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The role of ventral hippocampus (vHipp) astroglial gliotransmission in depression was studied using chronic restraint stress (CRS) and chronic unpredictable mild stress (CUMS) rodent models. CRS increased Cx43 hemichannel activity and extracellular glutamate levels in the vHipp and blocking astroglial Cx43 hemichannel-dependent gliotransmission during CRS prevented the development of depression and glutamate buildup. Moreover, the acute blockade of Cx43 hemichannels induced antidepressant effects in rats previously subjected to CRS or CUMS. This antidepressant effect was prevented by coinjection of glutamate and D-serine. Furthermore, Cx43 hemichannel blockade decreased postsynaptic NMDAR currents in vHipp slices in a glutamate and D-serine-dependent manner. Notably, chronic microinfusion of glutamate and D-serine, L-serine, or the NMDAR agonist NMDA, into the vHipp induced depressive-like symptoms in nonstressed rats. We also identified a small molecule, cacotheline, which blocks Cx43 hemichannels and its systemic administration induced rapid antidepressant effects, preventing stress-induced increases in astroglial Cx43 hemichannel activity and extracellular glutamate in the vHipp, without sedative or locomotor side effects. In conclusion, chronic stress increases Cx43 hemichannel-dependent release of glutamate and D-/L-serine from astrocytes in the vHipp, overactivating postsynaptic NMDARs and triggering depressive-like symptoms. This study highlights the critical role of astroglial gliotransmitter release in chronic stress-induced depression and suggests it can be used as a target for the prevention and treatment of depression., Competing Interests: Competing interests statement:M.A.R., D.G.-N., and J.S. authored a Patent application filed in 2013-05-31 (WO 2013/179264), which was granted in the US (US-9879058-B2) on the date 2018/01/30, entitled “Use of compounds that selectively modulate astrocytic release of substances through hemichannels of connexins and pannexins, without influencing gap junctions, for the treatment of psychiatric disorders,” which included cacotheline as an example. All other authors report no conflicts of interest.

Background: Epstein-Barr virus (EBV) is involved in the development of lymphomas, nasopharyngeal carcinomas (NPC), and a subgroup of gastric carcinomas (GC), and has also been detected in lung carcinomas, even though the role of the virus in this malignancy has not yet been established. BamH1-A Rightward Frame 1 (BARF1), a suggested exclusive epithelial EBV oncoprotein, is detected in both EBV-associated GCs (EBVaGC) and NPC. The expression and role of BARF1 in lung cancer is unknown., Methods: A total of 158 lung carcinomas including 80 adenocarcinomas (AdCs) and 78 squamous cell carcinomas (SQCs) from Chilean patients were analyzed for EBV presence via polymerase chain reaction (PCR), Immunohistochemistry (IHC), or chromogenic in situ hybridization (CISH). The expression of BARF1 was evaluated using Reverse Transcription Real-Time PCR (RT-qPCR). Additionally, A549 and BEAS-2B lung epithelial cells were transfected with a construct for ectopic BARF1 expression. Cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) were evaluated., Results: We found that EBV was present in 37 out of 158 (23%) lung carcinomas using PCR. Considering EBV-positive specimens using PCR, IHC for Epstein-Barr nuclear antigen 1 (EBNA1) detected EBV in 24 out of 30 (80%) cases, while EBERs were detected using CISH in 13 out of 16 (81%) cases. Overall, 13 out of 158 (8%) lung carcinomas were shown to be EBV-positive using PCR/IHC/CISH. BARF1 transcripts were detected in 6 out of 13 (46%) EBV-positive lung carcinomas using RT qPCR. Finally, lung cells ectopically expressing BARF1 showed increased migration, invasion, and EMT., Conclusions: EBV is frequently found in lung carcinomas from Chile with the expression of BARF1 in a significant subset of cases, suggesting that this viral protein may be involved in EBV-associated lung cancer progression.

In signaling proteins, intrinsically disordered regions often represent regulatory elements, which are sensitive to environmental effects, ligand binding, and post-translational modifications. The conformational space sampled by disordered regions can be affected by environmental stimuli and these changes trigger, vis a vis effector domain, downstream processes. The disordered nature of these regulatory elements enables signal integration and graded responses but prevents the application of classical approaches for drug screening based on the existence of a fixed three-dimensional structure. We have designed a genetically encodable biosensor for the N-terminal regulatory element of the c-Src kinase, the first discovered protooncogene and lead representative of the Src family of kinases. The biosensor is formed by two fluorescent proteins forming a FRET pair fused at the two extremes of a construct including the SH4, unique and SH3 domains of Src. An internal control is provided by an engineered proteolytic site allowing the generation of an identical mixture of the disconnected fluorophores. We show FRET variations induced by ligand binding. The biosensor has been used for a high-throughput screening of a library of 1669 compounds with seven hits confirmed by NMR.

Astrocytes release gliotransmitters via connexin 43 (Cx43) hemichannels into neighboring synapses, which can modulate synaptic activity and are necessary for fear memory consolidation. However, the gliotransmitters released, and their mechanisms of action remain elusive. Here, we report that fear conditioning training elevated Cx43 hemichannel activity in astrocytes from the basolateral amygdala (BLA). The selective blockade of Cx43 hemichannels by microinfusion of TAT-Cx43L2 peptide into the BLA induced memory deficits 1 and 24 h after training, without affecting learning. The memory impairments were prevented by the co-injection of glutamate and D-serine, but not by the injection of either alone, suggesting a role for NMDA receptors (NMDAR). The incubation with TAT-Cx43L2 decreased NMDAR-mediated currents in BLA slices, effect that was also prevented by the addition of glutamate and D-serine. NMDARs in primary neuronal cultures were unaffected by TAT-Cx43L2, ruling out direct effects of the peptide on NMDARs. Finally, we show that D-serine permeates through purified Cx43 hemichannels reconstituted in liposomes. We propose that the release of glutamate and D-serine from astrocytes through Cx43 hemichannels is necessary for the activation of post-synaptic NMDARs during training, to allow for the formation of short-term and subsequent long-term memory, but not for learning per se., (© 2022 Federation of American Societies for Experimental Biology.)

Traumatic Brain Injury (TBI) mediates neuronal death through several events involving many molecular pathways, including the glutamate-mediated excitotoxicity for excessive stimulation of N-methyl-D-aspartate receptors (NMDARs), producing activation of death signaling pathways. However, the contribution of NMDARs (distribution and signaling-associated to the distribution) remains incompletely understood. We propose a critical role of STEP 61 (Striatal-Enriched protein tyrosine phosphatase) in TBI; this phosphatase regulates the dephosphorylated state of the GluN2B subunit through two pathways: by direct dephosphorylation of tyrosine-1472 and indirectly via dephosphorylation and inactivation of Fyn kinase. We previously demonstrated oxidative stress's contribution to NMDAR signaling and distribution using SOD2 +/- mice such a model. We performed TBI protocol using a controlled frontal impact device using C57BL/6 mice and SOD2 +/- animals. After TBI, we found alterations in cognitive performance, NMDAR-dependent synaptic function (decreased synaptic form of NMDARs and decreased synaptic current NMDAR-dependent), and increased STEP 61 activity. These changes are reduced partially with the STEP 61 -inhibitor TC-2153 treatment in mice subjected to TBI protocol. This study contributes with evidence about the role of STEP 61 in the neuropathological progression after TBI and also the alteration in their activity, such as an early biomarker of synaptic damage in traumatic lesions.

Memory consolidation requires activation of a gene expression program that allows de novo protein synthesis. But the molecular mechanisms that favour or restrict that program are poorly understood. The kinase c-Abl can modulate gene expression through transcription factors and chromatin modifiers. Here, we show that c-Abl ablation in the brain improves learning acquisition and memory consolidation in mice. Its absence also affects gene expression profiles in the mouse hippocampus. We found that genes involved in synaptic plasticity and actin cytoskeleton dynamics, such as Arp2 and Thorase, are up-regulated at the mRNA and protein levels in trained c-Abl KO mice and by a chemical-LTP stimulus. Trained c-Abl KO mice also show that dendritic spines are larger than in wild-type mice and present at a higher density. These results indicate that c-Abl kinase is an important part of the mechanism that limits or restricts signalling of relevant gene programs involved in morphological and functional spine changes upon neuronal stimulation., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Cells comprise several intracellular membrane compartments that allow them to function properly. One of these functions is cargo movement, typically proteins and membranes within cells. These cargoes ride microtubules through vesicles from Golgi and recycling endosomes to the plasma membrane in order to be delivered and exocytosed. In neurons, synaptic functions employ this cargo trafficking to maintain inter-neuronal communication optimally. One of the complexes that oversee vesicle trafficking and tethering is the exocyst. The exocyst is a protein complex containing eight subunits first identified in yeast and then characterized in multicellular organisms. This complex is related to several cellular processes, including cellular growth, division, migration, and morphogenesis, among others. It has been associated with glutamatergic receptor trafficking and tethering into the synapse, providing the molecular machinery to deliver receptor-containing vesicles into the plasma membrane in a constitutive manner. In this review, we discuss the evidence so far published regarding receptor trafficking and the exocyst complex in both basal and stimulated levels, comparing constitutive trafficking and long-term potentiation-related trafficking.

Oxidative stress affects the survival and function of neurons. Hence, they have a complex and highly regulated machinery to handle oxidative changes. The dysregulation of this antioxidant machinery is associated with a wide range of neurodegenerative conditions. Therefore, we evaluated signaling alterations, synaptic properties and behavioral performance in 2 and 6-month-old heterozygous manganese superoxide dismutase knockout mice (SOD2 +/- mice). We found that their low antioxidant capacity generated direct oxidative damage in proteins, lipids, and DNA. However, only 6-month-old heterozygous knockout mice presented behavioral impairments. On the other hand, synaptic plasticity, synaptic strength and NMDA receptor (NMDAR) dependent postsynaptic potentials were decreased in an age-dependent manner. We also analyzed the phosphorylation state of the NMDAR subunit GluN2B. We found that while the levels of GluN2B phosphorylated on tyrosine 1472 (synaptic form) remain unchanged, we detected increased levels of GluN2B phosphorylated on tyrosine 1336 (extrasynaptic form), establishing alterations in the synaptic/extrasynaptic ratio of GluN2B. Additionally, we found increased levels of two phosphatases associated with dephosphorylation of p-1472: striatal-enriched protein tyrosine phosphatase (STEP) and phosphatase and tensin homolog deleted on chromosome Ten (PTEN). Moreover, we found decreased levels of p-CREB, a master transcription factor activated by synaptic stimulation. In summary, we describe mechanisms by which glutamatergic synapses are altered under oxidative stress conditions. Our results uncovered new putative therapeutic targets for conditions where NMDAR downstream signaling is altered. This work also contributes to our understanding of processes such as synapse formation, learning, and memory in neuropathological conditions., (Copyright © 2018 Elsevier B.V. All rights reserved.)

In the young population, binge drinking is a pattern of problematic alcohol consumption, characterized by a short period of heavy drinking followed by abstinence which is frequently repeated over time. This drinking pattern is associated with mental problems, use of other drugs, and an increased risk of excessive alcohol intake during adulthood. However, little is known about the effects of binge drinking on brain function in adolescents and its neurobiological impact during the adulthood. In the present study, we evaluated the effects of alcohol on hippocampal memory, synaptic plasticity, and mitochondrial function in adolescent rats after a binge drinking episode in vivo. These effects were analyzed at 1, 3, or 7 weeks post alcohol exposure. Our results showed that binge-like ethanol pre-treated (BEP) rats exhibited early alterations in learning and memory tests accompanied by an impairment of synaptic plasticity that was total and partially compensated, respectively. These changes could be attributed to a rapid increase in oxidative damage and a late inflammatory response induced by post ethanol exposure. Additionally, BEP alters the regulation of mitochondrial dynamics and modifies the expression of mitochondrial permeability transition pore (mPTP) components, such as cyclophilin D (Cyp-D) and the voltage-dependent anion channel (VDAC). These mitochondrial structural changes result in the impairment of mitochondrial bioenergetics, decreasing ATP production progressively until adulthood. These results strongly suggest that teenage alcohol binge drinking impairs the function of the adult hippocampus including memory and synaptic plasticity as a consequence of the mitochondrial damage induced by alcohol and that the recovery of hippocampal function could implicate the activation of alternative pathways that fail to reestablish mitochondrial function.

Amyloid-β peptide (Aβ) is one of the major players in the pathogenesis of Alzheimer's disease (AD). Despite numerous studies, the mechanisms by which Aβ induces neurodegeneration are not completely understood. Oxidative stress is considered a major contributor to the pathogenesis of AD, and accumulating evidence indicates that high levels of reactive oxygen species (ROS) are involved in Aβ-induced neurodegeneration. Moreover, Aβ can induce the deregulation of calcium homeostasis, which also affects mitochondrial function and triggers neuronal cell death. In the present study, we analyzed the effects of quercetin, a plant flavonoid with antioxidant properties, on oxidative stress- and Aβ-induced degeneration. Our results indicate that quercetin efficiently protected against H 2 O 2 -induced neuronal toxicity; however, this protection was only partial in rat hippocampal neurons that were treated with Aβ. Treatment with quercetin decreased ROS levels, recovered the normal morphology of mitochondria, and prevented mitochondrial dysfunction in neurons that were treated with H 2 O 2 . By contrast, quercetin treatment partially rescued hippocampal neurons from Aβ-induced mitochondrial injury. Most importantly, quercetin treatment prevented the toxic effects that are induced by H 2 O 2 in hippocampal neurons and, to a lesser extent, the Aβ-induced toxicity that is associated with the superoxide anion, which is a precursor of ROS production in mitochondria. Collectively, these results indicate that quercetin exerts differential effects on the prevention of H 2 O 2 - and Aβ-induced neurotoxicity in hippocampal neurons and may be a powerful tool for dissecting the molecular mechanisms underlying Aβ neurotoxicity.

Alzheimer's disease (AD) is a neurodegenerative disorder in which the amyloid-β (Aβ) peptide plays a key role in synaptic impairment and memory decline associated with neuronal dysfunction and intra-neuronal accumulation of hyperphosphorylated tau protein. Two novel enantiopure rhein-huprine hybrids ((+)-1 and (-)-1) exhibit potent inhibitory effects against human acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), BACE-1 and both Aβ and tau antiaggregation activity in vitro and reduction on the amyloid precursor protein (APP) processing in vivo. Interestingly, in this work, we observed beneficial effects with both (+)- and (-)-1 in the reversion of the neuropathology presented in the AβPPswe/PS-1 Alzheimer´s model, including a reduction in the Aβ levels, tau phosphorylation and memory impairment with both treatments. Also, in young transgenic mice that present early symptoms of synaptic failure and memory loss, we found a protection of cognitive functions, including long-term potentiation (LTP) and a reduction of the neuro-inflammation by both (+)- and (-)-1. Furthermore, animals with an advanced disease (11month-old) present an exacerbate neurodegeneration that is reversed only with the dextrorotatory enantiomer. These studies indicated that rhein-huprine derivatives with multiple properties might have interesting therapeutic potential for AD.

N-Methyl-D-aspartate receptors (NMDARs) have two opposing roles in the brain. On the one hand, NMDARs control critical events in the formation and development of synaptic organization and synaptic plasticity. On the other hand, the overactivation of NMDARs can promote neuronal death in neuropathological conditions. Ca(2+) influx acts as a primary modulator after NMDAR channel activation. An imbalance in Ca(2+) homeostasis is associated with several neurological diseases including schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. These chronic conditions have a lengthy progression depending on internal and external factors. External factors such as acute episodes of brain damage are associated with an earlier onset of several of these chronic mental conditions. Here, we will review some of the current evidence of how traumatic brain injury can hasten the onset of several neurological conditions, focusing on the role of NMDAR distribution and the functional consequences in calcium homeostasis associated with synaptic dysfunction and neuronal death present in this group of chronic diseases.

Alzheimer's disease (AD) is the most common neurodegenerative disorder and the leading cause of age-related dementia worldwide. Several models for AD have been developed to provide information regarding the initial changes that lead to degeneration. Transgenic mouse models recapitulate many, but not all, of the features of AD, most likely because of the high complexity of the pathology. In this context, the validation of a wild-type animal model of AD that mimics the neuropathological and behavioral abnormalities is necessary. In previous studies, we have reported that the Chilean rodent Octodon degus could represent a natural model for AD. In the present work, we further describe the age-related neurodegeneration observed in the O. degus brain. We report some histopathological markers associated with the onset progression of AD, such as glial activation, increase in oxidative stress markers, neuronal apoptosis and the expression of the peroxisome proliferative-activated receptor γ coactivator-1α (PGC-1α). With these results, we suggest that the O. degus could represent a new model for AD research and a powerful tool in the search for therapeutic strategies against AD., (© 2014 International Society of Neuropathology.)

Alzheimer's disease (AD) is a neurodegenerative disorder in which the amyloid-β (Aβ) oligomers are a key factor in synaptic impairment and in spatial memory decline associated with neuronal dysfunction. This impairment includes synaptic failure associated with the loss of synaptic proteins that contribute to AD progression. Interestingly, the use of natural compounds is an emergent conceptual strategy in the search for drugs with therapeutic potentials for treating neurodegenerative disorders. In the present study, we report that andrographolide (ANDRO), which is a labdane diterpene extracted from Andrographis paniculata, increases slope of field excitatory postsynaptic potentials (fEPSP) in the CA1 region of hippocampal slices and inhibits long-term depression (LTD), protecting the long-term potentiation (LTP) against the damage induced by Aβ oligomers in vitro, most likely by inhibiting glycogen synthase kinase-3β (GSK-3β). Additionally, ANDRO prevents changes in neuropathology in two different age groups (7- and 12-month-old mice) of an AβPPswe/PS-1 Alzheimer's model. ANDRO reduces the Aβ levels, changing the ontogeny of amyloid plaques in hippocampi and cortices in 7-month-old mice, and reduces tau phosphorylation around the Aβ oligomeric species in both age groups. Additionally, we observed that ANDRO recovers spatial memory functions that correlate with protecting synaptic plasticity and synaptic proteins in two different age groups. Our results suggest that ANDRO could be used in a potential preventive therapy during AD progression.

An emerging view on Alzheimer disease's (AD) pathogenesis considers amyloid-β (Aβ) oligomers as a key factor in synaptic impairment and rodent spatial memory decline. Alterations in the α7-nicotinic acetylcholine receptor (α7-nAChR) have been implicated in AD pathology. Herein, we report that nicotine, an unselective α7-nAChR agonist, protects from morphological and synaptic impairments induced by Aβ oligomers. Interestingly, nicotine prevents both early postsynaptic impairment and late presynaptic damage induced by Aβ oligomers through the α7-nAChR/phosphatidylinositol-3-kinase (PI3K) signaling pathway. On the other hand, a cross-talk between α7-nAChR and the Wnt/β-catenin signaling pathway was revealed by the following facts: (1) nicotine stabilizes β-catenin, in a concentration-dependent manner; (2) nicotine prevents Aβ-induced loss of β-catenin through the α7-nAChR; and (3) activation of canonical Wnt/β-catenin signaling induces α7-nAChR expression. Analysis of the α7-nAChR promoter indicates that this receptor is a new Wnt target gene. Taken together, these results demonstrate that nicotine prevents memory deficits and synaptic impairment induced by Aβ oligomers. In addition, nicotine improves memory in young APP/PS1 transgenic mice before extensive amyloid deposition and senile plaque development, and also in old mice where senile plaques have already formed. Activation of the α7-nAChR/PI3K signaling pathway and its cross-talk with the Wnt signaling pathway might well be therapeutic targets for potential AD treatments.

Recent studies showed that the activation of the retinoid X receptor, which dimerizes with peroxisome proliferator-activated receptors (PPARs), leads to an enhanced clearance of Aβ from the brain of transgenic mice model of Alzheimer's disease (AD), because an increased expression of apolipoprotein E and it main transporters. However, the effects observed must involve additional underlying mechanisms that have not been yet explored. Several studies conducted in our laboratory suggest that part of the effects observed for the PPARs agonist might involves mitochondrial function and, particularly, mitochondrial dynamics. In the present study we assessed the effects of oxidative stress challenge on mitochondrial morphology and mitochondrial dynamics-related proteins in hippocampal neurons. Using immunofluorescence, we evaluated the PPARγ co-activator 1α (PGC-1α), dynamin related protein 1 (DRP1), mitochondrial fission protein 1 (FIS1), and mitochondrial length, in order to determine if PPARs agonist pre-treatment is able to protect mitochondrial population from hippocampal neurons through modulation of the mitochondrial fusion-fission events. Our results suggest that both a PPARγ agonist (ciglitazone) and a PPARα agonist (WY 14.643) are able to protect neurons by modulating mitochondrial fusion and fission, leading to a better response of neurons to oxidative stress, suggesting that a PPAR based therapy could acts simultaneously in different cellular components. Additionally, our results suggest that PGC-1α and mitochondrial dynamics should be further studied in future therapy research oriented to ameliorate neurodegenerative disorders, such as AD.

St. John's wort has been the subject of studies focused on its therapeutic properties against several diseases, including Alzheimer's disease (AD). Amyloid β-peptide (Aβ), a critical peptide in AD, has been linked to the mitochondrial dysfunction often observed in this disease. Despite many efforts to prevent Aβ levels from increasing in AD, less has been done regarding the mitochondrial component. Therefore, we studied the effects of tetrahydrohyperforin (THH) on mitochondrial dysfunction of hippocampal neurons, challenged with Aβ oligomers (Aβo) and Aβo-AChE complexes. We show that THH prevents mitochondrial calcium overload and induces the modulation of fusion-fission events, arresting mitochondrial dysfunction. Moreover, our results suggest that the modulation of mitochondrial dynamics probably occurs through a peroxisome proliferator-activated receptor γ co-activator 1α-mediated mechanism, inducing mitochondrial fusion-fission protein expression. Our results offer further explanation for the effects observed for THH and the beneficial effects of this ethno-botanical drug in AD.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, amyloid-β peptide (Aβ) accumulation, neurofibrillary tangle deposition, synaptic alterations, and oxidative injury. In AD patients, acetylcholinesterase (AChE) activity is low in most regions of the brain, but increased within and around amyloid plaques, where it accelerates the Aβ assembly into oligomers and fibrils, increasing its neurotoxicity. Tetrahydrohyperforin (THH), a semi-synthetic derivative of hyperforin, reduces tau phosphorylation and Aβ accumulation in AD mouse models. In the present study, we examined the effects of THH on Aβ-AChE complexes, α7-nicotinic acetylcholine receptors (α7-nAChR), 4-hydroxynonenal (4-HNE) adducts, caspase-3 activation, and spatial memory in young AβPPSwe/PSEN1ΔE9 (AβPP/PS1) transgenic mice, in order to evaluate its potential preventive effects on the development of the disease. We report here that treatment with THH prevents the association of AChE to different types of amyloid plaques; partially restores the brain distribution of AChE molecular forms; increases α7-nAChR levels in the hippocampus of treated mice; decreases the amount of these receptors in amyloid plaques; and reduces the oxidative damage, evidenced by 4-HNE adduct formation and caspase-3 activation on AβPP/PS1 mice brain; demonstrating the neuroprotective properties of THH. Finally, we found that the acute treatment of hippocampal neurons with THH, in the presence of Aβ-AChE complexes, prevents 4-HNE adduct formation and caspase-3 activation. Our data support a therapeutic potential of THH for the treatment of AD.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, accumulation of the amyloid-β peptide (Aβ), increase of oxidative stress, and synaptic alterations. The scavenging of reactive oxygen species through their matrix enzyme catalase is one of the most recognized functions of peroxisomes. The induction of peroxisome proliferation is attained through different mechanisms by a set of structurally diverse molecules called peroxisome proliferators. In the present work, a double transgenic mouse model of AD that co-expresses a mutant human amyloid-β protein precursor (AβPPswe) and presenilin 1 without exon 9 (PS1dE9) was utilized in order to assess the effect of peroxisomal proliferation on Aβ neurotoxicity in vivo. Mice were tested for spatial memory and their brains analyzed by cytochemical, electrophysiological, and biochemical methods. We report here that peroxisomal proliferation significantly reduces (i) memory impairment, found in this model of AD; (ii) Aβ burden and plaque-associated acetylcholinesterase activity; (iii) neuroinflammation, measured by the extent of astrogliosis and microgliosis; and (iv) the decrease in postsynaptic proteins, while promoting synaptic plasticity in the form of long-term potentiation. We concluded that peroxisomal proliferation reduces various AD neuropathological markers and peroxisome proliferators may be considered as potential therapeutic agents against the disease.

Acetylcholinesterase (AChE; EC 3.1.1.7) plays a crucial role in the rapid hydrolysis of the neurotransmitter acetylcholine, in the central and peripheral nervous system and might also participate in non-cholinergic mechanism related to neurodegenerative diseases. Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, amyloid-β (Aβ) peptide accumulation and synaptic alterations. We have previously shown that AChE is able to accelerate the Aβ peptide assembly into Alzheimer-type aggregates increasing its neurotoxicity. Furthermore, AChE activity is altered in brain and blood of Alzheimer's patients. The enzyme associated to amyloid plaques changes its enzymatic and pharmacological properties, as well as, increases its resistant to low pH, inhibitors and excess of substrate. Here, we reviewed the effects of IDN 5706, a hyperforin derivative that has potential preventive effects on the development of AD. Our results show that treatment with IDN 5706 for 10 weeks increases brain AChE activity in 7-month-old double transgenic mice (APP(SWE)-PS1) and decreases the content of AChE associated with different types of amyloid plaques in this Alzheimer's model. We concluded that early treatment with IDN 5706 decreases AChE-Aβ interaction and this effect might be of therapeutic interest in the treatment of AD.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, amyloid-β peptide (Aβ) accumulation and synaptic alterations. Previous studies indicated that hyperforin, a component of the St John's Wort, prevents Aβ neurotoxicity and some behavioral impairments in a rat model of AD. In this study we examined the ability of tetrahydrohyperforin (IDN5607), a stable hyperforin derivative, to prevent the cognitive deficit and synaptic impairment in an in vivo model of AD. In double transgenic APPswe/PSEN1ΔE9 mice, IDN5706 improves memory and prevents the impairment of synaptic plasticity in a dose-dependent manner, inducing a recovery of long-term potentiation. In agreement with these findings, IDN5706 prevented the decrease in synaptic proteins in hippocampus and cortex. In addition, decreased levels of tau hyperphosphorylation, astrogliosis, and total fibrillar and oligomeric forms of Aβ were determined in double transgenic mice treated with IDN5706. In cultured cells, IDN5706 decreased the proteolytic processing of the amyloid precursor protein that leads to Aβ peptide generation. These findings indicate that IDN5706 ameliorates AD neuropathology and could be considered of therapeutic relevance in AD treatment.

A potential energy surface for CO2 is determined from experimental data using generalized internal vibrational coordinates. These coordinates are defined as two arbitrary distances and the angle between them and depend on two external parameters, which can be properly optimized. An optimal generalized internal coordinate system is obtained for CO2 by minimizing unconverged vibrational energies with respect to the external parameters. The optimal coordinates are shown to be superior to previously derived normal hyperspherical coordinates for this molecule. A nonlinear least-squares fit of the potential energy surface of CO2 to observed vibrational frequencies is made by using the optimal internal coordinates and fully variational calculations. The potential function is represented by a fourth-order Morse-cosine expansion and its quality is checked by computing highly excited vibrational transition frequencies which were not included in the fit. Copyright 1999 Academic Press.