Molecular mechanism and potential therapeutic targets of necroptosis and ferroptosis in Alzheimer's disease.

Alzheimer's disease (AD), a neurodegenerative condition, is defined by neurofibrillary tangles, amyloid plaques, and gradual cognitive decline. Regardless of the advances in understanding AD's pathogenesis and progression, its causes are still contested, and there are currently no efficient therapies for the illness. The post-mortem analyses revealed widespread neuronal loss in multiple brain regions in AD, evidenced by a decrease in neuronal density and correlated with the disease's progression and cognitive deterioration. AD's neurodegeneration is complicated, and different types of neuronal cell death, alone or in combination, play crucial roles in this process. Recently, the involvement of non-apoptotic programmed cell death in the neurodegenerative mechanisms of AD has received a lot of attention. Aberrant activation of necroptosis and ferroptosis, two newly discovered forms of regulated non-apoptotic cell death, is thought to contribute to neuronal cell death in AD. In this review, we first address the main features of necroptosis and ferroptosis, cellular signaling cascades, and the mechanisms involved in AD pathology. Then, we discuss the latest therapies targeting necroptosis and ferroptosis in AD animal/cell models and human research to provide vital information for AD treatment.

From cardiovascular system to brain, the potential protective role of Mas Receptors in COVID-19 infection.

Coronavirus disease 2019 (COVID-19) has been declared a new pandemic in March 2020. Although most patients are asymptomatic, those with underlying cardiovascular comorbidities may develop a more severe systemic infection which is often associated with fatal pneumonia. Nonetheless, neurological and cardiovascular manifestations could be present even without respiratory symptoms. To date, no COVID-19-specific drugs are able for preventing or treating the infection and generally, the symptoms are relieved with general anti-inflammatory drugs. Angiotensin-converting-enzyme 2 (ACE2) may function as the receptor for virus entry within the cells favoring the progression of infection in the organism. On the other hand, ACE2 is a relevant enzyme in renin angiotensin system (RAS) cascade fostering Ang1-7/Mas receptor activation which promotes protective effects in neurological and cardiovascular systems. It is known that RAS is composed by two functional countervailing axes the ACE/AngII/AT1 receptor and the ACE/AngII/AT2 receptor which counteracts the actions mediated by AngII/AT1 receptor by inducing anti-inflammatory, antioxidant and anti-growth functions. Subsequently an "alternative" ACE2/Ang1-7/Mas receptor axis has been described with functions similar to the latter protective arm. Here, we discuss the neurological and cardiovascular effects of COVID-19 highlighting the role of the stimulation of the RAS "alternative" protective arm in attenuating pulmonary, cerebral and cardiovascular damages. In conclusion, only two clinical trials are running for Mas receptor agonists but few other molecules are in preclinical phase and if successful these drugs might represent a successful strategy for the treatment of the acute phase of COVID-19 infection.

Retinoprotective compounds, current efficacy, and future prospective.

Retinal dysfunction is the most common cause of vision loss in several retinal disorders. It has been estimated a great increase in these pathologies that are becoming more globally widespread and numerous over time, also supported by the life expectancy increment. Among different types of retinopathies, we can account some that share causes, symptoms, and treatment including diabetic retinopathy, age-related macular degeneration, glaucoma, and retinitis pigmentosa. Molecular changes, environmental factors, and genetic predisposition might be some of the main causes that drive retinal tissue to chronic inflammation and neurodegeneration in these retinopathies. The treatments available on the market contain compounds that efficiently ameliorate some of the important clinical features of these pathologies like stabilization of the intraocular pressure, reduction of eye inflammation, control of eye oxidative stress which are considered the major molecular mechanisms related to retinal dysfunction. Indeed, the most commonly used drugs are anti-inflammatories, such as corticosteroids, antioxidant, hypotonic molecules and natural neuroprotective compounds. Unfortunately, these drugs, which are fundamental to treating disease symptoms, are not capable to cure the pathologies and so they are not life-changing for patients. This review provided an overview of current treatments on the market, but more interestingly, wants to be a quick window on the new treatments that are now in clinical trials. Additionally, it has been here highlighted that the recent technical enhancement of the investigation methods to identify the various retinopathies causes might be used as a sort of "precise medicine" approach to tailor the identification of molecular pathways involved and potentially study a dedicated treatment for each patient. This approach includes the use of cutting-edge technologies like gene therapy and metabolomics.

Non-SUMOylated alternative spliced isoforms of alpha-synuclein are more aggregation-prone and toxic.

The exon skipping of α-Synuclein (α-Syn), the main constituent of the abnormal protein aggregation in Lewy bodies of Parkinson's disease (PD), forms four isoforms. In contrast to the full length α-Syn (α-Syn 140), little is known about the splice isoforms' properties and functions. SUMOylation, a post-translational modification, regulates α-Syn function, aggregation, and degradation, but information about α-Syn isoforms and the effect of SUMOylation on them is unknown. Therefore, this study aims to characterize the SUMOylation of α-Syn isoforms and its impact on cell death and α-Syn aggregation. In a cellular model of PD induced by rotenone, cell toxicity, SUMOylation, and α-Syn aggregation with or without isoforms overexpression were evaluated. First, rotenone induced cell toxicity and α-Syn aggregation, with a significant reduction of SUMOylation and autophagy. Boosting SUMOylation prevented α-Syn aggregation, phosphorylation and recovery of autophagy. Moreover, α-Syn 140 and α-Syn 126 were SUMOylated while the other two isoforms, α-Syn 112 and 98 were not and their overexpression showed that were more toxic and induced more α-Syn aggregation. Rotenone increased their toxicity that was not affected by boosting SUMOylation. These results may indicate a role of SUMOylation in modulating α-Syn aggregation, inducing to understanding more about the behavior of α-Syn isoforms.

New Insights into Dose-Dependent Effects of Curcumin on ARPE-19 Cells.

Opposing dose-dependent effects of curcumin (Cur) have been documented in Retinal Pigment Epithelium (RPE); therefore, to shed the light on the mechanisms of action is crucial for ophthalmic applications. On this basis we explored new insights about the dose-dependent mechanisms triggered by Cur in human retinal pigment epithelial cells (ARPE-19). Three concentrations (0.01 mM; 0.05 mM; 0.1 mM) of Cur were tested, followed by morphological, molecular, and functional analysis of the cells. Cur 0.01 mM promotes a significant increase in cell proliferation, not affecting cell cycle progression and apoptosis; by contrast, Cur 0.05 mM and 0.1 mM block cellular proliferation and trigger S-phase cell cycle arrest without inducing apoptosis. The observation of neuronal-like morphological changes in Cur 0.05 mM and 0.1 mM were not associated with neuronal differentiation, as observed by the quantification of Neurofilament-200 and by the analysis of voltage-dependent currents by patch clamp. Evaluation of autophagic markers LC3BII and p62 revealed significant modulations, suggesting an important activation of autophagy in ARPE-19 cells treated with Cur 0.05 mM and Cur 0.1 mM; conversely, Cur 0.01 mM did not affect autophagy. Altogether, our findings show new dose-dependent mechanisms of action of Cur that suggest a wide therapeutic application in ocular diseases with different pathogenesis (i.e., proliferative vitreoretinopathy or Age-Related Macular Degeneration).

Syntaxin-1a and SNAP-25 expression level is increased in the blood samples of ischemic stroke patients.

The interest for the discovery of blood biomarkers for several neurological disorders, including Ischemic Stroke (IS), is growing and their identification in blood samples would be revolutionary allowing a fast and better pathology prediction or outcome and to collect information on patient recovery. The increased permeability of the blood-brain barrier, following a brain infarct, allows the detection of brain proteins in the blood flow. In this work, we analyzed the expression levels of two synaptic proteins Syntaxin (STX)-1a and Synaptosomal Associated Protein, 25 kDa (SNAP-25), in Peripheral Blood Mononuclear Cell (PBMC), serum and in Neuronal Derived Extracellular vesicles (NDEs) of IS patients, age and sex matched healthy control (HC) and younger HC (Y-HC). Interestingly, we identified STX-1a protein in the cytoplasm of PBMC and both STX-1a and SNAP-25 expression levels were significantly augmented in all IS patient's blood fractions compared to control subjects. In addition, STX-1a blood levels correlated with the IS clinical scales National Institutes of Health Stroke Scale (NIH-SS) and the modified Barthel Index (BI). These results prompted us to speculate that STX-1a and SNAP-25 hematic fluctuations depict the brain damage after an ischemic attack and that their hematic detection could represent a novel and accessible IS biomarkers.

Protective Effect of Curcuma Extract in an Ex Vivo Model of Retinal Degeneration via Antioxidant Activity and Targeting the SUMOylation.

Retinal degeneration is the major and principal cause behind many incurable blindness diseases. Several studies indicated the neuroprotective effect of Curcuma longa in eye pathologies, specifically retinopathy. However, the molecular mechanism behind its effect has not been completely elucidated. Using an ex vivo model of retinal degeneration obtained from an ex vivo optic nerve cut (ONC), we demonstrated that Curcuma extract (Cur) exerted a neuroprotective effect. Importantly, Cur was able to modulate apoptosis and MAPK signaling pathway activation and prevent retinal ganglion cell (RGC) loss. Other well-known neuroprotective pharmacological tools, including memantine (Mem), citicoline (Cit), and ginkgolic acid (GA), were used to compare the potential mechanisms of Cur. The antioxidant activity of retinas treated with Cur following optic nerve cut was significantly higher than control, but Cur failed to change the retina glutamate content. Considering the antioxidant effect of Cur and taking advantage of our recent findings on the crosstalk between oxidative stress and post-translational protein modifiers, in particular, small ubiquitin-related modifier (SUMO), we were interested in exploring the effect of Cur on SUMOylation. We found that Cur significantly prevented the increase of protein SUMOylation, confirming our previous in vitro data indicating the cytoprotective effect of curcumin through modulating the oxidative stress and SUMO-JNK axis. Altogether, these results suggest that Curcuma protects the retina from degeneration via antioxidant activity and targets SUMOylation. Therefore, it might be considered for the combination therapy with other neuroprotective agents with different mechanisms in preclinical studies on retinal degeneration.

An overview of the therapeutic effects of curcumin in reproductive disorders with a focus on the antiinflammatory and immunomodulatory activities.

Curcumin, the polyphenolic compound obtained from turmeric, has several pharmacological properties. These properties include antioxidant, antimicrobial, anti-angiogenic, anticarcinogenic, antiinflammatory, and immunomodulatory activities. Therefore, the clinical efficacy of this substance has been largely investigated for curing numerous disorders. Based on a growing body of literature, this review aimed to investigate curcumin's molecular and clinical effects on reproduction and related disorders. Curcumin in the female reproductive system attenuates folliculogenesis, promotes apoptosis of oocytes and blastocyst, and decreases embryo implantation and survival. Curcumin at <100 mg concentration shows protective effects against testicular injury. The concentration of >250 mg of curcumin exhibits immobilizing action on sperms, and at 500 mg concentration completely blocks pregnancy. Curcumin inhibits vaginal infections, attenuates the severity of the premenstrual syndrome, ameliorates inflammatory conditions in polycystic ovary syndrome, improves preeclampsia, and prevents ectopic endometrial lesions. Taken together, curcumin, because of the numerous biological activities, low level of toxicity, and lower adverse effects compared to the synthetic drugs, could be considered as a protective agent for preserving the semen quality parameters, a contraceptive, and chemotherapeutic or chemopreventive agent, as well as an appropriate agent for the treatment of female reproductive disorders.

Retinal ganglion cell loss in an ex vivo mouse model of optic nerve cut is prevented by curcumin treatment.

Retinal ganglion cell (RGC) loss is a pathologic feature common to several retinopathies associated to optic nerve damage, leading to visual loss and blindness. Although several scientific efforts have been spent to understand the molecular and cellular changes occurring in retinal degeneration, an effective therapy to counteract the retinal damage is still not available. Here we show that eyeballs, enucleated with the concomitant optic nerve cut (ONC), when kept in PBS for 24 h showed retinal and optic nerve degeneration. Examining retinas and optic nerves at different time points in a temporal window of 24 h, we found a thinning of some retinal layers especially RGC's layer, observing a powerful RGC loss after 24 h correlated with an apoptotic, MAPKs and degradative pathways dysfunctions. Specifically, we detected a time-dependent increase of Caspase-3, -9 and pro-apoptotic marker levels, associated with a strong reduction of BRN3A and NeuN levels. Importantly, a powerful activation of JNK, c-Jun, and ERK signaling (MAPKs) were observed, correlated with a significant augmented SUMO-1 and UBC9 protein levels. The degradation signaling pathways was also altered, causing a significant decrease of ubiquitination level and an increased LC3B activation. Notably, it was also detected an augmented Tau protein level. Curcumin, a powerful antioxidant natural compound, prevented the alterations of apoptotic cascade, MAPKs, and SUMO-1 pathways and the degradation system, preserving the RGC survival and the retinal layer thickness. This ex vivo retinal degeneration model could be a useful method to study, in a short time window, the effect of neuroprotective tools like curcumin that could represent a potential treatment to contrast retinal cell death.

Impaired antioxidant KEAP1-NRF2 system in amyotrophic lateral sclerosis: NRF2 activation as a potential therapeutic strategy.

BACKGROUND: Oxidative stress (OS) is an imbalance between oxidant and antioxidant species and, together with other numerous pathological mechanisms, leads to the degeneration and death of motor neurons (MNs) in amyotrophic lateral sclerosis (ALS). MAIN BODY: Two of the main players in the molecular and cellular response to OS are NRF2, the transcription nuclear factor erythroid 2-related factor 2, and its principal negative regulator, KEAP1, Kelch-like ECH (erythroid cell-derived protein with CNC homology)-associated protein 1. Here we first provide an overview of the structural organization, regulation, and critical role of the KEAP1-NRF2 system in counteracting OS, with a focus on its alteration in ALS. We then examine several compounds capable of promoting NRF2 activity thereby inducing cytoprotective effects, and which are currently in different stages of clinical development for many pathologies, including neurodegenerative diseases. CONCLUSIONS: Although challenges associated with some of these compounds remain, important advances have been made in the development of safer and more effective drugs that could actually represent a breakthrough for fatal degenerative diseases such as ALS.

SUMOylation Regulates TDP-43 Splicing Activity and Nucleocytoplasmic Distribution.

The nuclear RNA-binding protein TDP-43 forms abnormal cytoplasmic aggregates in the brains of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients and several molecular mechanisms promoting TDP-43 cytoplasmic mislocalization and aggregation have been proposed, including defects in nucleocytoplasmic transport, stress granules (SG) disassembly and post-translational modifications (PTM). SUMOylation is a PTM which regulates a variety of cellular processes and, similarly to ubiquitination, targets lysine residues. To investigate the possible regulatory effects of SUMOylation on TDP-43 activity and trafficking, we first assessed that TDP-43 is SUMO-conjugated in the nuclear compartment both covalently and non-covalently in the RRM1 domain at the predicted lysine 136 and SUMO-interacting motif (SIM, 106-110 residues), respectively. By using the SUMO-mutant TDP-43 K136R protein, we demonstrated that SUMOylation modifies TDP-43 splicing activity, specifically exon skipping, and influences its sub-cellular localization and recruitment to SG after oxidative stress. When promoting deSUMOylation by SENP1 enzyme over-expression or by treatment with the cell-permeable SENP1 peptide TS-1, the cytoplasmic localization of TDP-43 increased, depending on its SUMOylation. Moreover, deSUMOylation by TS-1 peptide favoured the formation of small cytoplasmic aggregates of the C-terminal TDP-43 fragment p35, still containing the SUMO lysine target 136, but had no effect on the already formed p25 aggregates. Our data suggest that TDP-43 can be post-translationally modified by SUMOylation which may regulate its splicing function and trafficking, indicating a novel and druggable mechanism to explore as its dysregulation may lead to TDP-43 pathological aggregation in ALS and FTD.

Effect of lobeglitazone on motor function in rat model of Parkinson's disease with diabetes co-morbidity.

Parkinson's disease (PD) and diabetes mellitus share similar pathophysiological characteristics, genetic and environmental factors. It has been reported that people with diabetes mellitus appear to have a remarkable higher incidence of PD than age matched non diabetic individuals. Evidences suggest that use of antidiabetic glitazone is associated with a diminished risk of PD incidence in patients with diabetes. This study examined the effect of lobeglitazone, a member of thiazolidinedione class, in rat model of Parkinson's disease with diabetes co-morbidity. Rats received either rotenone and/or a combination of streptozocin and a high calorie diet for disease induction and they were treated with different doses of lobeglitazone or its vehicle. Behavioral tests comprising rotarod, bar test and rearing test were conducted to evaluate the motor function. Changes in the level tyrosine hydroxylase, TNF-α and NF-κB were analyzed using ELISA. In the same brain regions the possible changes in PPAR-γ receptor level were evaluated. Findings showed that although lobeglitazone tends to reverse the effect of rotenone in animals with diabetes, it was just able to prevent partly the motor defect in rearing test. Furthermore, lobeglitazone (1 mg/kg) reversed, in substantia nigra and striatum, the changes in tyrosine hydroxylase, TNF-α, NF-κB and PPAR-γ receptor content induced by rotenone in rats with diabetic condition. Although other preclinical studies are needed, these findings suggest that lobeglitazone is a promising neuroprotective candidate for clinical trials for PD patients with diabetes co-morbidity.

A Novel Pharmacological Protective Role for Safranal in an Animal Model of Huntington's Disease.

Huntington's disease (HD) is a progressive, neurodegenerative and inherited disease and recent years have witnessed the understanding of the cellular and molecular mechanisms related to HD. Safranal, an organic compound isolated from saffron, has been reported to have anti-apoptotic, anti-inflammatory and antioxidant activity and has studied in chronic and neurodegenerative disease. Therefore, this study was aimed to investigate the effect of safranal on 3-NP induced locomotor activity and biochemical alterations in rats. To this aim, 40 male Wistar rats weighting 250-300 g were divided into 5 groups (n = 8) including sham, 3-NP group (10 mg/kg) as control and treatment groups (3-NP + safranal 0.75, 1.5 and 3 mg/kg) in two weeks duration of treatment. Behavioral/movement assessments in addition to oxidant/antioxidant markers in rat cortex and striatum were evaluated in control and treatment groups. Here, we found that safranal significantly alleviated 3-NP-induced changes of body weight, rotarod activity, number of vacuous chewing movements (VCMs), and locomotor activity. In addition, brain tissue assessments in cortex and striatum revealed that safranal could prevent the elevation of nitrite and malondialdehyde (MDA) levels as well as decrease of superoxide dismutase (SOD), catalase activity and glutathione (GSH) induced by 3-NP. In conclusion our results showed that safranal prevented the motor dysfunction induced by 3-NP in animal model of Huntington's disease. This effect might be due to its modulating effect on oxidants-antioxidant balance.

The Impact of Oxidative Stress on Blood-Retinal Barrier Physiology in Age-Related Macular Degeneration.

The blood retinal barrier (BRB) is a fundamental eye component, whose function is to select the flow of molecules from the blood to the retina and vice-versa, and its integrity allows the maintenance of a finely regulated microenvironment. The outer BRB, composed by the choriocapillaris, the Bruch's membrane, and the retinal pigment epithelium, undergoes structural and functional changes in age-related macular degeneration (AMD), the leading cause of blindness worldwide. BRB alterations lead to retinal dysfunction and neurodegeneration. Several risk factors have been associated with AMD onset in the past decades and oxidative stress is widely recognized as a key factor, even if the exact AMD pathophysiology has not been exactly elucidated yet. The present review describes the BRB physiology, the BRB changes occurring in AMD, the role of oxidative stress in AMD with a focus on the outer BRB structures. Moreover, we propose the use of cerium oxide nanoparticles as a new powerful anti-oxidant agent to combat AMD, based on the relevant existing data which demonstrated their beneficial effects in protecting the outer BRB in animal models of AMD.

Obstacles against the Marketing of Curcumin as a Drug.

Among the extensive public and scientific interest in the use of phytochemicals to prevent or treat human diseases in recent years, natural compounds have been highly investigated to elucidate their therapeutic effect on chronic human diseases including cancer, cardiovascular disease, and neurodegenerative disease. Curcumin, an active principle of the perennial herb Curcuma longa, has attracted an increasing research interest over the last half-century due to its diversity of molecular targets, including transcription factors, enzymes, protein kinases, growth factors, inflammatory cytokines, receptors, and it's interesting pharmacological activities. Despite that, the clinical effectiveness of the native curcumin is weak, owing to its low bioavailability and rapid metabolism. Preclinical data obtained from animal models and phase I clinical studies done in human volunteers confirmed a small amount of intestinal absorption, hepatic first pass effect, and some degree of intestinal metabolism, might explain its poor systemic availability when it is given via the oral route. During the last decade, researchers have attempted with new pharmaceutical methods such as nanoparticles, liposomes, micelles, solid dispersions, emulsions, and microspheres to improve the bioavailability of curcumin. As a result, a significant number of bioavailable curcumin-based formulations were introduced with a varying range of enhanced bioavailability. This manuscript critically reviews the available scientific evidence on the basic and clinical effects and molecular targets of curcumin. We also discuss its pharmacokinetic and problems for marketing curcumin as a drug.

Considerations around the SARS-CoV-2 Spike Protein with Particular Attention to COVID-19 Brain Infection and Neurological Symptoms.

Spike protein (S protein) is the virus "key" to infect cells and is able to strongly bind to the human angiotensin-converting enzyme2 (ACE2), as has been reported. In fact, Spike structure and function is known to be highly important for cell infection as well as for entering the brain. Growing evidence indicates that different types of coronaviruses not only affect the respiratory system, but they might also invade the central nervous system (CNS). However, very little evidence has been so far reported on the presence of COVID-19 in the brain, and the potential exploitation, by this virus, of the lung to brain axis to reach neurons has not been completely understood. In this Article, we assessed the SARS-CoV and SARS-CoV-2 Spike protein sequence, structure, and electrostatic potential using computational approaches. Our results showed that the S proteins of SARS-CoV-2 and SARS-CoV are highly similar, sharing a sequence identity of 77%. In addition, we found that the SARS-CoV-2 S protein is slightly more positively charged than that of SARS-CoV since it contains four more positively charged residues and five less negatively charged residues which may lead to an increased affinity to bind to negatively charged regions of other molecules through nonspecific and specific interactions. Analysis the S protein binding to the host ACE2 receptor showed a 30% higher binding energy for SARS-CoV-2 than for the SARS-CoV S protein. These results might be useful for understanding the mechanism of cell entry, blood-brain barrier crossing, and clinical features related to the CNS infection by SARS-CoV-2.

The pivotal role of SUMO-1-JNK-Tau axis in an in vitro model of oxidative stress counteracted by the protective effect of curcumin.

Oxidative stress is a toxic cellular condition, strictly related to inflammation and known to be a common feature of many neurodegenerative diseases. The imbalanced redox state modifies several molecular processes including protein SUMOylation, JNK and Tau protein activation, important actors in Alzheimer's disease. In this study, we showed a strong interaction among SUMO-1-JNK-Tau proteins and their molecular targets in an in vitro model (SHSY5Y cell line) of oxidative stress in which a significant reduction of cell viability and an augmented cell death was induced by increased doses of H2O2. The evoked oxidative stress led to a deficiency in the degradation system showing altered levels of Caspase-3, LC3BII/I and Ubiquitin. Curcumin, a natural compound with anti-oxidant and anti-inflammatory effects, demonstrated to tackle oxidative stress re-equilibrating SUMO-1, JNK and Tau functions. Importantly, 5 µM of curcumin induced an efficient recovery of cell viability, a reduction of cell death and a normalization of altered protein degradation marker levels. Interestingly, we found that H2O2 treatment induced a strong co-localization of SUMO-1-p-JNK-Tau proteins in nuclear bodies (NBs) and that curcumin was able to reduce these nuclear aggregates. These results highlight the SUMO-1-JNK-Tau axis key role in oxidative stress and the protective effect of curcumin against this pathological event, focusing on the importance of SUMO/deSUMOylation balance to regulate essential cellular processes.

Immediate early gene kakusei potentially plays a role in the daily foraging of honey bees.

kakusei is a non-coding RNA that is overexpressed in foraging bee brain. This study describes a possible role of the IEG kakusei during the daily foraging of honey bees. kakusei was found to be transiently upregulated within two hours during rewarded foraging. Interestingly, during unrewarded foraging the gene was also found to be up-regulated, but immediately lowered when food was not rewarded. Moreover, the kakusei overexpression was diminished within a very short time when the time schedule of feeding was changed. This indicates the potential role of kakusei on the motivation of learned reward foraging. These results provide evidence for a dynamic role of kakusei during for aging of bees, and eventually its possible involvement in learning and memory. Thus the kakusei gene could be used as search tool in finding distinct molecular pathways that mediate diverse behavioral components of foraging.

Targeting Synaptic Plasticity in Experimental Models of Alzheimer's Disease.

Long-term potentiation (LTP) and long-term depression (LTD) of hippocampal synaptic transmission represent the principal experimental models underlying learning and memory. Alterations of synaptic plasticity are observed in several neurodegenerative disorders, including Alzheimer's disease (AD). Indeed, synaptic dysfunction is an early event in AD, making it an attractive therapeutic target for pharmaceutical intervention. To date, intensive investigations have characterized hippocampal synaptic transmission, LTP, and LTD in in vitro and in murine models of AD. In this review, we describe the synaptic alterations across the main AD models generated so far. We then examine the clinical perspective of LTP/LTD studies and discuss the limitations of non-clinical models and how to improve their predictive validity in the drug discovery process.

The selective disruption of presynaptic JNK2/STX1a interaction reduces NMDA receptor-dependent glutamate release.

The neuronal loss caused by excessive glutamate release, or 'excitotoxicity', leads to several pathological conditions, including cerebral ischemia, epilepsy, and neurodegenerative diseases. Over-stimulation of presynaptic N-methyl-D-aspartate (NMDA) receptors is known to trigger and support glutamate spillover, while postsynaptic NMDA receptors are responsible for the subsequent apoptotic cascade. Almost all molecules developed so far are unable to selectively block presynaptic or postsynaptic NMDA receptors, therefore a deeper knowledge about intracellular NMDA pathways is required to design more specific inhibitors. Our previous work showed that presynaptic c-Jun N-terminal kinase 2 (JNK2) specifically regulates NMDA-evoked glutamate release and here we demonstrate that an interaction between Syntaxin-1a and JNK2 is fundamental to this mechanism. Based on this evidence, a new cell permeable peptide (CPP), "JGRi1", has been developed to disrupt the JNK2/STX1a interaction to indirectly, but specifically, inhibit presynaptic NMDA receptor signaling. JGRi1 reduces the NMDA-evoked release of glutamate both in in-vitro and ex-vivo experiments while also being able to widely diffuse throughout brain tissue via intraperitoneal administration. In conclusion, the JNK2/STX1 interaction is involved in presynaptic NMDA-evoked glutamate release and the novel CPP, JGRi1, acts as a pharmacological tool that promotes neuroprotection.