Publications by authors named "Claudio Grassi"

103 Publications

Does Impairment of Adult Neurogenesis Contribute to Pathophysiology of Alzheimer's Disease? A Still Open Question.

Front Mol Neurosci 2020 22;13:578211. Epub 2021 Jan 22.

Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy.

Adult hippocampal neurogenesis is a physiological mechanism contributing to hippocampal memory formation. Several studies associated altered hippocampal neurogenesis with aging and Alzheimer's disease (AD). However, whether amyloid-β protein (Aβ)/tau accumulation impairs adult hippocampal neurogenesis and, consequently, the hippocampal circuitry, involved in memory formation, or altered neurogenesis is an epiphenomenon of AD neuropathology contributing negligibly to the AD phenotype, is, especially in humans, still debated. The detrimental effects of Aβ/tau on synaptic function and neuronal viability have been clearly addressed both in and experimental models. Until some years ago, studies carried out on models investigating the action of Aβ/tau on proliferation and differentiation of hippocampal neural stem cells led to contrasting results, mainly due to discrepancies arising from different experimental conditions (e.g., different cellular/animal models, different Aβ and/or tau isoforms, concentrations, and/or aggregation profiles). To date, studies investigating adult hippocampal neurogenesis indicate severe impairment in most of transgenic AD mice; this impairment precedes by several months cognitive dysfunction. Using experimental tools, which only became available in the last few years, research in humans indicated that hippocampal neurogenesis is altered in cognitive declined individuals affected by either mild cognitive impairment or AD as well as in normal cognitive elderly with a significant inverse relationship between the number of newly formed neurons and cognitive impairment. However, despite that such information is available, the question whether impaired neurogenesis contributes to AD pathogenesis or is a mere consequence of Aβ/pTau accumulation is not definitively answered. Herein, we attempted to shed light on this complex and very intriguing topic by reviewing relevant literature on impairment of adult neurogenesis in mouse models of AD and in AD patients analyzing the temporal relationship between the occurrence of altered neurogenesis and the appearance of AD hallmarks and cognitive dysfunctions.
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http://dx.doi.org/10.3389/fnmol.2020.578211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862134PMC
January 2021

Metabolic Reprogramming by Malat1 Depletion in Prostate Cancer.

Cancers (Basel) 2020 Dec 22;13(1). Epub 2020 Dec 22.

National Research Council (CNR)-IASI, Department of Engineering, ICT and Technologies for Energy and Transportation, 00185 Rome, Italy.

The lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) promotes growth and progression in prostate cancer (PCa); however, little is known about its possible impact in PCa metabolism. The aim of this work has been the assessment of the metabolic reprogramming associated with MALAT1 silencing in human PCa cells and in an ex vivo model of organotypic slice cultures (OSCs). Cultured cells and OSCs derived from primary tumors were transfected with MALAT1 specific gapmers. Cell growth and survival, gene profiling, and evaluation of targeted metabolites and metabolic enzymes were assessed. Computational analysis was made considering expression changes occurring in metabolic markers following MALAT1 targeting in cultured OSCs. MALAT1 silencing reduced expression of some metabolic enzymes, including malic enzyme 3, pyruvate dehydrogenase kinases 1 and 3, and choline kinase A. Consequently, PCa metabolism switched toward a glycolytic phenotype characterized by increased lactate production paralleled by growth arrest and cell death. Conversely, the function of mitochondrial succinate dehydrogenase and the expression of oxidative phosphorylation enzymes were markedly reduced. A similar effect was observed in OSCs. Based on this, a predictive algorithm was developed aimed to predict tumor recurrence in a subset of patients. MALAT1 targeting by gapmer delivery restored normal metabolic energy pathway in PCa cells and OSCs.
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http://dx.doi.org/10.3390/cancers13010015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801945PMC
December 2020

Styrene targets sensory and neural cochlear function through the crossroad between oxidative stress and inflammation.

Free Radic Biol Med 2021 Feb 8;163:31-42. Epub 2020 Dec 8.

Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy; Department of Neuroscience, Università Cattolica Del Sacro Cuore, Roma, Italy.

Background: Although styrene is an established ototoxic agent at occupational exposure levels, the mechanisms of styrene toxicity in the auditory system are still unclear.

Objectives: The aim of this study was to identify the consequences of styrene chronic exposure in cochlear structures, looking for the mechanisms of ototoxicity of this organic compound and focusing on cell targets and oxidative stress/inflammatory processes.

Methods: Male adult Wistar rats were exposed to styrene (400 mg/kg by gavage for 5 days/week, 3 consecutive weeks). Hearing loss was evaluated by measuring auditory brainstem responses (ABR), morphological analysis were performed to evaluate hair cell and spiral ganglion neuron survival, as well as synaptic damage. Analysis of apoptotic (p53) and inflammatory (NF-κB, TNF-α, IL-1β and IL-10) mediators were performed by immunofluorescence analysis and western blot.

Results: Styrene ototoxic effects induced a hearing loss of about 35-40 dB. Immunofluorescence and western blotting analyses demonstrated that styrene administration induced redox imbalance and activated inflammatory processes, targeting sensory hair cell and neural dysfunction by a cross-talk between oxidative and inflammatory mediators.

Discussion: Major findings connect styrene ototoxicity to an interplay between redox imbalance and inflammation, leading to the intriguing assumption of a mixed sensory and neural styrene-induced ototoxicity. Thus, in a clinical perspective, data reported here have important implications for styrene risk assessment in humans.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.12.001DOI Listing
February 2021

Somatic Deletion in Exon 10 of Aryl Hydrocarbon Receptor Gene in Human GH-Secreting Pituitary Tumors.

Front Endocrinol (Lausanne) 2020 12;11:591039. Epub 2020 Nov 12.

Department of Human Pathology of Adulthood and Childhood, University of Messina, Messina, Italy.

Objective/purpose: The aryl hydrocarbon receptor (AHR) pathway plays a critical role in the biology of Growth Hormone (GH)-secreting pituitary tumor (somatotropinoma). Germline rs2066853 variant was found to be more frequent among acromegaly patients and associated with a more severe disease with larger invasive somatropinoma, and with resistance to somatostatin analogs treatment in patients living in polluted areas. However, no somatic changes in gene have been reported so far in acromegaly patients. On that basis, the aim of the study was to assess at the somatic level the gene status encompassing exon 10 region, also because of the high rate of variants found in this genomic region.

Methods: A cohort of 13 patients aged 20-76 years with biochemical, clinical and histological diagnosis of somatotropinoma was studied. DNA and RNA from pituitary tumor histological samples have been extracted and analyzed by PCR and direct sequencing for gene variants, and compared with corresponding patients' germline DNA as well as normal pituitary tissue as reference control.

Results: A degenerated letter codes in the region corresponding to exon 10 (c.1239-c.2056) was detected in somatotropinomas-derived DNA but not in that of matched germline and pituitary normal tissue. By multiple PCR and sequencing analysis, we observed amplification only before codon 1246 and after codon 1254, confirming the presence of a tumor-restricted somatic deletion in the 5' upstream region of exon 10. Analysis of PCR-amplified cDNA revealed a wildtype sequence of exon 9 and 10 in normal pituitary tissue, and a wildtype sequence of exon 9 and 10 up to codon 1246 and no sequence after the deletion region (c.1246-c.1254) in 6 out of 9 tumor samples. Patients carrying the germline rs2066853 variant showed no somatic LOH at the corresponding genetic locus.

Conclusion: This is the first demonstration of a recurrent somatic deletion in the exon 10 of the gene in somatotropinomas. The functional impact of this genetic finding needs to be clarified.
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http://dx.doi.org/10.3389/fendo.2020.591039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689685PMC
November 2020

Neural Stem Cell-Derived Exosomes Revert HFD-Dependent Memory Impairment via CREB-BDNF Signalling.

Int J Mol Sci 2020 Nov 26;21(23). Epub 2020 Nov 26.

Department of Neuroscience, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.

Overnutrition and metabolic disorders impair cognitive functions through molecular mechanisms still poorly understood. In mice fed with a high fat diet (HFD) we analysed the expression of synaptic plasticity-related genes and the activation of cAMP response element-binding protein (CREB)-brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signalling. We found that a HFD inhibited both CREB phosphorylation and the expression of a set of CREB target genes in the hippocampus. The intranasal administration of neural stem cell (NSC)-derived exosomes (exo-NSC) epigenetically restored the transcription of Bdnf, nNOS, Sirt1, Egr3, and RelA genes by inducing the recruitment of CREB on their regulatory sequences. Finally, exo-NSC administration rescued both BDNF signalling and memory in HFD mice. Collectively, our findings highlight novel mechanisms underlying HFD-related memory impairment and provide evidence of the potential therapeutic effect of exo-NSC against metabolic disease-related cognitive decline.
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http://dx.doi.org/10.3390/ijms21238994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729830PMC
November 2020

Publisher Correction: The dual role of curcumin and ferulic acid in counteracting chemoresistance and cisplatin-induced ototoxicity.

Sci Rep 2020 Sep 30;10(1):16468. Epub 2020 Sep 30.

Department of Neuroscience, Università Cattolica del Sacro Cuore, Roma, Italia.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-70073-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527566PMC
September 2020

Glucose Overload Inhibits Glutamatergic Synaptic Transmission: A Novel Role for CREB-Mediated Regulation of Synaptotagmins 2 and 4.

Front Cell Dev Biol 2020 19;8:810. Epub 2020 Aug 19.

Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy.

Glucose metabolism derangement is critically involved in the age-related memory loss but the underlying molecular mechanisms are still poorly understood. In a mouse model of type 1 diabetes we found memory impairment associated with inhibition of the transcription factor CREB and alteration of pre- and post-synaptic protein expression in the hippocampus. Accordingly, glucose excess negatively affected activity-dependent CREB phosphorylation and CREB-mediated mRNA expression of synaptic proteins in hippocampal primary neurons. Specifically, glucose excess inhibited the activity-dependent recruitment of CREB on the regulatory sequences of synaptotagmin (SYT) 2 and 4 promoters and the expression of SYT4 protein. As a result, high glucose affected both the frequency of miniature excitatory postsynaptic currents and NMDA receptor-mediated currents in autaptic hippocampal neuronal cultures. Collectively, our findings highlight novel mechanisms underlying hyperglycaemia-related memory loss, including CREB-dependent downregulation of synaptotagmin expression.
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http://dx.doi.org/10.3389/fcell.2020.00810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466440PMC
August 2020

Passive immunotherapy for N-truncated tau ameliorates the cognitive deficits in two mouse Alzheimer's disease models.

Brain Commun 2020 6;2(1):fcaa039. Epub 2020 Apr 6.

European Brain Research Institute (EBRI), 00161 Rome, Italy.

Clinical and neuropathological studies have shown that tau pathology better correlates with the severity of dementia than amyloid plaque burden, making tau an attractive target for the cure of Alzheimer's disease. We have explored whether passive immunization with the 12A12 monoclonal antibody (26-36aa of tau protein) could improve the Alzheimer's disease phenotype of two well-established mouse models, Tg2576 and 3xTg mice. 12A12 is a cleavage-specific monoclonal antibody which selectively binds the pathologically relevant neurotoxic NH26-230 fragment (i.e. NHhtau) of tau protein without cross-reacting with its full-length physiological form(s). We found out that intravenous administration of 12A12 monoclonal antibody into symptomatic (6 months old) animals: (i) reaches the hippocampus in its biologically active (antigen-binding competent) form and successfully neutralizes its target; (ii) reduces both pathological tau and amyloid precursor protein/amyloidβ metabolisms involved in early disease-associated synaptic deterioration; (iii) improves episodic-like type of learning/memory skills in hippocampal-based novel object recognition and object place recognition behavioural tasks; (iv) restores the specific up-regulation of the activity-regulated cytoskeleton-associated protein involved in consolidation of experience-dependent synaptic plasticity; (v) relieves the loss of dendritic spine connectivity in pyramidal hippocampal CA1 neurons; (vi) rescues the Alzheimer's disease-related electrophysiological deficits in hippocampal long-term potentiation at the CA3-CA1 synapses; and (vii) mitigates the neuroinflammatory response (reactive gliosis). These findings indicate that the 20-22 kDa NH-terminal tau fragment is crucial target for Alzheimer's disease therapy and prospect immunotherapy with 12A12 monoclonal antibody as safe (normal tau-preserving), beneficial approach in contrasting the early Amyloidβ-dependent and independent neuropathological and cognitive alterations in affected subjects.
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http://dx.doi.org/10.1093/braincomms/fcaa039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425324PMC
April 2020

Ca -dependent release of ATP from astrocytes affects herpes simplex virus type 1 infection of neurons.

Glia 2021 Jan 20;69(1):201-215. Epub 2020 Aug 20.

Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy.

Astrocytes provide metabolic support for neurons and modulate their functions by releasing a plethora of neuroactive molecules diffusing to neighboring cells. Here we report that astrocytes also play a role in cortical neurons' vulnerability to Herpes simplex virus type-1 (HSV-1) infection through the release of extracellular ATP. We found that the interaction of HSV-1 with heparan sulfate proteoglycans expressed on the plasma membrane of astrocytes triggered phospholipase C-mediated IP -dependent intracellular Ca transients causing extracellular release of ATP. ATP binds membrane purinergic P2 receptors (P2Rs) of both neurons and astrocytes causing an increase in intracellular Ca concentration that activates the Glycogen Synthase Kinase (GSK)-3β, whose action is necessary for HSV-1 entry/replication in these cells. Indeed, in co-cultures of neurons and astrocytes HSV-1-infected neurons were only found in proximity of infected astrocytes releasing ATP, whereas in the presence of fluorocitrate, an inhibitor of astrocyte metabolism, switching-off the HSV-1-induced ATP release, very few neurons were infected. The addition of exogenous ATP, mimicking that released by astrocytes after HSV-1 challenge, restored the ability of HSV-1 to infect neurons co-cultured with metabolically-inhibited astrocytes. The ATP-activated, P2R-mediated, and GSK-3-dependent molecular pathway underlying HSV-1 infection is likely shared by neurons and astrocytes, given that the blockade of either P2Rs or GSK-3 activation inhibited infection of both cell types. These results add a new layer of information to our understanding of the critical role played by astrocytes in regulating neuronal functions and their response to noxious stimuli including microbial agents via Ca -dependent release of neuroactive molecules.
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http://dx.doi.org/10.1002/glia.23895DOI Listing
January 2021

Brain insulin resistance impairs hippocampal plasticity.

Vitam Horm 2020 18;114:281-306. Epub 2020 Jun 18.

Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy; Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. Electronic address:

Nutrient-related signals have been demonstrated to influence brain development and cognitive functions. In particular, insulin signaling has been shown to impact on molecular cascades underlying hippocampal plasticity, learning and memory. Alteration of brain insulin signaling interferes with the maintenance of neural stem cell niche and neuronal activity in the hippocampus. Brain insulin resistance is also emerging as key factor causing the cognitive impairment observed in metabolic and neurodegenerative diseases. Here, we review the molecular mechanisms involved in the insulin modulation of both adult neurogenesis and synaptic activity in the hippocampus. We also summarize the effects of altered insulin sensitivity on hippocampal plasticity. Finally, we reassume the experimental and epidemiological evidence highlighting the critical role of brain insulin resistance at the crossroad between type 2 diabetes and Alzheimer's disease.
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http://dx.doi.org/10.1016/bs.vh.2020.04.005DOI Listing
June 2020

Plasma BDNF Levels Following Transcranial Direct Current Stimulation Allow Prediction of Synaptic Plasticity and Memory Deficits in 3×Tg-AD Mice.

Front Cell Dev Biol 2020 3;8:541. Epub 2020 Jul 3.

Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy.

Early diagnosis of Alzheimer's disease (AD) supposedly increases the effectiveness of therapeutic interventions. However, presently available diagnostic procedures are either invasive or require complex and expensive technologies, which cannot be applied at a larger scale to screen populations at risk of AD. We were looking for a biomarker allowing to unveil a dysfunction of molecular mechanisms, which underly synaptic plasticity and memory, before the AD phenotype is manifested and investigated the effects of transcranial direct current stimulation (tDCS) in 3×Tg-AD mice, an experimental model of AD which does not exhibit any long-term potentiation (LTP) and memory deficits at the age of 3 months (3×Tg-AD-3M). Our results demonstrated that tDCS differentially affected 3×Tg-AD-3M and age-matched wild-type (WT) mice. While tDCS increased LTP at CA3-CA1 synapses and memory in WT mice, it failed to elicit these effects in 3×Tg-AD-3M mice. Remarkably, 3×Tg-AD-3M mice did not show the tDCS-dependent increases in pCREB and pCaMKII , which were found in WT mice. Of relevance, tDCS induced a significant increase of plasma BDNF levels in WT mice, which was not found in 3×Tg-AD-3M mice. Collectively, our results showed that plasticity mechanisms are resistant to tDCS effects in the pre-AD stage. In particular, the lack of BDNF responsiveness to tDCS in 3×Tg-AD-3M mice suggests that combining tDCS with dosages of plasma BDNF levels may provide an easy-to-detect and low-cost biomarker of covert impairment of synaptic plasticity mechanisms underlying memory, which could be clinically applicable. Testing proposed here might be useful to identify AD in its preclinical stage, allowing timely and, hopefully, more effective disease-modifying interventions.
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http://dx.doi.org/10.3389/fcell.2020.00541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349675PMC
July 2020

NIR multiphoton ablation of cancer cells, fluorescence quenching and cellular uptake of dansyl-glutathione-coated gold nanoparticles.

Sci Rep 2020 07 9;10(1):11380. Epub 2020 Jul 9.

Department of Chemistry and Biology "Adolfo Zambelli", University of Salerno, Via Giovanni Paolo II, 84084, Fisciano, SA, Italy.

Theranostics based on two-photon excitation of therapeutics in the NIR region is an emerging and powerful tool in cancer therapy since this radiation deeply penetrates healthy biological tissues and produces selective cell death. Aggregates of gold nanoparticles coated with glutathione corona functionalized with the dansyl chromophore (a-DG-AuNPs) were synthesized and found efficient nanodevice for applications in photothermal therapy (PTT). Actually the nanoparticle aggregation enhances the quenching of radiative excitation and the consequent conversion into heat. The a-DG-AuNPs are readily internalized in Hep G2 where the chromophore acts as both antenna and transducer of the NIR radiation under two-photons excitation, determining efficient cell ablation via photothermal effect.
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http://dx.doi.org/10.1038/s41598-020-68397-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347844PMC
July 2020

Anti-oxidant and anti-inflammatory effects of caffeic acid: in vivo evidences in a model of noise-induced hearing loss.

Food Chem Toxicol 2020 Sep 5;143:111555. Epub 2020 Jul 5.

Fondazione Policlinico Universitario A, Gemelli IRCCS, Roma, Italy; Department of Head and Neck Surgery, Università Cattolica del Sacro Cuore, Roma, Italy. Electronic address:

Scope: The imbalance of cellular redox status, in conjunction with the activation of inflammatory processes, have been considered common predominant mechanisms of noise-induced hearing loss. The identification of novel natural products as potential therapeuticstargeting oxidative stress and inflammatory pathways is an emerging field. Here, we focused on the polyphenol caffeic acid (CA), the major representative of hydroxycinnamic acids and phenolic acid, in order to investigate its protective capacity in a model of sensorineural hearing loss induced by noise.

Methods And Results: Hearing loss was induced by exposing animals (Wistar rats) to a pure tone, 120 dB, 10 kHz for 60 min. By using auditory brainstem responses (ABRs) and immunofluorescence analysis, we found that CA protects auditory function and limits cell death in the cochlear middle/basal turn, damaged by noise exposure. Immunofluorescence analysis provided evidence that CA mediates multiple cell protection mechanisms involving both anti-inflammatory and anti-oxidant effects by decreasing NF-κB and IL-1β expression in the cochlea and opposing the oxidative/nitrosative damage induced by noise insult.

Conclusions: These results demonstrate that the supplementation of polyphenol CA can be considered a valid therapeutic strategy for attenuating noise-induced hearing loss and cochlear damage targeting both inflammatory signalling and cochlear redox balance.
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http://dx.doi.org/10.1016/j.fct.2020.111555DOI Listing
September 2020

Tau is not necessary for amyloid-β-induced synaptic and memory impairments.

J Clin Invest 2020 09;130(9):4831-4844

Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, and.

The amyloid hypothesis posits that the amyloid-beta (Aβ) protein precedes and requires microtubule-associated protein tau in a sort of trigger-bullet mechanism leading to Alzheimer's disease (AD) pathology. This sequence of events has become dogmatic in the AD field and is used to explain clinical trial failures due to a late start of the intervention when Aβ already activated tau. Here, using a multidisciplinary approach combining molecular biological, biochemical, histopathological, electrophysiological, and behavioral methods, we demonstrated that tau suppression did not protect against Aβ-induced damage of long-term synaptic plasticity and memory, or from amyloid deposition. Tau suppression could even unravel a defect in basal synaptic transmission in a mouse model of amyloid deposition. Similarly, tau suppression did not protect against exogenous oligomeric tau-induced impairment of long-term synaptic plasticity and memory. The protective effect of tau suppression was, in turn, confined to short-term plasticity and memory. Taken together, our data suggest that therapies downstream of Aβ and tau together are more suitable to combat AD than therapies against one or the other alone.
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http://dx.doi.org/10.1172/JCI137040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456211PMC
September 2020

Signaling through estrogen receptors modulates long non-coding RNAs in prostate cancer.

Mol Cell Endocrinol 2020 07 13;511:110864. Epub 2020 May 13.

Institute for Systems Analysis and Computer Science "A. Ruberti" (IASI), National Research Council (CNR), 00185, Rome, Italy. Electronic address:

Prostate cancer (PCa) is a sex-steroid hormone-dependent cancer in which estrogens play a critical role in both initiation and progression. Recently, several long non-coding RNAs (lncRNAs) have been associated with PCa and are supposedly playing a pivotal role in the biology and progression of this type of cancer. In this review, we focused on some lncRNAs that are known for their androgen and estrogen transcriptional responsiveness in PCa. Specifically, we summarized recent pieces of evidence about lncRNAs NEAT1, H19, MALAT1, and HOTAIR, in estrogen signaling, emphasizing their role in PCa progression and the acquisition of a castration-resistant phenotype. Here, the reader will find information about lncRNAs present in estrogen-dependent transcriptional complexes. The potential role of lncRNA/estrogen signaling as a novel pathway for PCa treatment will be discussed.
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http://dx.doi.org/10.1016/j.mce.2020.110864DOI Listing
July 2020

Herpes Simplex Virus-1 in the Brain: The Dark Side of a Sneaky Infection.

Trends Microbiol 2020 10 5;28(10):808-820. Epub 2020 May 5.

Institute of Translational Pharmacology, National Research Council, Rome, Italy.

Herpes simplex virus-1 (HSV-1) establishes latency preferentially in sensory neurons of peripheral ganglia. A variety of stresses can induce recurrent reactivations of the virus, which spreads and then actively replicates to the site of primary infection (usually the lips or eyes). Viral particles produced following reactivation can also reach the brain, causing a rare but severe form of diffuse acute infection, namely herpes simplex encephalitis. Most of the time, this infection is clinically asymptomatic. However, it was recently correlated with the production and accumulation of neuropathological biomarkers of Alzheimer's disease. In this review we discuss the different cellular and molecular mechanisms underlying the acute and long-term damage caused by HSV-1 infection in the brain.
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http://dx.doi.org/10.1016/j.tim.2020.03.003DOI Listing
October 2020

Resveratrol corrects aberrant splicing of pre-mRNA and Ca signal in myotonic dystrophy type 1 myotubes.

Neural Regen Res 2020 Sep;15(9):1757-1766

Department of Neuroscience, Università Cattolica del Sacro Cuore; Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

Myotonic dystrophy type 1 (DM1) is a spliceopathy related to the mis-splicing of several genes caused by sequestration of nuclear transcriptional RNA-binding factors from non-coding CUG repeats of DMPK pre-mRNAs. Dysregulation of ryanodine receptor 1 (RYR1), sarcoplasmatic/endoplasmatic Ca-ATPase (SERCA) and α1S subunit of voltage-gated Ca channels (Ca1.1) is related to Ca homeostasis and excitation-contraction coupling impairment. Though no pharmacological treatment for DM1 exists, aberrant splicing correction represents one major therapeutic target for this disease. Resveratrol (RES, 3,5,4'-trihydroxy-trans-stilbene) is a promising pharmacological tools for DM1 treatment for its ability to directly bind the DNA and RNA influencing gene expression and alternative splicing. Herein, we analyzed the therapeutic effects of RES in DM1 myotubes in a pilot study including cultured myotubes from two DM1 patients and two healthy controls. Our results indicated that RES treatment corrected the aberrant splicing of RYR1, and this event appeared associated with restoring of depolarization-induced Ca release from RYR1 dependent on the electro-mechanical coupling between RYR1 and Ca1.1. Interestingly, immunoblotting studies showed that RES treatment was associated with a reduction in the levels of CUGBP Elav-like family member 1, while RYR1, Ca1.1 and SERCA1 protein levels were unchanged. Finally, RES treatment did not induce any major changes either in the amount of ribonuclear foci or sequestration of muscleblind-like splicing regulator 1. Overall, the results of this pilot study would support RES as an attractive compound for future clinical trials in DM1. Ethical approval was obtained from the Ethical Committee of IRCCS Fondazione Policlinico Universitario A. Gemelli, Rome, Italy (rs9879/14) on May 20, 2014.
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http://dx.doi.org/10.4103/1673-5374.276336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437583PMC
September 2020

Chronic mild stress alters synaptic plasticity in the nucleus accumbens through GSK3β-dependent modulation of Kv4.2 channels.

Proc Natl Acad Sci U S A 2020 04 24;117(14):8143-8153. Epub 2020 Mar 24.

Department of Neuroscience, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.

Although major depressive disorder (MDD) is highly prevalent, its pathophysiology is poorly understood. Recent evidence suggests that glycogen-synthase kinase 3β (GSK3β) plays a key role in memory formation, yet its role in mood regulation remains controversial. Here, we investigated whether GSK3β activity in the nucleus accumbens (NAc) is associated with depression-like behaviors and synaptic plasticity. We performed whole-cell patch-clamp recordings of medium spiny neurons (MSNs) in the NAc and determined the role of GSK3β in spike timing-dependent long-term potentiation (tLTP) in the chronic unpredictable mild stress (CUMS) mouse model of depression. To assess the specific role of GSK3β in tLTP, we used in vivo genetic silencing by an adeno-associated viral vector (AAV2) short hairpin RNA against GSK3β. In addition, we examined the role of the voltage-gated potassium Kv4.2 subunit, a molecular determinant of A-type K currents, as a potential downstream target of GSK3β. We found increased levels of active GSK3β and augmented tLTP in CUMS mice, a phenotype that was prevented by selective GSK3β knockdown. Furthermore, knockdown of GSK3β in the NAc ameliorated depressive-like behavior in CUMS mice. Electrophysiological, immunohistochemical, biochemical, and pharmacological experiments revealed that inhibition of the Kv4.2 channel through direct phosphorylation at Ser-616 mediated the GSK3β-dependent tLTP changes in CUMS mice. Our results identify GSK3β regulation of Kv4.2 channels as a molecular mechanism of MSN maladaptive plasticity underlying depression-like behaviors and suggest that the GSK3β-Kv4.2 axis may be an attractive therapeutic target for MDD.
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http://dx.doi.org/10.1073/pnas.1917423117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7149226PMC
April 2020

The dual role of curcumin and ferulic acid in counteracting chemoresistance and cisplatin-induced ototoxicity.

Sci Rep 2020 01 23;10(1):1063. Epub 2020 Jan 23.

Department of Neuroscience, Università Cattolica del Sacro Cuore, Roma, Italia.

Platinum-based agents, such as cisplatin, form the mainstay of currently used chemotherapeutic regimens for several malignancies; however, the main limitations are chemoresistance and ototoxic side effects. In this study we used two different polyphenols, curcumin and ferulic acid as adjuvant chemotherapeutics evaluating (1) in vivo their antioxidant effects in protecting against cisplatin ototoxicity and (2) in vitro the transcription factors involved in tumor progression and cisplatin resistance. We reported that both polyphenols show antioxidant and oto-protective activity in the cochlea by up-regulating Nrf-2/HO-1 pathway and downregulating p53 phosphorylation. However, only curcumin is able to influence inflammatory pathways counteracting NF-κB activation. In human cancer cells, curcumin converts the anti-oxidant effect into a pro-oxidant and anti-inflammatory one. Curcumin exerts permissive and chemosensitive properties by targeting the cisplatin chemoresistant factors Nrf-2, NF-κB and STAT-3 phosphorylation. Ferulic acid shows a biphasic response: it is pro-oxidant at lower concentrations and anti-oxidant at higher concentrations promoting chemoresistance. Thus, polyphenols, mainly curcumin, targeting ROS-modulated pathways may be a promising tool for cancer therapy. Thanks to their biphasic activity of antioxidant in normal cells undergoing stressful conditions and pro-oxidant in cancer cells, these polyphenols probably engage an interplay among the key factors Nrf-2, NF-κB, STAT-3 and p53.
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http://dx.doi.org/10.1038/s41598-020-57965-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978317PMC
January 2020

Enhancing Plasticity Mechanisms in the Mouse Motor Cortex by Anodal Transcranial Direct-Current Stimulation: The Contribution of Nitric Oxide Signaling.

Cereb Cortex 2020 05;30(5):2972-2985

Istituto di Fisiologia Umana, Università Cattolica del Sacro Cuore, Roma 00168, Italy.

Consistent body of evidence shows that transcranial direct-current stimulation (tDCS) over the primary motor cortex (M1) facilitates motor learning and promotes recovery after stroke. However, the knowledge of molecular mechanisms behind tDCS effects needs to be deepened for a more rational use of this technique in clinical settings. Here we characterized the effects of anodal tDCS of M1, focusing on its impact on glutamatergic synaptic transmission and plasticity. Mice subjected to tDCS displayed increased long-term potentiation (LTP) and enhanced basal synaptic transmission at layer II/III horizontal connections. They performed better than sham-stimulated mice in the single-pellet reaching task and exhibited increased forelimb strength. Dendritic spine density of layer II/III pyramidal neurons was also increased by tDCS. At molecular level, tDCS enhanced: 1) BDNF expression, 2) phosphorylation of CREB, CaMKII, and GluA1, and 3) S-nitrosylation of GluA1 and HDAC2. Blockade of nitric oxide synthesis by L-NAME prevented the tDCS-induced enhancement of GluA1 phosphorylation at Ser831 and BDNF levels, as well as of miniature excitatory postsynaptic current (mEPSC) frequency, LTP and reaching performance. Collectively, these findings demonstrate that anodal tDCS engages plasticity mechanisms in the M1 and highlight a role for nitric oxide (NO) as a novel mediator of tDCS effects.
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http://dx.doi.org/10.1093/cercor/bhz288DOI Listing
May 2020

Maternal insulin resistance multigenerationally impairs synaptic plasticity and memory via gametic mechanisms.

Nat Commun 2019 10 22;10(1):4799. Epub 2019 Oct 22.

Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168, Rome, Italy.

Metabolic diseases harm brain health and cognitive functions, but whether maternal metabolic unbalance may affect brain plasticity of next generations is still unclear. Here, we demonstrate that maternal high fat diet (HFD)-dependent insulin resistance multigenerationally impairs synaptic plasticity, learning and memory. HFD downregulates BDNF and insulin signaling in maternal tissues and epigenetically inhibits BDNF expression in both germline and hippocampus of progeny. Notably, exposure of the HFD offspring to novel enriched environment restores Bdnf epigenetic activation in the male germline and counteracts the transmission of cognitive impairment to the next generations. BDNF administration to HFD-fed mothers or preserved insulin sensitivity in HFD-fed p66Shc KO mice also prevents the intergenerational transmission of brain damage to the progeny. Collectively, our data suggest that maternal diet multigenerationally impacts on descendants' brain health via gametic mechanisms susceptible to lifestyle.
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http://dx.doi.org/10.1038/s41467-019-12793-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805915PMC
October 2019

H19-Dependent Transcriptional Regulation of β3 and β4 Integrins Upon Estrogen and Hypoxia Favors Metastatic Potential in Prostate Cancer.

Int J Mol Sci 2019 Aug 17;20(16). Epub 2019 Aug 17.

Istituto di Patologia Medica, Università Cattolica del Sacro Cuore, 00168 Roma, Italy.

Estrogen and hypoxia promote an aggressive phenotype in prostate cancer (PCa), driving transcription of progression-associated genes. Here, we molecularly dissect the contribution of long non-coding RNA H19 to PCa metastatic potential under combined stimuli, a topic largely uncovered. The effects of estrogen and hypoxia on H19 and cell adhesion molecules' expression were investigated in PCa cells and PCa-derived organotypic slice cultures (OSCs) by qPCR and Western blot. The molecular mechanism was addressed by chromatin immunoprecipitations, overexpression, and silencing assays. PCa cells' metastatic potential was analyzed by in vitro cell-cell adhesion, motility test, and trans-well invasion assay. We found that combined treatment caused a significant H19 down-regulation as compared with hypoxia. In turn, H19 acts as a transcriptional repressor of cell adhesion molecules, as revealed by up-regulation of both β3 and β4 integrins and E-cadherin upon H19 silencing or combined treatment. Importantly, H19 down-regulation and β integrins induction were also observed in treated OSCs. Combined treatment increased both cell motility and invasion of PCa cells. Lastly, reduction of β integrins and invasion was achieved through epigenetic modulation of H19-dependent transcription. Our study revealed that estrogen and hypoxia transcriptionally regulate, via H19, cell adhesion molecules redirecting metastatic dissemination from EMT to a β integrin-mediated invasion.
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http://dx.doi.org/10.3390/ijms20164012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720303PMC
August 2019

Brain Insulin Resistance and Hippocampal Plasticity: Mechanisms and Biomarkers of Cognitive Decline.

Front Neurosci 2019 31;13:788. Epub 2019 Jul 31.

Institute of Human Physiology, Università Cattolica del Sacro Cuore, Rome, Italy.

In the last decade, much attention has been devoted to the effects of nutrient-related signals on brain development and cognitive functions. A turning point was the discovery that brain areas other than the hypothalamus expressed receptors for hormones related to metabolism. In particular, insulin signaling has been demonstrated to impact on molecular cascades underlying hippocampal plasticity, learning and memory. Here, we summarize the molecular evidence linking alteration of hippocampal insulin sensitivity with changes of both adult neurogenesis and synaptic plasticity. We also review the epidemiological studies and experimental models emphasizing the critical role of brain insulin resistance at the crossroad between metabolic and neurodegenerative disease. Finally, we brief novel findings suggesting how biomarkers of brain insulin resistance, involving the study of brain-derived extracellular vesicles and brain glucose metabolism, may predict the onset and/or the progression of cognitive decline.
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http://dx.doi.org/10.3389/fnins.2019.00788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685093PMC
July 2019

Glutamate/GABA co-release selectively influences postsynaptic glutamate receptors in mouse cortical neurons.

Neuropharmacology 2019 12 7;161:107737. Epub 2019 Aug 7.

Department of Experimental and Clinical Medicine, Section of Neuroscience and Cell Biology, Università Politecnica delle Marche, 60026, Ancona, Italy; Center for Neurobiology of Aging, INRCA, IRCCS, Ancona, Italy.

Cultured rat cortical neurons co-expressing VGLUT1 and VGAT (mixed synapses) co-release Glu and GABA. Here, mixed synapses were studied in cultured mouse cortical neurons to verify whether in mice mixed synapses co-release Glu and GABA, and to gain insight into how they may influence excitation/inhibition balance. Results showed the existence of synapses and autapses that co-release Glu and GABA in cultured mouse cortical neurons, and the ability of both neurotransmitters to evoke postsynaptic responses mediated by ionotropic receptors. We studied the short-term plasticity of glutamatergic, GABAergic, and mixed responses and we found that the kinetics of mixPSC amplitude depression was similar to that observed in EPSCs, but it was different from that of IPSCs. We found similar presynaptic release characteristics in glutamatergic and mixed synapses. Analysis of postsynaptic features, obtained by measuring AMPAR- and NMDAR-mediated currents, showed that AMPAR-mediated currents were significantly higher in pure glutamatergic than in mixed synapses, whereas NMDAR-mediated currents were not significantly different from those measured in mixed synapses. Overall, our findings demonstrate that glutamatergic and mixed synapses share similar electrophysiological properties. However, co-release of GABA and Glu influences postsynaptic ionotropic glutamatergic receptor subtypes, thus selectively influencing AMPAR-mediated currents. These findings strengthen the view that mixed neurons can play a key role in CNS development and in maintaining the excitation-inhibition balance.
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http://dx.doi.org/10.1016/j.neuropharm.2019.107737DOI Listing
December 2019

Herpes Simplex Virus Type-1 Infection Impairs Adult Hippocampal Neurogenesis via Amyloid-β Protein Accumulation.

Stem Cells 2019 11 22;37(11):1467-1480. Epub 2019 Aug 22.

Institute of Human Physiology, Università Cattolica del Sacro Cuore, Rome, Italy.

We previously reported that Herpes simplex virus type-1 (HSV-1) infection of cultured neurons triggered intracellular accumulation of amyloid-β protein (Aβ) markedly impinging on neuronal functions. Here, we demonstrated that HSV-1 affects in vitro and in vivo adult hippocampal neurogenesis by reducing neural stem/progenitor cell (NSC) proliferation and their neuronal differentiation via intracellular Aβ accumulation. Specifically, cultured NSCs were more permissive for HSV-1 replication than mature neurons and, once infected, they exhibited reduced proliferation (assessed by 5'-bromo-deoxyuridine incorporation, Ki67 immunoreactivity, and Sox2 mRNA expression) and impaired neuronal differentiation in favor of glial phenotype (evaluated by immunoreactivity for the neuronal marker MAP2, the glial marker glial fibrillary astrocyte protein, and the expression of the proneuronal genes Mash1 and NeuroD1). Similarly, impaired adult neurogenesis was observed in the subgranular zone of hippocampal dentate gyrus of an in vivo model of recurrent HSV-1 infections, that we recently set up and characterized, with respect to mock-infected mice. The effects of HSV-1 on neurogenesis did not depend on cell death and were due to Aβ accumulation in infected NSCs. Indeed, they were: (a) reverted, in vitro, by the presence of either β/γ-secretase inhibitors preventing Aβ production or the specific 4G8 antibody counteracting the action of intracellular Aβ; (b) not detectable, in vivo, in HSV-1-infected amyloid precursor protein knockout mice, unable to produce and accumulate Aβ. Given the critical role played by adult neurogenesis in hippocampal-dependent memory and learning, our results suggest that multiple virus reactivations in the brain may contribute to Alzheimer's disease phenotype by also targeting NSCs. Stem Cells 2019;37:1467-1480.
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http://dx.doi.org/10.1002/stem.3072DOI Listing
November 2019

Neuromodulatory Action of Picomolar Extracellular Aβ42 Oligomers on Presynaptic and Postsynaptic Mechanisms Underlying Synaptic Function and Memory.

J Neurosci 2019 07 24;39(30):5986-6000. Epub 2019 May 24.

Department Biomedical and Biotechnological Sciences, University of Catania, Catania 95123, Italy,

Failure of anti-amyloid-β peptide (Aβ) therapies against Alzheimer's disease (AD), a neurodegenerative disorder characterized by high amounts of the peptide in the brain, raised the question of the physiological role of Aβ released at low concentrations in the healthy brain. To address this question, we studied the presynaptic and postsynaptic mechanisms underlying the neuromodulatory action of picomolar amounts of oligomeric Aβ (oAβ) on synaptic glutamatergic function in male and female mice. We found that 200 pm oAβ induces an increase of frequency of miniature EPSCs and a decrease of paired pulse facilitation, associated with an increase in docked vesicle number, indicating that it augments neurotransmitter release at presynaptic level. oAβ also produced postsynaptic changes as shown by an increased length of postsynaptic density, accompanied by an increased expression of plasticity-related proteins such as cAMP-responsive element binding protein phosphorylated at Ser133, calcium-calmodulin-dependent kinase II phosphorylated at Thr286, and brain-derived neurotrophic factor, suggesting a role for Aβ in synaptic tagging. These changes resulted in the conversion of early into late long-term potentiation through the nitric oxide/cGMP/protein kinase G intracellular cascade consistent with a cGMP-dependent switch from short- to long-term memory observed after intrahippocampal administration of picomolar amounts of oAβ These effects were present upon extracellular but not intracellular application of the peptide and involved α7 nicotinic acetylcholine receptors. These observations clarified the physiological role of oAβ in synaptic function and memory formation providing solid fundamentals for investigating the pathological effects of high Aβ levels in the AD brains. High levels of oligomeric amyloid-β (oAβ) induce synaptic dysfunction leading to memory impairment in Alzheimer's disease (AD). However, at picomolar concentrations, the peptide is needed to ensure long-term potentiation (LTP) and memory. Here, we show that extracellular 200 pm oAβ concentrations increase neurotransmitter release, number of docked vesicles, postsynaptic density length, and expression of plasticity-related proteins leading to the conversion of early LTP into late LTP and of short-term memory into long-term memory. These effects require α7 nicotinic acetylcholine receptors and are mediated through the nitric oxide/cGMP/protein kinase G pathway. The knowledge of Aβ function in the healthy brain might be useful to understand the causes leading to its increase and detrimental effect in AD.
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http://dx.doi.org/10.1523/JNEUROSCI.0163-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650983PMC
July 2019

Recurrent herpes simplex virus-1 infection induces hallmarks of neurodegeneration and cognitive deficits in mice.

PLoS Pathog 2019 03 14;15(3):e1007617. Epub 2019 Mar 14.

Department of Public Health and Infectious Diseases, Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy.

Herpes simplex virus type 1 (HSV-1) is a DNA neurotropic virus, usually establishing latent infections in the trigeminal ganglia followed by periodic reactivations. Although numerous findings suggested potential links between HSV-1 and Alzheimer's disease (AD), a causal relation has not been demonstrated yet. Hence, we set up a model of recurrent HSV-1 infection in mice undergoing repeated cycles of viral reactivation. By virological and molecular analyses we found: i) HSV-1 spreading and replication in different brain regions after thermal stress-induced virus reactivations; ii) accumulation of AD hallmarks including amyloid-β protein, tau hyperphosphorylation, and neuroinflammation markers (astrogliosis, IL-1β and IL-6). Remarkably, the progressive accumulation of AD molecular biomarkers in neocortex and hippocampus of HSV-1 infected mice, triggered by repeated virus reactivations, correlated with increasing cognitive deficits becoming irreversible after seven cycles of reactivation. Collectively, our findings provide evidence that mild and recurrent HSV-1 infections in the central nervous system produce an AD-like phenotype and suggest that they are a risk factor for AD.
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http://dx.doi.org/10.1371/journal.ppat.1007617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6417650PMC
March 2019

Correction to: The Medial Septum Is Insulin Resistant in the AD Presymptomatic Phase: Rescue by Nerve Growth Factor-Driven IRS Activation.

Mol Neurobiol 2019 Apr;56(4):3068

European Brain Research Institute (EBRI) Rita Levi-Montalcini Foundation, Viale Regina Elena 295, Rome, Italy.

The authors, due to the change in one of the University name at the affiliation, hereby correct the proof.
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http://dx.doi.org/10.1007/s12035-019-1525-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828395PMC
April 2019