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PubMedDate not supplied

Alzheimer's disease and aging: effects on perforant pathway perikarya and synapses.

The hippocampal perforant pathway originates in the entorhinal cortex (ERC) and terminates in the outer molecular layer of the dentate gyrus (DG). To compare the effects of normal aging and Alzheimer's disease (AD) on the elements of the perforant pathway, we compared relative perikaryal numbers (determined by counting cell bodies and estimating volumes) in layer II of the ERC with synaptic quantities (estimated from immunoreactivity for the synaptic terminal protein synapsin I and DG volume) in the molecular layer of the DG. The brains of 5 young and 9 elderly cognitively normal individuals, and of 9 AD patients were studied. In normal aging we found a significant age-related decline in perikaryal numbers in the ERC without demonstrable synaptic loss in the DG. In AD there was marked and equivalent, (or proportional) reduction in both ERC perikaryal numbers and DG synapses. These data suggest that in normal aging remaining neurons may continue to support a full array of synapses, perhaps due to mechanisms such as axonal sprouting, synaptic enlargement, or synaptic ingrowth. In AD, however, the accelerated neuronal loss may overwhelm such compensatory mechanisms or alternatively, independent synaptic and perikaryal losses may occur.

Adult↗
PubMed1996

Decrease in neuron-restrictive silencer factor (NRSF) mRNA levels during differentiation of cultured neuroblastoma cells.

Non-neuronal cells and undifferentiated neuronal progenitors express the neuron-restrictive silencer factor (NRSF), a silencer protein which represses neuronal gene transcription in these cell types. Neuroblastoma, a childhood tumor of neuroectodermal origin, shares some biological properties with neuronal progenitor cells and can acquire neuronal phenotypes in response to a variety of agents, including cyclic AMP and staurosporine. We report here that NRSF mRNA content was markedly decreased in a human neuroblastoma cell line following differentiation induced by staurosporine plus cyclic AMP, with a concomitant increase in mRNA levels of synapsin I, whose expression is restricted to neuronal cell types. Our novel finding suggests that NRSF expression is related to an undifferentiated state and regarded as a biochemical marker of neuronal differentiation in neuroblastoma cells.

Actins↗
PubMed1995

Changes in mobility of synaptic vesicles with assembly and disassembly of actin network.

In a presynaptic terminal, neurotransmitters are stored in synaptic vesicles and secreted into the synaptic cleft as a final step of cell signal transduction. At a static state, the vesicles are retained in the highly dense actin network. Prior to exocytosis, the dense actin network must disassemble or largely be organized. Actin networks are formed in vitro which retain synaptic vesicles prepared from rat cerebral cortex. Dynamic behaviors of synaptic vesicles are measured by the dynamic light scattering method. The D(app) values of synaptic vesicles confined in actin network became less than 1/4 those of free vesicles. The motions of synaptic vesicles are substantially restricted. This means that synaptic vesicles which are liberated from the actin network by detachment of synapsin 1 molecules are still trapped in the cage-like space of actin filaments. The actin network is disassembled by the actin severing protein, gelsolin, which is activated in the presence of microM level free Ca2+ ions. The D(app)(v) values of synaptic vesicles after severing the actin network return to those of free vesicles in the presence of short actin fragments. A molecular model for exocytosis in the synaptic terminal is constructed on the basis of these results.

Actin Cytoskeleton↗
PubMed1985

D-1 and D-2 dopaminergic receptors regulate protein phosphorylation in the rat neurohypophysis.

Dopamine stimulates the phosphorylation of the neuron-specific synaptic vesicle proteins Synapsin I, Protein IIIa and Protein IIIb in the posterior pituitary gland of the rat [Tsou and Greengard (1982) Proc. natn. Acad. Sci. U.S.A. 79, 6075-6079]. This effect has been characterized in the present investigation. The stimulatory effect of dopamine was mimicked by the selective D-1 receptor agonist SKF 38393 and was competitively and potently inhibited by the selective D-1 receptor antagonist SKF 83509 as well as by the mixed D-1/D-2 antagonist fluphenazine. Conversely, the effect of dopamine was attenuated by a D-2 receptor agonist (LY 141865) and potentiated by a D-2 receptor antagonist (sulpiride). Norepinephrine also stimulated phosphorylation of the synaptic vesicle proteins, apparently through activation of the D-1 receptor. D-1 and D-2 dopaminergic receptors may play a role in the regulation of hormone secretion from the neurohypophysis. Evidence exists that in the isolated neurophypophysis activation of D-1 receptors facilitates, while activation of D-2 receptors inhibits, release of vasopressin. Further work will be required to determine whether the regulation by D-1 and D-2 receptors of the protein phosphorylation in the neurohypophysial peptidergic terminals is related to the regulation by those receptors of the neurohypophysial hormone secretion.

1-Methyl-3-isobutylxanthine↗
PubMed1991

Protein phosphorylation in guinea-pig myenteric ganglia and brain: presence of calmodulin kinase II. protein kinase C and cyclic AMP kinase and characterization of major phosphoproteins.

The aim of this study was to demonstrate the presence of calmodulin-stimulated protein kinase II, protein kinase C, and cyclic AMP-stimulated protein kinase in isolated myenteric ganglia and to characterize the major ganglia phosphoproteins using biochemical and immunochemical techniques. Ganglia from the small intestine of guinea-pigs were isolated, disrupted by sonication in Triton X-100, and phosphorylated. The phosphoprotein patterns obtained were compared with those of synaptosomes from guinea-pig and rat cerebral cortex. Myenteric ganglia were as rich in protein kinase C and cyclic AMP-stimulated protein kinase as brain tissue, but the level of calmodulin-stimulated protein kinase II was relatively lower. The alpha subunit of calmodulin-stimulated protein kinase II was detected by immunoblotting and the beta subunit by autophosphorylation. The ratio of beta to alpha subunit was considerably higher in ganglia than in brain and ganglia beta subunit had a lower apparent molecular weight than the brain enzyme. A number of neuronal phosphoproteins were found in ganglia including the 87,000 mol. wt phosphoprotein, synapsins 1a and 1b, and proteins IIIa and IIIb. A phosphoprotein of 48,000 mol. wt had many of the characteristics of the B-50 protein but was not the same. In addition, a number of other phosphoproteins not previously identified in neurons were found in ganglia including those with apparent molecular weights of 60,000 and 58,000 that were the major calmodulin kinase substrates. The guinea-pig enteric nervous system has been extensively studied but, unlike other parts of the mammalian nervous system, little is known about the intracellular mechanisms underlying its functions. A technique for isolating myenteric ganglia is now available and we have used this preparation to characterize the major protein kinase and phosphoproteins present in this tissue. The results obtained will allow the phosphorylation of the various proteins to be investigated after physiological or pharmacological manipulation of myenteric ganglia in situ and in vivo.

Animals↗
PubMed1986

The effect of calmodulin inhibitors on the release of acetylcholine and protein phosphorylation induced by tityustoxin, K+ and ouabain.

In this paper we describe our studies of the effects of calmodulin inhibitors on the relationship between the release of acetylcholine (ACh) and protein phosphorylation induced by tityustoxin (TsTX), K+ and ouabain. We observed that in cortical slices of brain, the TsTX induced release of ACh was inhibited in the presence of the calmodulin inhibitors trifluoperazine, W-7 and prenylamine, but not by trifluoperazine sulphoxide. The release of ACh elicited by ouabain and K+ (33 mM) was also inhibited by trifluoperazine and chlorpromazine. Studies on protein phosphorylation with crude or purified synaptosome fractions showed that TsTX and K+ (33 mM) increased the incorporation of 32P into a protein with the same apparent molecular weight of synapsin I. Surprisingly, ouabain did not stimulate phosphorylation of this protein. Trifluoperazine, at the same concentrations that inhibited the release of ACh, blocked the stimulatory effect of tityustoxin and K+ on protein phosphorylation. On the other hand, tetrodotoxin inhibited the effect of tityustoxin on protein phosphorylation but had no effect on phosphorylation evoked by K+. Our results demonstrate for the first time that, at least for ouabain, the release of neurotransmitter is not dependent on protein phosphorylation.

Acetylcholine↗
PubMed1994

Differential distribution of tau proteins in developing cat cerebellum.

The differential distribution and phosphorylation of tau proteins in cat cerebellum was studied with two well characterized antibodies, TAU-1 and TAU-2. TAU-1 detects tau proteins in axons, and the epitope in perikarya and dendrites is masked by phosphorylation. TAU-2 detects a phosphorylation-independent epitope on tau proteins. The molecular composition of tau proteins in the range of 45 kD to 64 kD at birth changed after the first postnatal month to a set of several adult variants of higher molecular weights in the range of 59 kD to 95 kD. The appearance of tau proteins in subsets of axons corresponds to the axonal maturation of cerebellar local-circuit neurons in granular and molecular layers and confirms previous studies. Tau proteins were also identified in synapses by immunofluorescent double-staining with synapsin I, located in the pinceau around the Purkinje cells, and in glomeruli. Dephosphorylation of juvenile cerebellar tissue by alkaline phosphatase indicated indirectly the presence of differentially phosphorylated tau forms mainly in juvenile ages. Additional TAU-1 immunoreactivity was unmasked in numerous perikarya and dendrites of stellate cells, and in cell bodies of granule cells. Purkinje cell bodies were stained transiently at juvenile ages. During postnatal development, the intensity of the phosphate-dependent staining decreased, suggesting that phosphorylation of tau proteins in perikarya and dendrites may be essential for early steps in neuronal morphogenesis during cat cerebellum development.

Animals↗
PubMed1995

[3H]-noradrenaline release from streptolysin-O permeated rat cortical synaptosomes: enhancement of the Ca(2+)-induced signal.

We examined [3H]-noradrenaline ([3H]-NA) release from rat brain cortical synaptosomes permeated with streptolysin-O (SLO) under a variety of conditions. Three temperatures (20 degrees C, 25 degrees C, and 30 degrees C) were tested at different times of permeation. Lowering the incubation temperature to 20 degrees C decreased basal release, but Ca(2+)-induced [3H]-NA release increased slightly. Also, the incubation time to achieve the maximal ratio of Ca(2+)-induced release to basal release shifted to longer times with decreasing incubation temperature. If the synaptosomes were permeated with SLO before release was triggered, similar results were observed. Permeation at 20 degrees C allowed [gamma-32P] ATP and cAMP-dependent protein kinase (PKA) catalytic subunit to rapidly enter the synaptosomes to phosphorylate synapsins. Lactate dehydrogenase (LDH) efflux was time- and SLO-concentration dependent. The fact that 0.1 mM Cd2+ did not inhibit [3H]-NA release from permeabilized synaptosomes indicated that permeabilization by SLO was complete under these conditions. This also suggests that the release machinery involved after Ca2+ entry is not sensitive to Cd2+.

Animals↗
PubMedDate not supplied

Brain MAP-2 phosphorylation is decreased following prenatal alcohol exposure in rats.

The effects of prenatal alcohol treatment on the development and in vitro phosphorylation of specific neuronal phosphoproteins isolated from the frontal cortex and hippocampus of rat brains were studied. In vitro phosphorylation of microtubule-associated protein-2 (MAP-2) was decreased in the frontal cortex but not the hippocampus of animals exposed prenatally to alcohol. Phosphorylation of additional phosphoproteins, including tau proteins, Synapsin I, and GAP-43, was not affected by prenatal alcohol exposure. Littermates of animals used for the phosphorylation assays showed impaired passive avoidance learning. These data demonstrate that the previously reported structural changes in the development of the cerebral cortex following prenatal alcohol exposure and behavioral deficits are accompanied by changes in the phosphorylation of the important cytoskeletal protein MAP-2.

Animals↗
PubMed1989

Deltamethrin causes changes in protein phosphorylation activities associated with post-depolarization events in the synaptosomes from the optic lobe of squid, Loligo pealei.

1. Deltamethrin causes a significant change in protein phosphorylation activities which follow depolarization. 2. The most significant change caused by deltamethrin was the prolonged elevation of the level of phosphorylation on a number of key synaptic proteins beyond the normal time of their recovery to the dephosphorylated state. 3. The best marker proteins reacting to deltamethrin in this manner were calcium-calmodulin dependent protein kinase and synapsin I.

Animals↗
PubMed1995

Glutamate transporters in glial plasma membranes: highly differentiated localizations revealed by quantitative ultrastructural immunocytochemistry.

The glutamate transporters GLT-1 and GLAST were studied by immunogold labeling on ultrathin sections of rat brain tissue embedded in acrylic resins at low temperature after freeze substitution. Both proteins were selective markers of astrocytic plasma membranes. GLT-1 was much higher in hippocampal astrocytes than in cerebellar astrocytes. Astroglial membrane GLAST densities ranked as follows: Bergmann > cerebellar granular layer approximately hippocampus > cerebellar white matter. No astrocyte appeared unlabeled. Astrocytic membranes facing capillaries, pia, or stem dendrites were lower in glutamate transporters than those facing nerve terminals, axons, and spines. Parallel fiber boutons (glutamatergic) synapsin on interneuron dendritic shafts were surrounded by lower transporter densities than those synapsing on Purkinje cell spines. Our findings suggest the localizations of glutamate transporters are carefully regulated.

ATP-Binding Cassette Transporters↗
PubMed1994

Distribution of synaptic markers in the retina: implications for synaptic vesicle traffic in ribbon synapses.

Synapses in the retina are present in two layers that can easily be distinguished morphologically: the thin outer plexiform layer (OPL) containing the photoreceptor ribbon synapses, and the more complex inner plexiform layer (IPL) containing mostly conventional synapses. In the current study we have used the exquisite spatial separation between ribbon and conventional synapses in the retina to investigate by immunocytochemistry the protein components of these two types of synapses. Our results show that all of the synaptic vesicle proteins tested are present in the ribbon synapses of photoreceptors except for the synapsins which were previously described to be absent from ribbon synapses. Thus, synaptic vesicles of ribbon and conventional synapses are likely to be very similar molecularly in spite of their different modes of trafficking. Furthermore, proteins with a likely function in synaptic vesicle docking and fusion (SNAP-25, munc-18) and endocytosis (dynamin) were also highly enriched in ribbon synapses, indicating that the basic machineries for synaptic membrane traffic are similar in ribbon and conventional synapses. Interestingly, photoreceptor cells contained only low concentrations of syntaxin I (which functions in the synaptic vesicle fusion complex) and GDI (which regulates the membrane association of rab-proteins as a function of GTP/GDP binding). These results raise the possibility that photoreceptors express other isoforms of these proteins, or that the functions of these proteins are not required for the tonical release mode of their synapses.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Calcium/calmodulin-dependent protein kinase II.

There is a great deal known about the in vitro properties of CaM kinase II, both in terms of its substrate specificity and its regulation by calmodulin and autophosphorylation. Much of this characterization is based on experiments performed with the rat brain isozyme of CaM kinase II, although in the aspects examined to date isozymes of the kinase from other tissues appear to behave in a broadly similar manner in vitro. However, relatively little is known about the functions of the kinase in vivo. The proteins phosphorylated by the kinase (with the probable exception of synapsin I and tyrosine hydroxylase) and the role of kinase autophosphorylation in vivo remain largely unknown. Investigation of the physiological role of the kinase in brain and other tissues will be a particularly exciting area for future work. The current knowledge of the in vitro properties and the availability of cDNA clones will hopefully expedite this research.

Amino Acid Sequence↗
PubMed2004

Characterization of early endosome antigen 1 in neural tissues.

The finding that patients and mice bearing autoantibodies directed against early endosome antigen 1 (EEA1) develop neurological signs and deficits prompted an investigation of EEA1 distribution, localization, and interaction with synaptic proteins found in neural tissues. We detected EEA1 in a variety of neural tissues and in cells of neural origin where it co-localized with SNAP-25. The interaction between EEA1 and SNAP-25 was dependent on the leucine zipper and a newly identified methyl-accepting domain of EEA1. The C-terminal zinc-binding FYVE finger motif (EEA1(1271-1411)) of EEA1 also interacted with native SNAP-25 but only in the presence of 100microM Ca(2+). In contrast, EEA1 did not bind to cysteine string protein or synapsin in these binding assays. These results suggest that EEA1 is involved in neuronal synaptic vesicle function and axonal transport and growth. EEA1 may undergo calcium-dependent conformational changes that are required for binding to SNAP-25.

Animals↗
PubMed2005

Regulation of hippocampal gene expression is conserved in two species subjected to different stressors and antidepressant treatments.

BACKGROUND: Chronic stress has significant effects on hippocampal structure and function. We have previously identified nerve growth factor (NGF), membrane glycoprotein 6a (M6a), the guanine nucleotide binding protein (G protein) alpha q polypeptide (GNAQ), and CDC-like kinase 1 (CLK-1) as genes regulated by psychosocial stress and clomipramine treatment in the hippocampus of tree shrews. These genes encode proteins involved in neurite outgrowth. METHODS: To analyze whether regulation of the above-mentioned genes is conserved between different species, stressors, and antidepressant drugs, we subjected mice to repeated restraint stress and tianeptine treatment and measured hippocampal messenger RNA (mRNA) levels by real time reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Chronically stressed mice displayed a reduction in transcript levels for NGF, M6a, GNAQ, and CLK-1. In addition, other genes implicated in neuronal plasticity, such as brain-derived neurotrophic factor (BDNF), cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), protein kinase C (PKC), neural cell adhesion molecule (NCAM), and synapsin I were downregulated in stressed mice. Tianeptine treatment reversed the stress effects for the genes analyzed. Alterations in gene expression were dependent on the duration of the stress treatment and, in some cases, were only observed in male mice. CONCLUSIONS: These results suggest that genes involved in neurite remodeling are one of the main targets for regulation by chronic stress. The finding that this regulation is conserved in different stress models and antidepressant treatments highlights the biological relevance of the genes analyzed and suggests that they might be involved in stress-related disorders.

Animals↗
PubMed2006

Immature neuronal phenotype derived from mouse skin precursor cells differentiated in vitro.

Recent findings indicate that skin-derived precursor cells (SKPs) of mouse dermis can differentiate in cells with neuronal-like morphology. However, direct evidence supporting the establishment of functional phenotype is missing. In the present study, SKP cells were obtained using published in vitro techniques and studied at 14- to 21-day differentiation, when neuronal-like morphology was observed. The experiment was repeated 39 times. Co-cultures with cortical astrocytes were also used to enhance the process of neural differentiation. Expression of GAP43 and light-chain MAP-2(c) but not markers of dendritic and synaptic terminal differentiation such as heavy-chain MAP-2(ab) and synapsin were observed. Voltage-clamp electrophysiology recordings showed potassium currents, but neither action potentials generation nor electrotonic response to exogenous administration of nicotine or kainic acid. These observations suggest that mouse SKPs do not differentiate into mature functional neurons, at least using the published methodologies for in vitro differentiation.

4-Aminopyridine↗
PubMed2006

Evaluation of neuronal phosphoproteins as effectors of caffeine and mediators of striatal adenosine A2A receptor signaling.

Adenosine A(2A) receptors are predominantly expressed in the dendrites of enkephalin-positive gamma-aminobutyric acidergic medium spiny neurons in the striatum. Evidence indicates that these receptors modulate striatal dopaminergic neurotransmission and regulate motor control, vigilance, alertness, and arousal. Although the physiological and behavioral correlates of adenosine A(2A) receptor signaling have been extensively studied using a combination of pharmacological and genetic tools, relatively little is known about the signal transduction pathways that mediate the diverse biological functions attributed to this adenosine receptor subtype. Using a candidate approach based on the coupling of these receptors to adenylate cyclase-activating G proteins, a number of membranal, cytosolic, and nuclear phosphoproteins regulated by PKA were evaluated as potential mediators of adenosine A(2A) receptor signaling in the striatum. Specifically, the adenosine A(2A) receptor agonist, CGS 21680, was used to determine whether the phosphorylation state of each of the following PKA targets is responsive to adenosine A(2A) receptor stimulation in this tissue: Ser40 of tyrosine hydroxylase, Ser9 of synapsin, Ser897 of the NR1 subunit of the N-methyl-d-aspartate-type glutamate receptor, Ser845 of the GluR1 subunit of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-type glutamate receptor, Ser94 of spinophilin, Thr34 of the dopamine- and cAMP-regulated phosphoprotein, M(r) 32,000, Ser133 of the cAMP-response element-binding protein, Thr286 of Ca(2+)/calmodulin-dependent protein kinase II, and Thr202/Tyr204 and Thr183/Tyr185 of the p44 and p42 isoforms, respectively, of mitogen-activated protein kinase. Although the substrates studied differed considerably in their responsiveness to selective adenosine A(2A) receptor activation, the phosphorylation state of all postsynaptic PKA targets was up-regulated in a time- and dose-dependent manner by treatment with CGS 21680, whereas presynaptic PKA substrates were unresponsive to this agent, consistent with the postsynaptic localization of adenosine A(2A) receptors. Finally, the phosphorylation state of these proteins was further assessed in vivo by systemic administration of caffeine.

Adenosine↗
PubMed2005

From proteomics to biomarker discovery in Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia in the elderly. AD is an invariably fatal neurodegenerative disorder with no effective treatment or definitive antemortem diagnostic test. Little is known about the changes in the brain preceding or accompanying initiation of the disease. Understanding the biological processes, which occur during AD onset and/or progression, will improve the diagnosis and treatment of the disease. As we will discuss in this review article, using high-throughput cDNA microarray we identified candidate genes whose expression is altered in the brain of cases at risk for AD dementia. However, it is possible that the use of the cDNA microarray technology alone may underestimate post-transcriptional modifications and therefore provides only a partial view of the biological problem of interest. As such, the combination of cDNA and protein arrays may provide a more global picture of the biological processes being studied. Based on this hypothesis, we initiated a series of high-throughput proteomic studies and found that the expressions of proteins involved in synaptic plasticity are selectively altered in the brain of cases at high risk to develop AD dementia (mild cognitive impairment; MCI). This is consistent with our cDNA microarray evidence showing that the expression of a-type synapsins is selectively altered in the brain of MCI cases. Collectively, these studies support the feasibility and usefulness of high-throughput cDNA microarray and proteomics techniques to study the sequential changes of distinctive gene expression patterns in the brain as a function of the progression of AD dementia.

Alzheimer Disease↗