Clinical Application of Induced Hepatocyte-like Cells Produced from Mesenchymal Stromal Cells: A Literature Review.

Liver disease is a leading cause of mortality worldwide, resulting in 1.3 million deaths annually. The vast majority of liver disease is caused by metabolic disease (i.

Protection against β-amyloid-induced synaptic and memory impairments via altering β-amyloid assembly by bis(heptyl)-cognitin.

β-amyloid (Aβ) oligomers have been closely implicated in the pathogenesis of Alzheimer's disease (AD). We found, for the first time, that bis(heptyl)-cognitin, a novel dimeric acetylcholinesterase (AChE) inhibitor derived from tacrine, prevented Aβ oligomers-induced inhibition of long-term potentiation (LTP) at concentrations that did not interfere with normal LTP. Bis(heptyl)-cognitin also prevented Aβ oligomers-induced synaptotoxicity in primary hippocampal neurons.

Rosiglitazone prevents amyloid-β oligomer-induced impairment of synapse formation and plasticity via increasing dendrite and spine mitochondrial number.

Rosiglitazone has been known to attenuate neurodegeneration in Alzheimer's disease (AD), but the underlying mechanisms remain to be fully elucidated. In this study, living-cell image, immunocytochemistry, and electrophysiology were used to examine the effects of soluble amyloid-β protein (Aβ) oligomers and rosiglitazone on the synapse formation, plasticity, and mitochondrial distribution in cultured neurons. Incubation of hippocampal cultures with amyloid-β (Aβ)42 oligomers (0.

Enhancement of long-term depression by soluble amyloid β protein in rat hippocampus is mediated by metabotropic glutamate receptor and involves activation of p38MAPK, STEP and caspase-3.

It is reported that the amyloid-β protein (Aβ)-induced impairments in synaptic plasticity coincide with memory decline and dementia. Although Aβ-induced inhibition of hippocampal long-term potentiation has been intensively investigated, the underlying mechanism of Aβ-enhanced long-term depression (LTD) is not clear. Here, we report that acute exposure of rat hippocampal slices to soluble Aβ-enhanced LTD induced by weak low-frequency stimulation (wLFS; 1Hz for 3 min, 180 pulses) in granule cells of the dentate gyrus.

Chronic pre-treatment with memantine prevents amyloid-beta protein-mediated long-term potentiation disruption.

Previous studies indicate that memantine, a low-affinity N-methyl-D-aspartate receptor antagonist, exerted acute protective effects against amyloid-β protein-induced neurotoxicity. In the present study, the chronic effects and mechanisms of memantine were investigated further using electrophysiological methods. The results showed that 7-day intraperitoneal application of memantine, at doses of 5 mg/kg or 20 mg/kg, did not alter hippocampal long-term potentiation induction in rats, while 40 mg/kg memantine presented potent long-term potentiation inhibition.

Plasticity of NMDA receptor-mediated excitatory postsynaptic currents at perforant path inputs to dendrite-targeting interneurons.

Synaptic plasticity of NMDA receptors (NMDARs) has been recently described in a number of brain regions and we have previously characterised LTP and LTD of glutamatergic NMDA receptor-mediated EPSCs (NMDAR-EPSCs) in granule cells of dentate gyrus. The functional significance of NMDAR plasticity at perforant path synapses on hippocampal network activity depends on whether this is a common feature of perforant path synapses on all postsynaptic target cells or if this plasticity occurs only at synapses on principal cells. We recorded NMDAR-EPSCs at medial perforant path synapses on interneurons in dentate gyrus which had significantly slower decay kinetics compared to those recorded in granule cells.

Activation of α7 nicotinic acetylcholine receptors persistently enhances hippocampal synaptic transmission and prevents Aß-mediated inhibition of LTP in the rat hippocampus.

Nicotinic acetylcholine receptors mediate fast cholinergic modulation of glutamatergic transmission and synaptic plasticity. Here we investigated the effects of subtype selective activation of the α7 nicotinic acetylcholine receptors on hippocampal transmission and the inhibition of synaptic long-term potentiation by the Alzheimer's disease associated amyloid ß-protein (Aß). The α7 nicotinic acetylcholine receptor agonist "compound A" ((R)-N-(1-azabicyclo[2.

Small-molecule conversion of toxic oligomers to nontoxic β-sheet-rich amyloid fibrils.

Several lines of evidence indicate that prefibrillar assemblies of amyloid-β (Aβ) polypeptides, such as soluble oligomers or protofibrils, rather than mature, end-stage amyloid fibrils cause neuronal dysfunction and memory impairment in Alzheimer's disease. These findings suggest that reducing the prevalence of transient intermediates by small molecule-mediated stimulation of amyloid polymerization might decrease toxicity. Here we demonstrate the acceleration of Aβ fibrillogenesis through the action of the orcein-related small molecule O4, which directly binds to hydrophobic amino acid residues in Aβ peptides and stabilizes the self-assembly of seeding-competent, β-sheet-rich protofibrils and fibrils.

Inhibition of the slow afterhyperpolarization restores the classical spike timing-dependent plasticity rule obeyed in layer 2/3 pyramidal cells of the prefrontal cortex.

The induction of long-term potentiation (LTP) and long-term depression (LTD) of excitatory postsynaptic currents was investigated in proximal synapses of layer 2/3 pyramidal cells of the rat medial prefrontal cortex. The spike timing-dependent plasticity (STDP) induction protocol of negative timing, with postsynaptic leading presynaptic stimulation of action potentials (APs), induced LTD as expected from the classical STDP rule. However, the positive STDP protocol of presynaptic leading postsynaptic stimulation of APs predominantly induced a presynaptically expressed LTD rather than the expected postsynaptically expressed LTP.

GluN2B subunit-containing NMDA receptor antagonists prevent Abeta-mediated synaptic plasticity disruption in vivo.

Currently, treatment with the relatively low-affinity NMDA receptor antagonist memantine provides limited benefit in Alzheimer's disease (AD). One probable dose-limiting factor in the use of memantine is the inhibition of NMDA receptor-dependent synaptic plasticity mechanisms believed to underlie certain forms of memory. Moreover, amyloid-beta protein (Abeta) oligomers that are implicated in causing the cognitive deficits of AD potently inhibit this form of plasticity.

Metabotropic glutamate receptor-dependent long-term potentiation.

The induction of the most common form of LTP is well known to involve activation of N-methyl-D-aspartate receptors. However, considerable evidence has also shown that certain forms of LTP induction at excitatory synapses onto both principle cells and interneurons are dependent on activation of metabotropic glutamate receptors (mGluRs). mGluR-dependent LTP occurs in widespread areas of the brain including the neocortex, hippocampus, striatum and nucleus accumbens.

Protection against Aβ-mediated rapid disruption of synaptic plasticity and memory by memantine.

Soluble amyloid-β protein (Aβ) may cause cognitive impairment in Alzheimer's disease in the absence of significant neurodegeneration. Here, the ability of the NMDA receptor (NMDAR) antagonist memantine to prevent synthetic Aβ-mediated rapid functional deficits in learned behavior and synaptic plasticity was assessed in the rat. In vitro, pretreatment with a clinically relevant, NMDAR blocking concentration of memantine partially inhibited the induction of long-term potentiation (LTP) in the dentate gyrus and prevented further inhibition caused by exposure to Aβ(1-42).

Intracellular mechanisms underlying the nicotinic enhancement of LTP in the rat dentate gyrus.

We have previously shown that activation of nicotinic acetylcholine receptors (nAChRs) enhanced long-term potentiation (LTP) in the rat dentate gyrus in vitro via activation of alpha7 nAChR. In the present studies, mechanisms underlying the acute and chronic nicotinic enhancement of LTP were examined. In particular, the involvement of activation of intracellular kinases was examined using selective kinase antagonists, and the effects of enhancing cholinergic function with positive allosteric modulators of the alpha7 nAChR and with acetylcholinesterase (AChE) inhibitors were also investigated.

Extrasynaptic NR2D-containing NMDARs are recruited to the synapse during LTP of NMDAR-EPSCs.

Long-term potentiation of NMDA-receptor-mediated synaptic transmission (NMDAR-LTP) is a little-understood form of plasticity. In the present study, we investigated whether NMDAR-LTP in the dentate gyrus involves recruitment of extrasynaptic NMDARs, because NMDARs are expressed both synaptically and extrasynaptically with evidence for subtype differences at different locations. We show that before induction of NMDAR-LTP, pharmacological inhibition of glutamate transporters resulted in glutamate spillover from the synapse and activation of extrasynaptic NMDARs.

Remodelling by early-life stress of NMDA receptor-dependent synaptic plasticity in a gene-environment rat model of depression.

An animal model of depression combining genetic vulnerability and early-life stress (ELS) was prepared by submitting the Flinders Sensitive Line (FSL) rats to a standard paradigm of maternal separation. We analysed hippocampal synaptic transmission and plasticity in vivo and ionotropic receptors for glutamate in FSL rats, in their controls Flinders Resistant Line (FRL) rats, and in both lines subjected to ELS. A strong inhibition of long-term potentiation (LTP) and lower synaptic expression of NR1 subunit of the NMDA receptor were found in FSL rats.

5-HT2 receptor-mediated reversal of the inhibition of hippocampal long-term potentiation by acute inescapable stress.

The serotonergic system is known to modulate and mediate many of the central nervous system effects of stress. Here we investigated the ability of serotonergic agents to reverse the inhibition of the induction of hippocampal long-term potentiation (LTP) caused by prior exposure to inescapable stress. Elevated platform stress prevented the induction of LTP in the CA1 area of anaesthetized rats.

Amyloid beta protein dimer-containing human CSF disrupts synaptic plasticity: prevention by systemic passive immunization.

The current development of immunotherapy for Alzheimer's disease is based on the assumption that human-derived amyloid beta protein (Abeta) can be targeted in a similar manner to animal cell-derived or synthetic Abeta. Because the structure of Abeta depends on its source and the presence of cofactors, it is of great interest to determine whether human-derived oligomeric Abeta species impair brain function and, if so, whether or not their disruptive effects can be prevented using antibodies. We report that untreated ex vivo human CSF that contains Abeta dimers rapidly inhibits hippocampal long-term potentiation in vivo and that acute systemic infusion of an anti-Abeta monoclonal antibody can prevent this disruption of synaptic plasticity.

Involvement of group I mGluRs in LTP induced by strong high frequency stimulation in the dentate gyrus in vitro.

The involvement of group I metabotropic glutamate receptors (mGluRs) and ryanodine receptors was investigated in the induction of LTP induced either by application of one standard high frequency stimulation (HFS) or by strong multiple HFS in the medial perforant path to granule cell synapse of the rat dentate gyrus. Whilst a standard brief HFS induced LTP close to 50%, strong stimulation consisting of multiple HFS induced a much larger LTP. mGluR5 was found to be partially involved in the induction of the enhanced LTP induced by the strong HFS but not in the standard LTP induced by the brief HFS.

Cyclooxygenase-2 inhibition improves amyloid-beta-mediated suppression of memory and synaptic plasticity.

Non-steroidal anti-inflammatory agents (NSAIDs) are associated with a marked reduction in the risk of developing Alzheimer's disease, a form of dementia characterized by the accumulation of amyloid plaques containing the amyloid-beta protein (Abeta). Studies of the effects of NSAIDs upon the inflammatory response surrounding amyloid plaques and upon the generation of Abeta from the amyloid precursor protein (APP) have led to two proposed mechanisms by which NSAIDs may protect against Alzheimer's disease: one, the selective lowering of Abeta42 by a subset of NSAIDs; and two, the reduction of inflammation. Although Alzheimer's disease is a disorder of brain and synaptic function, the effects of NSAIDs on Abeta-mediated suppression of synaptic plasticity and memory function have never been reported.

Inhibition of LTP by beta-amyloid is prevented by activation of beta2 adrenoceptors and stimulation of the cAMP/PKA signalling pathway.

Beta-amyloid (Abeta) is the main component of the extracellular plaques present in patients with Alzheimer's disease (AD) and studies have shown that exogenous application of Abeta results in neurodegeneration. As a model of the neurodegenerative action of Abeta, we have previously shown that acutely applied Abeta inhibits the induction of LTP in the hippocampus in vitro. In the present studies, we have studied the effect of beta-adrenoceptor activation on the Abeta inhibition of LTP.

A role for protein kinase A and protein kinase M zeta in muscarinic acetylcholine receptor-initiated persistent synaptic enhancement in rat hippocampus in vivo.

Antagonists at presynaptic muscarinic autoreceptors increase endogenous acetylcholine (ACh) release and enhance cognition but little is known regarding their actions on plasticity at glutamatergic synapses. Here the mechanisms of the persistent enhancement of hippocampal excitatory transmission induced by the M2/M4 muscarinic ACh receptor antagonist methoctramine were investigated in vivo. The persistent facilitatory effect of i.

Synaptic memory mechanisms: Alzheimer's disease amyloid beta-peptide-induced dysfunction.

There is growing evidence that mild cognitive impairment in early AD (Alzheimer's disease) may be due to synaptic dysfunction caused by the accumulation of non-fibrillar, oligomeric Abeta (amyloid beta-peptide), long before widespread synaptic loss and neurodegeneration occurs. Soluble Abeta oligomers can rapidly disrupt synaptic memory mechanisms at extremely low concentrations via stress-activated kinases and oxidative/nitrosative stress mediators. Here, we summarize experiments that investigated whether certain putative receptors for Abeta, the alphav integrin extracellular cell matrix-binding protein and the cytokine TNFalpha (tumour necrosis factor alpha) type-1 death receptor mediate Abeta oligomer-induced inhibition of LTP (long-term potentiation).

Performance- and task-dependent effects of the dopamine D1/D5 receptor agonist SKF 38393 on learning and memory in the rat.

Dopamine D(1)/D(5) receptor agonists may enhance cognition by mimicking dopamine's neurophysiological actions on the processes underlying learning and memory. The present study examined the task- and performance- dependence of the cognitive effects of a partial agonist at dopamine D(1)/D(5) receptors, SKF 38393 [(+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrobromide], in rats. Spatial working memory was assessed in a T-maze, spatial reference memory in a water maze and habituation learning in a novel environment, a hole board.

Beta-amyloid blocks high frequency stimulation induced LTP but not nicotine enhanced LTP.

Nicotine has been postulated to be a possible neuroprotective agent in Alzheimer's Disease (AD). In the present studies, the effect of beta-amyloid (Abeta) was investigated on the nicotine enhancement of high-frequency-induced LTP. Perfusion of nicotine substantially enhanced HFS-induced LTP in both rat and mouse dentate gyrus.

Alpha v integrins mediate beta-amyloid induced inhibition of long-term potentiation.

Beta-amyloid (Abeta) is the principal component of the extracellular plaques present in patients with Alzheimer's disease. Several studies have recently shown that acutely applied Abeta inhibits the induction of LTP in the hippocampus. In the present studies, we have investigated the role of integrins in such Abeta-mediated block of LTP in the dentate gyrus in vitro and in the CA1 in vivo.