microglia-macrophages and possibly other cells in rat brain rapidly up-regulate C-mRNAs in response to deafferentation and local neuron injury. These experimental responses provide models to analyze changes in C components during Alzheimer's disease and other chronic neurodegenerative conditions.

Animals↗
PubMed1991

Long-term effect of thrombolytic therapy on left ventricular ejection fraction after acute myocardial infarction.

To assess the long-term effect of thrombolytic therapy on left ventricular (LV) systolic function, 222 patients with acute myocardial infarction treated with intravenous tissue plasminogen activator within 4 hours of symptom onset underwent assessment of LV ejection fraction (EF) by radionuclide equilibrium angiography at hospital discharge and 1 year later. Mean EF at hospital discharge (46 +/- 12) was similar to that at 1 year (45 +/- 13). Stepwise multivariate linear regression analysis identified EF at discharge and patency of the infarct-related artery before discharge as independent predictors of EF change at 1 year (p = 0.0002 and 0.003, respectively). Random assignments to invasive versus conservative treatment strategies or to early versus delayed beta-blocker therapy did not affect EF change during follow-up. No significant deterioration of EF was observed in patients with larger infarcts. However, EF decreased from 45 +/- 10 at hospital discharge to 39 +/- 12 (p = 0.005) at 1-year follow-up in a subgroup of patients with history of prior infarction. Thus, patients with acute myocardial infarction, treated with intravenous tissue plasminogen activator early after onset of symptoms, appear to have stable LV function between hospital discharge and 1 year follow-up. The change in EF between hospital discharge and 1 year can be predicted from the EF value at discharge, patency of the infarct-related artery before discharge and history of previous myocardial infarction.

Aged↗
PubMed1981

The role of M.D.-Ph.D. training in increasing the supply of physician-scientists.

Since 1968 the number of postdoctoral research fellows with M.D.s or other professional degrees has fallen from about 4100 to 1730 in training each year. By 1980, the number of M.D. postdoctoral fellows entering and completing research training was about 850 per year. During the past 12 years, the number of M.D.-Ph.D. trainees has risen to about 650 in the federal Medical Scientist Training Program (MSTP) and about 500 in nonfederal programs. The attrition rate in non-federal M.D.-Ph.D. programs has been shown to be 44 per cent, and that from the MSTP, 9 per cent. When the length of the training program, the attrition rate, and other factors are considered, present trainees will account for about 150 M.D.-Ph.D. graduates annually in the immediate future. Current training programs can meet only about half the estimated national need for physician researchers. The federal M.D.-Ph.D. program should be expanded to ensure that the country's future research and teaching needs will be met.

Education, Graduate↗
PubMed1980

Bifunctional enzyme activity at the same active site: competitive inhibition kinetics with 3 alpha/20 beta-hydroxysteroid dehydrogenase.

20 beta-Hydroxy-5 alpha-pregnan-3-one (HPO) is a competitive inhibitor of reduction by 3 alpha/20 beta-hydroxysteroid dehydrogenase (3 alpha/20 beta-HSD; E.C.1.1.1.53) of 17 beta-hydroxy-5 alpha-androstan-3-one (DHT; 3 alpha-activity; Ki = 4.6x10(-5)M), and of 6 beta-acetoxyprogesterone (6 beta-AP; 20 beta-activity; Ki = 4.34x10(-5)M). HPO and DHT inhibit affinity alkylation of 3 alpha/20 beta-HSD by 6 beta-bromoacetoxyprogesterone (6 beta-BAP). The facts that 1) enzyme 3 alpha-activity and 20 beta-activity are both competitively inhibited by HPO with practically identical Ki-values, 2) 6 beta-BAP is solely a 20 beta-activity substrate for 3 alpha/20 beta-HSD, 3) one mole of 6 beta-BAP reacts with one mole of 3 alpha/20 beta-HSD to simultaneously inactivate 3 alpha- and 20 beta-activity, and 4) inactivation of 3 alpha/20 beta-HSD by 6 beta-BAP is inhibited by DHT (a C19-steroid) or HPO (a C21-steroid), support the view that the same active site of 3 alpha/20 beta-HSD possesses both 3 alpha- and 20 beta-activity. Bifunctional activity at the same active site is considered for other steroid-specific enzymes in female mammalian reproductive systems.

20-Hydroxysteroid Dehydrogenases↗