DNA damage-inducing agent-elicited gamma-secretase activity is dependent on Bax/Bcl-2 pathway but not on caspase cascades.
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Amyloid Precursor Protein Secretases↗
Biomedical subjects
I Mook-Jung
Publications and source records attributed to I Mook-Jung.
Circulating beta amyloid protein is elevated in patients with acute ischemic stroke.
Recent clinical and experimental studies suggest that ischemic strokes may play an important role in the pathogenesis of Alzheimer's disease (AD). Beta amyloid (Abeta), a major component of senile plaque in AD, is known to be derived from ischemic brain or activated platelets. We prospectively enrolled 62 patients with acute ischemic stroke and 27 age-matched controls. The serum Abeta and P-selectin levels were determined using the Sandwich-ELISA. We divided ischemic strokes into subgroups according to the clinical syndrome, pathogenesis, and infarct size, and compared the Abeta level between each subgroup. The Abeta1-40 level was markedly elevated in ischemic stroke patients, as compared to controls (140.2 +/- 54.0 vs 88.44 +/- 34.96 pg/ml, p<0.001). Cardioembolic and larger artery atherosclerotic infarcts had higher Abeta1-40 level than small vessel disease (p = 0.001). Both infarct size and the initial NIHSS score had significantly positive correlations with the serum level of Abeta1-40 (r = 0.539, p<0.001 and r = 0.425, p = 0.001, respectively). However, the P-selectin level was not significantly correlated with serum Abeta1-40. Our data suggest that elevated circulating Abeta1-40 in ischemic stroke patients may be derived from brain as a consequence of ischemic insults.
Acute Disease↗
ER stress-induced caspase-12 activation is inhibited by PKC in neuronal cells.
Caspase-12 is activated when the cells are exposed to excess levels of various stimuli, which cause endoplasmic reticulum (ER) stress. Protein kinase C (PKC) plays an important role in many signaling pathways in cells, and the activation of PKC has multiple actions in the signaling function of the ER. This study examined whether or not phorbol 12, 13-dibutyrate (PDBu)-induced PKC activation modulates caspase-12 cleavage and it's processing, using a wild type caspase-12 overexpressing neuronal cell line, known as Cas-12 cells. The thapsigargin treatment induced caspase-12 fragmentation in the Cas-12 cells. This was inhibited by PKC, which had previously been stimulated by PDBu. The PDBu treatment attenuated the ER stress-induced translocation of caspase-12 from the ER to the cytoplasm. The caspase-3 specific inhibitor blocked caspase-12 fragmentation, and purified caspase-12 was cleaved by the active caspase-3 in vitro, suggesting that caspase-12 might be a substrate for caspase-3. In addition, the PDBu treatment influenced the decrease of active caspase-3 fragment. These results suggest that an ER stress induces the activation of caspase-12 via caspase-3, and that PKC regulates both caspase-12 and caspase-3 activations in Cas-12 cells.
Animals↗
Dynamics of population code for working memory in the prefrontal cortex.
Some neurons (delay cells) in the prefrontal cortex elevate their activities throughout the time period during which the animal is required to remember past events and prepare future behavior, suggesting that working memory is mediated by continuous neural activity. It is unknown, however, how working memory is represented within a population of prefrontal cortical neurons. We recorded from neuronal ensembles in the prefrontal cortex as rats learned a new delayed alternation task. Ensemble activities changed in parallel with behavioral learning so that they increasingly allowed correct decoding of previous and future goal choices. In well-trained rats, considerable decoding was possible based on only a few neurons and after removing continuously active delay cells. These results show that neural activity in the prefrontal cortex changes dynamically during new task learning so that working memory is robustly represented and that working memory can be mediated by sequential activation of different neural populations.
Action Potentials↗
Interferon gamma stimulates beta-secretase expression and sAPPbeta production in astrocytes.
Neurons, but not astrocytes, are known as the major source of Abeta, because astrocytes express low levels of putative beta-secretase (BACE). Astrocytes near senile plaque cores show enhanced levels of BACE protein expression, however, suggesting that astrocytes can contribute to Abeta production under pathological conditions. To investigate factors that stimulate BACE protein expression in astrocytes, we tested the effects of interleukin-1beta (IL-1beta) and interferon-gamma (IFN-gamma) on BACE protein expression in U373MG astrocytoma cells and primary astrocyte cultures from Tg2576 mouse brains. BACE protein expression and sAPPbeta production were dramatically increased, without changes in holo APP levels, following IFN-gamma treatment in both cell types. AG490, which is a blocker of IFN-gamma-induced STAT signaling, decreased IFN-gamma-induced BACE protein expression and sAPPbeta production in a dose-dependent manner. These results show that astrocytes are capable of expressing BACE and producing sAPPbeta in response to certain stimulating factors, and IFN-gamma is one such factor.
Amyloid Precursor Protein Secretases↗
Long-term potentiation in visual cortical projections to the medial prefrontal cortex of the rat.
In order to investigate neural mechanisms by which the prefrontal cortex adaptively modifies its activities based on past experience, we examined whether or not sensory cortical projections to the medial prefrontal cortex support long-term potentiation (LTP) in rats. Monosynaptic projections from the secondary visual cortex, mediomedial area (V2MM) to the infralimbic cortex were confirmed by orthodromic as well as antidromic activation of single units. High-frequency stimulation (50 Hz, 2 s) induced LTP (approximately 45% increase over the baseline) in the V2MM projection to the infralimbic cortex. LTP induction in this pathway was completely blocked by an injection (i.p.) of CPP, an N-methyl-D-aspartate receptor antagonist. LTP was also induced in the ventral hippocampal projection to the infralimbic cortex by the same high-frequency stimulation. The present results suggest that modification of synaptic weights of afferent sensory cortical projections is one mechanism underlying learning-induced changes in prefrontal cortical neural activities.
Animals↗
Cholinergic modulation of synaptic physiology in deep layer entorhinal cortex of the rat.
We have recently shown that cholinergic effects on synaptic transmission and plasticity in the superficial (II/III) layers of the rat medial entorhinal cortex (EC) are similar, but not identical, to those in the hippocampus (Yun et al. [2000] Neuroscience 97:671-676). Because the superficial and deep layers of the EC preferentially convey afferent and efferent hippocampal projections, respectively, it is of interest to compare cholinergic effects between the two regions. We therefore investigated the physiological effects of cholinergic agents in the layer V of medial EC slices under experimental conditions identical to those in the previous study. Bath application of carbachol (0.5 microM) induced transient depression of field potential responses in all cases tested (30 of 30; 18.5% +/- 2.3%) and rarely induced long-lasting potentiation (only 3 of 30; 20.4% +/- 3.2% in successful cases). At 5 microM, carbachol induced transient depression only (20 of 20, 48.9% +/- 2.8%), which was blocked by atropine (10 microM). Paired-pulse facilitation was enhanced during carbachol-induced depression, suggesting presynaptic action of carbachol. Long-term potentiation (LTP) could be induced in the presence of 10 microM atropine by theta burst stimulation, but its magnitude was significantly lower (9.1% +/- 4.7%, n = 15) compared to LTP in control slices (22.4% +/- 3.9%, n = 20). These results, combined with our previous findings, demonstrate remarkably similar cholinergic modulation of synaptic transmission and plasticity across the superficial and deep layers of EC.
Acetylcholine↗
Zinc enhances synthesis of presenilin 1 in mouse primary cortical culture.
Whether zinc interacts with presenilin 1 (PS1), one of the causative genes of familial Alzheimer's disease (AD), is not known. Here we report that zinc modulates the synthesis of PS1. Exogenous zinc enhanced the amount of C-terminal fragments of PS1 (PS1-CTF) in neonatal mouse cortical cultures in a dose-dependent manner. Zinc also induced cell death in a dose-dependent manner. These effects of zinc were not mimicked by calcium, copper, or iron, and were blocked by a zinc-specific chelator, TPEN. Experiments using metabolic labeling and cycloheximide treatment revealed that zinc increased PS1-CTF by elevating the de novo synthesis of PS1. Time course experiments revealed that cell death commenced sooner (0.5-1 h) than enhancement of PS1-CTF (1-2 h) following zinc treatment. However, the amount of PS1-CTF remained unchanged during etoposide- or H(2)O(2)-induced cell death, suggesting that enhancement of PS1 synthesis is specifically correlated with zinc-induced cell death.
Alzheimer Disease↗
Negative regulation of the SAPK/JNK signaling pathway by presenilin 1.
Presenilin 1 (PS1) plays a pivotal role in Notch signaling and the intracellular metabolism of the amyloid beta-protein. To understand intracellular signaling events downstream of PS1, we investigated in this study the action of PS1 on mitogen-activated protein kinase pathways. Overexpressed PS1 suppressed the stress-induced stimulation of stress-activated protein kinase (SAPK)/c-Jun NH(2)-terminal kinase (JNK) in human embryonic kidney 293 cells. Interestingly, two functionally inactive PS1 mutants, PS1(D257A) and PS1(D385A), failed to inhibit UV-stimulated SAPK/JNK. Furthermore, H(2)O(2-) or UV-stimulated SAPK activity was higher in mouse embryonic fibroblast (MEF) cells from PS1-null mice than in MEF cells from PS(+/+) mice. MEF(PS1(-/-)) cells were more sensitive to the H(2)O(2)-induced apoptosis than MEF(PS1(+/+)) cells. Ectopic expression of PS1 in MEF(PS1(-/-)) cells suppressed H(2)O(2)-stimulated SAPK/JNK activity and apoptotic cell death. Together, our data suggest that PS1 inhibits the stress-activated signaling by suppressing the SAPK/JNK pathway.
Animals↗
Neuroprotective effects of estrogen against beta-amyloid toxicity are mediated by estrogen receptors in cultured neuronal cells.
Although estrogen is known to exert beneficial effects on Alzheimer's disease, its underlying cellular mechanisms have not been clear. In this study we investigated whether or not neuroprotective effects of estrogen are mediated by estrogen receptors (ERs). Treatment of estrogen (1.8 nM) reduced beta-amyloid (Abeta)-induced death of ER-expressing W4 cells. This effect of estrogen was blocked by a specific ER blocker ICI 182,780. When estrogen was treated to HT22 cells, which lack functional ERs, Abeta-induced cell death was not affected. Transfection of HT22 cells with human ERalpha, but not ERbeta, restored protective action of estrogen against Abeta. Hoechst staining revealed that estrogen protected ERalpha-expressing cells by blocking Abeta-induced apoptosis. These results indicate that estrogen blocks Abeta-induced cell death via ERalpha-dependent pathways.
Amyloid beta-Peptides↗
Ginsenoside Rb1 and Rg1 improve spatial learning and increase hippocampal synaptophysin level in mice.
We investigated the cognition enhancing effects of ginsenoside Rb1 and Rg1. Mice were trained in a Morris water maze following injection (i.p.) of Rb1 (1 mg/kg) or Rg1 (1 mg/kg) for 4 days. Both Rb1- and Rg1-injected mice showed enhanced spatial learning compared to control animals. The hippocampus, but not the frontal cortex, of treated mice contained higher density of a synaptic marker protein, synaptophysin, compared to control mice. Electrophysiological recordings in hippocampal slices revealed that Rb1 or Rg1 injection did not change the magnitude of paired-pulse facilitation or long-term potentiation. Our results suggest that Rb1 and Rg1 enhance spatial learning ability by increasing hippocampal synaptic density without changing plasticity of individual synapses.
Animals↗
Haloperidol and clozapine increase neural activity in the rat prefrontal cortex.
Haloperidol and clozapine have been widely used to alleviate schizophrenic symptoms, but their physiological effects in the prefrontal cortex (PFC) are not known. Effects of haloperidol and clozapine on single unit activity were investigated in the medial PFC of anesthetized rats. Injection (intraperitoneal) of haloperidol (1 mg/kg) or clozapine (20 mg/kg) significantly elevated discharge rates of PFC neurons. Considering that hypofrontality is one characteristic of schizophrenic symptoms, these results raise the possibility that enhancement of PFC neural activity contributes to therapeutic effects of haloperidol and clozapine.
Action Potentials↗
Blockade of PKC epsilon activation attenuates phorbol ester-induced increase of alpha-secretase-derived secreted form of amyloid precursor protein.
The role of PKC epsilon in amyloid precursor protein (APP) processing was investigated using APP-overexpressing B103 cells. As reported previously, a PKC activator, phorbol-12,13-dibutyrate (PDBu), enhanced secretion of APP alpha, and this effect was blocked by a PKC inhibitor, GF109203X in this system. Selective inhibition of PKC epsilon by overexpressing the PKC epsilon V1 region, which binds specifically to the receptor for activated C-kinase (RACK), blocked PDBu-induced enhancement of APP alpha secretion as well as PDBu-induced decrease in beta-secretase-derived APP C-terminal fragment production. On the other hand, the level of PKC epsilon, but not that of PKC alpha or PKC gamma, was substantially lower in the brains of Alzheimer's disease patients compared to age-matched controls. These results add to a growing body of evidence that PKC epsilon plays an important role in modulating APP processing, and suggest that reduced PKC epsilon activity may contribute to the development of Alzheimer's disease.
Alzheimer Disease↗
Fast spiking and regular spiking neural correlates of fear conditioning in the medial prefrontal cortex of the rat.
In order to investigate whether and how medial prefrontal cortex (mPFC) of the rat is involved in processing of information related to fear conditioning, we recorded from single units in the prelimbic and infralimbic cortex of fear-conditioned rats in response to an explicit conditional stimulus (CS; an auditory tone) or contextual cues (conditioning box). The majority of units changed their activities significantly in response to the CS in a delay or trace conditioning paradigm. Both transient and tonic activity changes, including delay cell activity, were observed as in other behavioral tasks. When exposed to the context without CS delivery, most units changed their activities as well. These results show that both tone and contextual information are processed in the rat mPFC in expectation of the delivery of an aversive stimulus (electric foot shock). Interestingly, fast spiking cells (putative inhibitory interneurons) and regular spiking cells (putative projection neurons) showed different patterns of responses. Fast spiking cells tended to show transient responses and increased their firing rates following CS presentation, whereas a complementary pattern was observed in the regular spiking cells. Our results enhance our understanding of the neural mechanisms underlying prediction of an aversive stimulus in the mPFC.
Acoustic Stimulation↗
Relationship among discharges of neighboring neurons in the rat prefrontal cortex during spatial working memory tasks.
The relationship among discharges of neurons that were recorded simultaneously with tetrodes in the rat medial prefrontal cortex was analyzed. Spatial working memory tasks were divided into several distinct stages based on the behavioral correlates of individual neurons, and interneuronal correlation of signal (mean discharge rate at each stage) and noise (trial-to-trial deviation from the signal) was calculated. Behavioral correlates of neighboring neurons were quite heterogeneous and, accordingly, average signal correlation was relatively low ( approximately 0.16). Noise correlation was even lower ( approximately 0.06), but neuronal noise was more correlated among the neurons with similar signals. Spikes underlying the signal and noise correlation among the prefrontal cortical neurons were loosely synchronized over a few hundred milliseconds. These results suggest that neighboring prefrontal cortical neurons process largely independent information and have weakly correlated noise and that precisely synchronized spikes play a relatively minor role in producing the correlated signal and noise among these neurons.
Action Potentials↗
Structure-activity relationship study of asiatic acid derivatives against beta amyloid (A beta)-induced neurotoxicity.
8 Semi-synthetic derivatives of asiatic acid were prepared and their protective effect against A beta-induced neurotoxicity was evaluated. Among them, asiatic acid (2), and 4, 16 showed 97, 92 and 87% of protective effect, respectively.
Alzheimer Disease↗
Cholinergic modulation of synaptic transmission and plasticity in entorhinal cortex and hippocampus of the rat.
Effects of cholinergic agents on synaptic transmission and plasticity were examined in entorhinal cortex and hippocampus. Bath application of carbachol (0.25-0.75 microM) induced transient depression of field potential responses in all cases tested (24/24 in layer III of medial entorhinal cortex slices and 24/24 in CA1 of hippocampal slices; 11.0+/-1.9% and 7.8+/-2.5%, respectively) and long-lasting potentiation in some cases (4/24 in entorhinal cortex and 12/24 in hippocampus; 33.7+/-3.7% and 32.1+/-9.9%, respectively, in successful cases). Carbachol (0.5 microM) induced transient depression, but not long-lasting potentiation, of N-methyl-D-aspartate receptor-mediated responses in entorhinal cortex. At 5 microM, carbachol induced transient depression only (55. 9+/-4.7% in entorhinal cortex and 41.4+/-2.9% in hippocampus), which was blocked by atropine. Paired-pulse facilitation was not altered during carbachol-induced potentiation but enhanced during carbachol-induced depression. These results suggest that the underlying mechanisms of carbachol-induced depression and potentiation are decreased transmitter release and selective enhancement of non-N-methyl-D-aspartate receptor-mediated responses, respectively. Long-term potentiation could be induced in the presence of 10 microM atropine by theta burst stimulation. The magnitude was significantly lower (15.2+/-5.2%, n=9) compared with control (37.2+/-6.1%, n=8) in entorhinal cortex, however. These results demonstrate similar, but not identical, cholinergic modulation of synaptic transmission and plasticity in entorhinal cortex and hippocampus.
6-Cyano-7-nitroquinoxaline-2,3-dione↗
Protective effects of asiaticoside derivatives against beta-amyloid neurotoxicity.
Asiaticoside (AS) derivatives were tested for potential protective effects against Abeta-induced cell death. Of the 28 AS derivatives tested, asiatic acid (AA), asiaticoside 6 (AS6), and SM2 showed strong inhibition of Abeta-induced death of B103 cells at 1 microM. The three AS derivatives were further tested for their effects on free radical injury and apoptosis. All three AS derivatives reduced H(2)O(2)-induced cell death and lowered intracellular free radical concentration, but AA showed the strongest protection. In contrast, SM2 was the most effective blocker of staurosporine-induced apoptosis. These results suggest that the three AS derivatives block Abeta toxicity by acting through different cellular mechanisms. When applied to hippocampal slices, AA, SM2, and AS6 did not alter n-methyl-D-aspartic acid (NMDA) or non-NMDA receptor-mediated synaptic transmission, paired-pulse facilitation or induction of long-term potentiation in the field CA1. These results indicate that the three AS derivatives do not alter physiological properties of the hippocampus at the concentration that blocks Abeta-induced cell death. Therefore AS6, AA, and SM2 can be regarded as reasonable candidates for a therapeutic Alzheimer's disease drug that protects neurons from Abeta toxicity.
6-Cyano-7-nitroquinoxaline-2,3-dione↗