26 results on '"Sara Cocco"'
Search Results
2. Maternal High Fat Diet Anticipates the AD-like Phenotype in 3xTg-AD Mice by Epigenetic Dysregulation of Aβ Metabolism
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Francesca Natale, Matteo Spinelli, Marco Rinaudo, Sara Cocco, Ida Nifo Sarrapochiello, Salvatore Fusco, and Claudio Grassi
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STAT3 ,epigenetics ,maternal HFD ,Settore BIO/09 - FISIOLOGIA ,amyloid-β-protein ,Alzheimer’s disease ,Bace1 ,Insulin degrading enzyme ,NF-kB ,General Medicine - Abstract
Maternal overnutrition has been reported to affect brain plasticity of the offspring by altering gene expression, regulating both synaptic plasticity and adult neurogenesis. However, whether perinatal metabolic stress may influence the accumulation of misfolded proteins and the development of neurodegeneration remains to be clarified. We investigated the impact of maternal high fat diet (HFD) in an experimental model of Alzheimer’s disease (AD). The 3xTg-AD mice born to overfed mothers showed an impairment of synaptic plasticity and cognitive deficits earlier than controls. Maternal HFD also altered the expression of genes regulating amyloid-β-protein (Aβ) metabolism (i.e., Bace1, Ern1, Ide and Nicastrin) and enhanced Aβ deposition in the hippocampus. Finally, we found an epigenetic derangement and an aberrant recruitment of transcription factors NF-kB and STAT3 and chromatin remodeler HDAC2 on the regulatory sequences of the same genes. Collectively, our data indicate that early life metabolic stress worsens the AD phenotype via epigenetic alteration of genes regulating Aβ synthesis and clearance.
- Published
- 2023
3. Enhancing Plasticity Mechanisms in the Mouse Motor Cortex by Anodal Transcranial Direct-Current Stimulation: The Contribution of Nitric Oxide Signaling
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Claudio Grassi, Claudia Colussi, Andrea Mattera, Katia Gironi, Saviana Antonella Barbati, Valentina Longo, Maria Vittoria Podda, Fabiola Paciello, Sara Cocco, and Matteo Spinelli
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Male ,Dendritic spine ,Settore BIO/09 - FISIOLOGIA ,Cognitive Neuroscience ,medicine.medical_treatment ,Neurotransmission ,Nitric Oxide ,Transcranial Direct Current Stimulation ,TDCS ,Mice ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Organ Culture Techniques ,0302 clinical medicine ,medicine ,Animals ,AMPA receptor ,Electrodes ,long-term potentiation ,030304 developmental biology ,0303 health sciences ,Neuronal Plasticity ,Transcranial direct-current stimulation ,Chemistry ,nitrosylation ,Motor Cortex ,Long-term potentiation ,personalized medicine ,Mice, Inbred C57BL ,BDNF ,NG-Nitroarginine Methyl Ester ,medicine.anatomical_structure ,Excitatory postsynaptic potential ,Primary motor cortex ,Motor learning ,Neuroscience ,030217 neurology & neurosurgery ,Signal Transduction ,Motor cortex - Abstract
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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- 2019
4. Maternal insulin resistance multigenerationally impairs synaptic plasticity and memory via gametic mechanisms
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Claudio Grassi, Cristian Ripoli, Marco Rinaudo, Salvatore Fusco, Sara Cocco, Alessia Mastrodonato, Matteo Spinelli, Francesca Natale, and Giulia Livrizzi
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0301 basic medicine ,Male ,General Physics and Astronomy ,Hippocampus ,Histone Deacetylase 2 ,Epigenesis, Genetic ,0302 clinical medicine ,Sirtuin 2 ,Epigenetics in the nervous system ,Cyclic AMP Response Element-Binding Protein ,lcsh:Science ,Mice, Knockout ,Multidisciplinary ,Neuronal Plasticity ,Forkhead Box Protein O3 ,Neurotrophic factors ,Female ,medicine.symptom ,Pre-diabetes ,medicine.medical_specialty ,Src Homology 2 Domain-Containing, Transforming Protein 1 ,Offspring ,Settore BIO/09 - FISIOLOGIA ,Science ,Brain damage ,Biology ,Diet, High-Fat ,General Biochemistry, Genetics and Molecular Biology ,Article ,Synaptic plasticity ,03 medical and health sciences ,Insulin resistance ,Memory ,Internal medicine ,Neuroplasticity ,medicine ,Animals ,Learning ,Environmental enrichment ,Brain-Derived Neurotrophic Factor ,Ovary ,Metabolic diseases ,General Chemistry ,medicine.disease ,Mice, Inbred C57BL ,Insulin receptor ,030104 developmental biology ,Endocrinology ,Gene Expression Regulation ,biology.protein ,lcsh:Q ,Insulin Resistance ,brain plasticity ,030217 neurology & neurosurgery - Abstract
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., It’s well known that hippocampal synaptic plasticity and memory are impaired in experimental models of metabolic diseases, however, it is unclear if maternal diet or metabolic alterations around the gestational age may multigenerationally affect learning and memory. In this study, authors demonstrate that maternal high fat diet-dependent insulin resistance affects synaptic plasticity and memory of descendants until the third generation via reduced exon specific brain-derived neurotrophic factor expression in the hippocampus of descendants
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- 2019
5. Author response: Auditory sensory deprivation induced by noise exposure exacerbates cognitive decline in a mouse model of Alzheimer’s disease
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Anna Pisani, Maria Vittoria Podda, Valentina Longo, Gaetano Paludetti, Marco Rinaudo, Anna Rita Fetoni, Giulia Conforto, Claudio Grassi, Fabiola Paciello, and Sara Cocco
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medicine.medical_specialty ,Noise exposure ,business.industry ,Medicine ,Sensory deprivation ,Disease ,Cognitive decline ,Audiology ,business - Published
- 2021
6. Auditory sensory deprivation induced by noise exposure exacerbates cognitive decline in a mouse model of Alzheimer’s disease
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Gaetano Paludetti, Valentina Longo, Sara Cocco, Marco Rinaudo, Anna Pisani, Giulia Conforto, Claudio Grassi, Maria Vittoria Podda, Fabiola Paciello, Anna Rita Fetoni, Paciello, F., Rinaudo, M., Longo, V., Cocco, S., Conforto, G., Pisani, A., Podda, M. V., Fetoni, A. R., Paludetti, G., and Grassi, C.
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Male ,Hearing loss ,QH301-705.5 ,Settore BIO/09 - FISIOLOGIA ,Science ,Mice, Transgenic ,Hippocampal formation ,medicine.disease_cause ,Auditory cortex ,General Biochemistry, Genetics and Molecular Biology ,neuroinflammation ,neuroscience ,Mice ,Hearing ,Alzheimer Disease ,Medicine ,Dementia ,Animals ,oxidative stress ,Sensory deprivation ,Cognitive Dysfunction ,Cognitive decline ,Biology (General) ,Neuroinflammation ,mouse ,hearing loss ,oxidative stre ,General Immunology and Microbiology ,business.industry ,Animal ,General Neuroscience ,tau phosphorylation ,General Medicine ,hearing lo ,medicine.disease ,Disease Models, Animal ,Auditory Perception ,medicine.symptom ,Sensory Deprivation ,business ,Noise ,Neuroscience ,Oxidative stress ,Research Article ,dementia - Abstract
Although association between hearing impairment and dementia has been widely documented by epidemiological studies, the role of auditory sensory deprivation in cognitive decline remains to be fully understood. To address this issue we investigated the impact of hearing loss on the onset and time-course of cognitive decline in an animal model of Alzheimer’s disease (AD), that is the 3×Tg-AD mice and the underlying mechanisms. We found that hearing loss induced by noise exposure in the 3×Tg-AD mice before the phenotype is manifested caused persistent synaptic and morphological alterations in the auditory cortex. This was associated with earlier hippocampal dysfunction, increased tau phosphorylation, neuroinflammation, and redox imbalance, along with anticipated memory deficits compared to the expected time-course of the neurodegenerative phenotype. Our data suggest that a mouse model of AD is more vulnerable to central damage induced by hearing loss and shows reduced ability to counteract noise-induced detrimental effects, which accelerates the neurodegenerative disease onset.
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- 2021
7. Passive immunotherapy for N-truncated tau ameliorates the cognitive deficits in two mouse Alzheimer’s disease models
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Marcello D'Amelio, Marco Rinaudo, Sara Cocco, Antonella Borreca, Paraskevi Krashia, Rita Florio, Pietro Calissano, Valentina Latina, Francesca Natale, Martine Ammassari-Teule, Annabella Pignataro, Francesca Malerba, Claudio Grassi, Giacomo Giacovazzo, Roberta Ciarapica, Roberto Coccurello, Veronica Corsetti, G. Amadoro, and AMADORO GIUSEPPINA
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0301 basic medicine ,Dendritic spine ,Tau protein ,Hippocampus ,Hippocampal formation ,tau protein ,03 medical and health sciences ,0302 clinical medicine ,Amyloid precursor protein ,Medicine ,Dementia ,biology ,business.industry ,tauopathies ,General Engineering ,Long-term potentiation ,medicine.disease ,3. Good health ,Alzheimer's disease ,immunotherapy ,tau cleavage ,030104 developmental biology ,Synaptic plasticity ,biology.protein ,Original Article ,business ,Alzheimer’s disease ,Neuroscience ,030217 neurology & neurosurgery - Abstract
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 NH226-230 fragment (i.e. NH2htau) 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 NH2-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., Intercepting the pathologically relevant species without interfering with the physiological form(s) of protein is one of the challenges of tau-directed immunotherapy. The present study shows that antibody-mediated selective neutralization of the toxic N-truncated tau fragment in hippocampi from two transgenic Alzheimer’s disease mice significantly improves the synaptic functions., Graphical Abstract Graphical Abstract
- Published
- 2020
8. Plasma BDNF levels following transcranial direct current stimulation allow prediction of synaptic plasticity and memory deficits in 3×Tg-AD mice
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Sara Cocco, Marco Rinaudo, Salvatore Fusco, Valentina Longo, Katia Gironi, Pietro Renna, Giuseppe Aceto, Alessia Mastrodonato, Domenica Donatella Li Puma, Maria Vittoria Podda, and Claudio Grassi
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0301 basic medicine ,medicine.medical_treatment ,Settore BIO/09 - FISIOLOGIA ,neuroplasticity ,tDCS ,03 medical and health sciences ,Cell and Developmental Biology ,0302 clinical medicine ,Neuroplasticity ,Medicine ,lcsh:QH301-705.5 ,Original Research ,Transcranial direct-current stimulation ,Experimental model ,business.industry ,Long-term potentiation ,Cell Biology ,blood biomarkers ,personalized medicine ,030104 developmental biology ,BDNF ,lcsh:Biology (General) ,Blood biomarkers ,030220 oncology & carcinogenesis ,Synaptic plasticity ,Biomarker (medicine) ,Preclinical stage ,business ,Neuroscience ,Alzheimer’s disease ,Developmental Biology - Abstract
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 Ser133 and pCaMKII Thr286 , 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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- 2020
9. Anodal transcranial direct current stimulation affects auditory cortex plasticity in normal-hearing and noise-exposed rats
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Sara Cocco, Claudio Grassi, Maria Vittoria Podda, Gaetano Paludetti, Laura Petrosini, Fabiola Paciello, Rolando Rolesi, Anna Rita Fetoni, Diana Troiani, Paciello, F, Podda, Mv, Rolesi, R, Cocco, S, Petrosini, L, Troiani, D, Fetoni, Ar, Paludetti, G, and Grassi, G
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Male ,0301 basic medicine ,Dendritic spine ,Settore BIO/09 - FISIOLOGIA ,medicine.medical_treatment ,Biophysics ,Neurotransmission ,Transcranial Direct Current Stimulation ,Auditory cortex ,tDCS ,lcsh:RC321-571 ,03 medical and health sciences ,0302 clinical medicine ,Hearing ,otorhinolaryngologic diseases ,medicine ,Animals ,auditory cortex ,synaptic transmission ,Rats, Wistar ,Electrodes ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Brain-derived neurotrophic factor ,Neuronal Plasticity ,biology ,Transcranial direct-current stimulation ,Chemistry ,Pyramidal Cells ,General Neuroscience ,brain-derived neurotrophic factor ,Dendrites ,dendritic spines ,personalized medicine ,Rats ,Electrophysiology ,030104 developmental biology ,Synaptic plasticity ,Synaptophysin ,biology.protein ,Neurology (clinical) ,Noise ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Background Transcranial direct current stimulation (tDCS) is a non-invasive tool capable to modulate cortical functions by affecting neuronal excitability and synaptic plasticity. Objective Here we investigated the effects of anodal tDCS on auditory cortex (ACx) in normal-hearing rats and following a paradigm of noise-induced hearing loss (NIHL), that causes morphological alterations in ACx pyramidal neurons. Methods Male rats exposed to intense pure tone (10 kHz) were subsequently subjected to unilateral anodal tDCS of ACx and changes in dendritic morphology and spines were assessed by Golgi-Cox staining 30 days after the onset of the acoustic trauma. Molecular and functional changes were investigated by Western immunoblotting, immunofluorescence experiments and electrophysiological recordings in brain slices. Results We found that NIHL altered dendritic morphology by decreasing spine density, mostly in layer 2/3 pyramidal neurons. Interestingly, tDCS increased ACx spine density, targeting apical dendrites of layer 2/3 and 5/6 pyramidal neurons in rats with normal auditory function and both apical and basal arborizations in layer 2/3 of NIHL rats. Twenty-four hours after tDCS, Bdnf and synaptophysin levels in ACx increased both in normal-hearing and noise-exposed rats. Field recordings showed that basal synaptic transmission at layer 2/3 horizontal connections was significantly reduced in noise-exposed rats compared to normal-hearing animals and, notably, input-output curves of noise-exposed animals subjected to tDCS were similar to those of normal-hearing rats. Conclusions Our findings provide novel evidence that anodal tDCS affects structural plasticity in the ACx suggesting that it might be beneficial in treating cortical alterations due to cochlear damage.
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- 2018
10. Whole Blood Transcriptome Characterization of 3xTg-AD Mouse and Its Modulation by Transcranial Direct Current Stimulation (tDCS)
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Chiara Magri, Paolo Martini, Marco Rinaudo, Edoardo Giacopuzzi, Massimo Gennarelli, Alessandro Barbon, Erika Vitali, Claudio Grassi, and Sara Cocco
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Male ,0301 basic medicine ,medicine.medical_treatment ,RNA-Seq ,3xTg‐AD mouse ,Alzheimer’s disease ,RNA‐Seq ,Transcranial direct current stimulation ,Alzheimer Disease ,Amyloid beta-Peptides ,Amyloid beta-Protein Precursor ,Animals ,Blood Cells ,Disease Models, Animal ,Gene Expression Profiling ,Mice ,Mice, Inbred C57BL ,Mice, Transgenic ,Transcranial Direct Current Stimulation ,Transcriptome ,Whole Exome Sequencing ,tau Proteins ,Disease ,Inbred C57BL ,Transgenic ,0302 clinical medicine ,Gene expression ,Biology (General) ,Spectroscopy ,Whole blood ,Transcranial direct-current stimulation ,General Medicine ,Computer Science Applications ,Peripheral ,Chemistry ,Differentially expressed genes ,QH301-705.5 ,Settore BIO/09 - FISIOLOGIA ,Biology ,Article ,Catalysis ,Inorganic Chemistry ,03 medical and health sciences ,3xTg-AD mouse ,Exome Sequencing ,medicine ,Physical and Theoretical Chemistry ,QD1-999 ,Molecular Biology ,Animal ,Organic Chemistry ,030104 developmental biology ,Disease Models ,Neuroscience ,030217 neurology & neurosurgery - Abstract
The 3xTg-AD mouse is a widely used model in the study of Alzheimer’s Disease (AD). It has been extensively characterized from both the anatomical and behavioral point of view, but poorly studied at the transcriptomic level. For the first time, we characterize the whole blood transcriptome of the 3xTg-AD mouse at three and six months of age and evaluate how its gene expression is modulated by transcranial direct current stimulation (tDCS). RNA-seq analysis revealed 183 differentially expressed genes (DEGs) that represent a direct signature of the genetic background of the mouse. Moreover, in the 6-month-old 3xTg-AD mice, we observed a high number of DEGs that could represent good peripheral biomarkers of AD symptomatology onset. Finally, tDCS was associated with gene expression changes in the 3xTg-AD, but not in the control mice. In conclusion, this study provides an in-depth molecular characterization of the 3xTg-AD mouse and suggests that blood gene expression can be used to identify new biomarkers of AD progression and treatment effects.
- Published
- 2021
11. Neuromodulatory Action of Picomolar Extracellular Aβ42 Oligomers on Presynaptic and Postsynaptic Mechanisms Underlying Synaptic Function and Memory
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Claudio Grassi, Salvatore Giunta, Agostino Palmeri, Nicola Origlia, Fiorenzo Conti, Maria Rosaria Tropea, Cristian Ripoli, Marcello Melone, Domenica Donatella Li Puma, Walter Gulisano, Ottavio Arancio, Daniele Marcotulli, Daniela Puzzo, and Sara Cocco
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0301 basic medicine ,Male ,Mice, 129 Strain ,Settore BIO/09 - FISIOLOGIA ,Neural facilitation ,Presynaptic Terminals ,Amyloid precursor protein ,Amyloid-beta oligomers ,Neurotransmitter release ,Nicotinic receptors ,Synaptic plasticity ,Synaptic transmission ,Neurotransmission ,Hippocampus ,Synaptic Transmission ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Organ Culture Techniques ,Postsynaptic potential ,Memory ,Animals ,Rats, Wistar ,Neurotransmitter ,Research Articles ,Injections, Intraventricular ,Mice, Knockout ,Neurotransmitter Agents ,Amyloid beta-Peptides ,Chemistry ,General Neuroscience ,Long-term potentiation ,Extracellular Fluid ,Peptide Fragments ,Cell biology ,Rats ,Mice, Inbred C57BL ,030104 developmental biology ,Synapses ,Female ,Postsynaptic density ,Synaptic tagging ,030217 neurology & neurosurgery - Abstract
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(42) (oAβ(42)) on synaptic glutamatergic function in male and female mice. We found that 200 pm oAβ(42) 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(42) 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 in vivo after intrahippocampal administration of picomolar amounts of oAβ(42). 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(42) in synaptic function and memory formation providing solid fundamentals for investigating the pathological effects of high Aβ levels in the AD brains. SIGNIFICANCE STATEMENT High levels of oligomeric amyloid-β(42) (oAβ(42)) 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(42) 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.
- Published
- 2019
12. Glutamate/GABA co-release selectively influences postsynaptic glutamate receptors in mouse cortical neurons
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Sara Cocco, Claudio Grassi, Fiorenzo Conti, Giorgia Fattorini, Matteo Spinelli, Cristian Ripoli, and Andrea Mattera
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0301 basic medicine ,Vesicular Inhibitory Amino Acid Transport Proteins ,Settore BIO/09 - FISIOLOGIA ,Presynaptic Terminals ,Glutamic Acid ,AMPA receptor ,Receptors, N-Methyl-D-Aspartate ,GABA ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Glutamatergic ,Mice ,0302 clinical medicine ,Postsynaptic potential ,medicine ,Animals ,Receptors, AMPA ,AMPA receptors ,Cells, Cultured ,gamma-Aminobutyric Acid ,Pharmacology ,Cerebral Cortex ,Neurons ,Neuronal Plasticity ,Chemistry ,Glutamate receptor ,Excitatory Postsynaptic Potentials ,Electrophysiological Phenomena ,Mice, Inbred C57BL ,Electrophysiology ,Kinetics ,030104 developmental biology ,medicine.anatomical_structure ,Excitation-inhibition balance ,nervous system ,Receptors, Glutamate ,Cerebral cortex ,Vesicular Glutamate Transport Protein 1 ,GABAergic ,Co-release ,Glutamate ,Neuroscience ,030217 neurology & neurosurgery ,Ionotropic effect - Abstract
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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- 2018
13. Role of BDNF Signaling in Memory Enhancement Induced by Transcranial Direct Current Stimulation
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Sara Cocco, Maria V. Podda, and Claudio Grassi
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0301 basic medicine ,Settore BIO/09 - FISIOLOGIA ,Mini Review ,medicine.medical_treatment ,Disease ,tDCS ,lcsh:RC321-571 ,memory ,03 medical and health sciences ,0302 clinical medicine ,Medicine ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,synaptic plasticity ,epigenetics ,Transcranial direct-current stimulation ,biology ,business.industry ,General Neuroscience ,Cognition ,personalized medicine ,BDNF ,030104 developmental biology ,Physiological Aging ,Brain stimulation ,Synaptic plasticity ,biology.protein ,Animal studies ,business ,Neuroscience ,030217 neurology & neurosurgery ,Neurotrophin - Abstract
In the recent years numerous studies have provided encouraging results supporting the use of transcranial direct current stimulation (tDCS) as non-invasive brain stimulation technique to improve motor and cognitive functions in patients suffering from neurological and neuropsychiatric disorders as well as in healthy subjects. Among the multiple effects elicited by tDCS on cognitive functions, experimental evidence and clinical findings have highlighted the beneficial impact on long-term memory. Memory deficits occur during physiological aging as well as in neurological and neurodegenerative disorders, including Alzheimer’s disease (AD). In this scenario, non-invasive techniques for memory enhancement, such as tDCS, are receiving increasing attention. The knowledge of molecular mechanisms subtending tDCS effects is of pivotal importance for a more rationale use of this technique in clinical settings. Although we are still far from having a clear picture, recent literature on human and animal studies has pointed to the involvement of synaptic plasticity mechanisms in mediating tDCS effects on long-term memory. Here we review these studies focusing on the neurotrophin “brain-derived neurotrophic factor” (BDNF) as critical tDCS effector.
- Published
- 2018
14. Author response: LTP and memory impairment caused by extracellular Aβ and Tau oligomers is APP-dependent
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Agnes Staniszewski, Maria Rosaria Tropea, Walter Gulisano, Paul E. Fraser, Mauro Fa, Agostino Palmeri, Ottavio Arancio, Roberto Piacentini, Claudio Grassi, Domenica Donatella Li Puma, Hong Zhang, Sara Cocco, Luciano D'Adamio, and Daniela Puzzo
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Chemistry ,Extracellular ,Memory impairment ,Long-term potentiation ,Neuroscience - Published
- 2017
15. LTP and memory impairment caused by extracellular Aβ and Tau oligomers is APP-dependent
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Agostino Palmeri, Walter Gulisano, Mauro Fa, Agnes Staniszewski, Sara Cocco, Daniela Puzzo, Luciano D'Adamio, Domenica Donatella Li Puma, Roberto Piacentini, Paul E. Fraser, Ottavio Arancio, Hong Zhang, Maria Rosaria Tropea, and Claudio Grassi
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0301 basic medicine ,Amyloid beta ,QH301-705.5 ,Settore BIO/09 - FISIOLOGIA ,Science ,Plasma protein binding ,urologic and male genital diseases ,General Biochemistry, Genetics and Molecular Biology ,neuroscience ,memory ,03 medical and health sciences ,0302 clinical medicine ,mental disorders ,Extracellular ,medicine ,Amyloid precursor protein ,Memory impairment ,tau ,Biology (General) ,mouse ,synaptic plasticity ,General Immunology and Microbiology ,biology ,Chemistry ,General Neuroscience ,Long-term potentiation ,General Medicine ,Alzheimer's disease ,medicine.disease ,female genital diseases and pregnancy complications ,humanities ,amyloid-beta ,3. Good health ,030104 developmental biology ,Synaptic plasticity ,biology.protein ,Medicine ,APP ,Neuroscience ,030217 neurology & neurosurgery ,Research Article - Abstract
The concurrent application of subtoxic doses of soluble oligomeric forms of human amyloid-beta (oAβ) and Tau (oTau) proteins impairs memory and its electrophysiological surrogate long-term potentiation (LTP), effects that may be mediated by intra-neuronal oligomers uptake. Intrigued by these findings, we investigated whether oAβ and oTau share a common mechanism when they impair memory and LTP in mice. We found that as already shown for oAβ, also oTau can bind to amyloid precursor protein (APP). Moreover, efficient intra-neuronal uptake of oAβ and oTau requires expression of APP. Finally, the toxic effect of both extracellular oAβ and oTau on memory and LTP is dependent upon APP since APP-KO mice were resistant to oAβ- and oTau-induced defects in spatial/associative memory and LTP. Thus, APP might serve as a common therapeutic target against Alzheimer's Disease (AD) and a host of other neurodegenerative diseases characterized by abnormal levels of Aβ and/or Tau. DOI: http://dx.doi.org/10.7554/eLife.26991.001
- Published
- 2017
16. P1-219: EFFECTS OF TRANSCRANIAL DIRECT CURRENT STIMULATION (TDCS) ON BRAIN CORTEX PLASTICITY IN A MOUSE MODEL OF ALZHEIMER'S DISEASE
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Marco Rinaudo, Claudio Grassi, Maria Vittoria Podda, Sara Cocco, Saviana Antonella Barbati, and Katia Gironi
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Transcranial direct-current stimulation ,Epidemiology ,business.industry ,Health Policy ,medicine.medical_treatment ,Brain cortex ,Disease ,Plasticity ,Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,medicine ,Neurology (clinical) ,Geriatrics and Gerontology ,business ,Neuroscience - Published
- 2019
17. Primary motor cortex plasticity is enhanced by transcranial direct current stimulation in mice: underlying molecular mechanisms and impact on motor performance
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Maria Vittoria Podda, V. Longo, Saviana Antonella Barbati, K. Gironi, M. Spinelli, Sara Cocco, Claudio Grassi, and A. Mattera
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Transcranial direct-current stimulation ,business.industry ,General Neuroscience ,medicine.medical_treatment ,Biophysics ,Medicine ,Neurology (clinical) ,Primary motor cortex ,Plasticity ,business ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Neuroscience ,lcsh:RC321-571 - Published
- 2019
18. Transcranial direct current stimulation allows to early detect synaptic dysfunction and memory impairment in a mouse model of Alzheimer’s disease
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K. Gironi, Maria Vittoria Podda, Claudio Grassi, Sara Cocco, Saviana Antonella Barbati, Cristian Ripoli, and M. Rinaudo
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Transcranial direct-current stimulation ,business.industry ,General Neuroscience ,medicine.medical_treatment ,Biophysics ,Medicine ,Memory impairment ,Neurology (clinical) ,Disease ,business ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Neuroscience ,lcsh:RC321-571 - Published
- 2019
19. Anodal transcranial direct current stimulation boosts synaptic plasticity and memory in mice via epigenetic regulation of Bdnf expression
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Claudia Colussi, Maria Vittoria Podda, Salvatore Fusco, Claudio Grassi, Saviana Antonella Barbati, Alessia Mastrodonato, Lucia Leone, Cristian Ripoli, and Sara Cocco
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Male ,0301 basic medicine ,Settore BIO/09 - FISIOLOGIA ,medicine.medical_treatment ,Long-Term Potentiation ,Tropomyosin receptor kinase B ,Hippocampal formation ,Biology ,Bioinformatics ,Hippocampus ,Article ,Epigenesis, Genetic ,memory ,Mice ,03 medical and health sciences ,Bdnf ,0302 clinical medicine ,Neurotrophic factors ,Neuroplasticity ,medicine ,Animals ,Receptor, trkB ,Cyclic AMP Response Element-Binding Protein ,Brain-derived neurotrophic factor ,synaptic plasticity ,Multidisciplinary ,epigenetics ,Transcranial direct-current stimulation ,Brain-Derived Neurotrophic Factor ,Long-term potentiation ,Chromatin Assembly and Disassembly ,Mice, Inbred C57BL ,030104 developmental biology ,nervous system ,Synaptic plasticity ,transcranial direct current stimulation ,Neuroscience ,030217 neurology & neurosurgery - Abstract
The effects of transcranial direct current stimulation (tDCS) on brain functions and the underlying molecular mechanisms are yet largely unknown. Here we report that mice subjected to 20-min anodal tDCS exhibited one-week lasting increases in hippocampal LTP, learning and memory. These effects were associated with enhanced: i) acetylation of brain-derived neurotrophic factor (Bdnf) promoter I; ii) expression of Bdnf exons I and IX; iii) Bdnf protein levels. The hippocampi of stimulated mice also exhibited enhanced CREB phosphorylation, pCREB binding to Bdnf promoter I and recruitment of CBP on the same regulatory sequence. Inhibition of acetylation and blockade of TrkB receptors hindered tDCS effects at molecular, electrophysiological and behavioral levels. Collectively, our findings suggest that anodal tDCS increases hippocampal LTP and memory via chromatin remodeling of Bdnf regulatory sequences leading to increased expression of this gene and support the therapeutic potential of tDCS for brain diseases associated with impaired neuroplasticity.
- Published
- 2016
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20. Expression of olfactory-type cyclic nucleotide-gated channels in rat cortical astrocytes
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Maria Vittoria Podda, Claudio Grassi, Roberto Piacentini, Lucia Leone, Marcello D'Ascenzo, Sara Cocco, and Daniele Mezzogori
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Patch-Clamp Techniques ,Settore BIO/09 - FISIOLOGIA ,Wistar ,Cyclic Nucleotide-Gated Cation Channels ,Biology ,Hippocampal formation ,Diltiazem ,Cellular and Molecular Neuroscience ,medicine ,Extracellular ,Animals ,Channel blocker ,Patch clamp ,Rats, Wistar ,Cyclic nucleotide-gated ion channel ,Receptor ,Cyclic GMP ,Cerebral Cortex ,Rats ,Cell biology ,medicine.anatomical_structure ,nervous system ,Neurology ,Cerebral cortex ,Astrocytes ,Forebrain ,Ion Channel Gating ,Neuroscience - Abstract
Cyclic nucleotide-gated (CNG) channels are nonselective cation channels activated by cyclic AMP (cAMP) or cyclic GMP (cGMP). They were originally identified in retinal and olfactory receptors, but evidence has also emerged for their expression in several mammalian brain areas. Because cGMP and cAMP control important aspects of glial cell physiology, we wondered whether CNG channels are expressed in astrocytes, the most functionally relevant glial cells in the CNS. Immunoblot and immunofluorescence experiments demonstrated expression of the CNG channel olfactory-type A subunit, CNGA2, in cultured rat cortical astrocytes. In patch-clamp experiments, currents elicited in these cells by voltage ramps from -100 to +100 mV in the presence of the cGMP analogue, dB-cGMP, were significantly reduced by the CNG channel blockers, L-cis-diltiazem (LCD) and Cd(2+) . The reversal potentials of the LCD- and Cd(2+) -sensitive currents were more positive than that of K(+) , as expected for a mixed cation current. Noninactivating, voltage-independent currents were also elicited by extracellular application of the membrane permeant cGMP analogue, 8-Br-cGMP. These effects were blocked by LCD and were mimicked by natriuretic peptide receptor activation and inhibition of phosphodiesterase activity. Voltage-independent, LCD-sensitive currents were also elicited by 8-Br-cGMP in astrocytes of hippocampal and neocortical brain slices. Immunohistochemistry confirmed a broad distribution of CNG channels in astrocytes of the rat forebrain, midbrain, and hindbrain. These findings suggest that CNG channels are downstream targets of cyclic nucleotides in astrocytes, and they may be involved in the glial-mediated regulation of CNS functions under physiological and pathological conditions.
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- 2012
21. P020 Epigenetic regulation of brain-derived neurotrophic factor (Bdnf) expression mediates the effects of anodal transcranial direct current stimulation (tDCS) on hippocampal synaptic plasticity and memory in mice
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Sara Cocco, Claudio Grassi, C. Colussi, Alessia Mastrodonato, Saviana Antonella Barbati, Cristian Ripoli, Maria Vittoria Podda, G. Livrizzi, Lucia Leone, and Salvatore Fusco
- Subjects
Brain-derived neurotrophic factor ,Transcranial direct-current stimulation ,biology ,medicine.medical_treatment ,Morris water navigation task ,Long-term potentiation ,Tropomyosin receptor kinase B ,Hippocampal formation ,CREB ,tDCS ,Sensory Systems ,Neurology ,Physiology (medical) ,Neuroplasticity ,medicine ,biology.protein ,Neurology (clinical) ,Psychology ,Neuroscience - Abstract
Question Understanding the cellular and molecular mechanisms underlying tDCS action is critical for a rationale use of this technique in clinical settings. Here we investigated the effects of tDCS on hippocampal synaptic plasticity and memory focusing on epigenetic mechanisms affecting the expression of plasticity-related genes. Methods Electrophysiological, behavioral and molecular indices of hippocampal plasticity were investigated following 20-min anodal tDCS delivered to awake mice. Results Hippocampal slices from tDCS-mice showed greater long-term potentiation (LTP) at CA3-CA1 synapses compared to sham-stimulated controls. Enhanced LTP was associated with improved hippocampal-dependent learning and memory assessed by the Morris water maze and novel object recognition tests. Remarkably, all these effects persisted 1 week after tDCS. Real-time PCR, Western Blotting and chromatin immunoprecipitation experiments revealed that tDCS effects were due to an intracellular signaling cascade including: (i) increased phosphorylation of cAMP response element-binding protein (CREB); (ii) enhanced CREB binding to the Bdnf promoter I; and, (iii) recruitment of the histone acetyltransferase CBP (CREB-binding protein) leading to enhanced histone 3 acetylation on Bdnf promoter I. As a consequence, the expression of Bdnf exons I and IX mRNAs was increased in the hippocampi of tDCS mice along with Bdnf protein levels. Accordingly, molecular, electrophysiological and behavioral effects of tDCS were prevented by mice treatment with either the acetylation inhibitor, curcumin, or the Bdnf receptor TrkB antagonist, ANA-12. Remarkably, we found that tDCS enhanced glycogen synthase kinase-3β(GSK-3β) phosphorylation at Ser9 that was prevented by ANA-12, thus suggesting that GSK-3βinhibition plays a role in the tDCS-induced increase of hippocampal plasticity. Conclusion Our findings show that anodal tDCS increases hippocampal LTP and memory via chromatin remodeling of Bdnf regulatory sequences leading to increased expression of this gene. These results lend support to the use of tDCS for prevention and treatment of brain diseases associated with impaired neuroplasticity.
- Published
- 2017
22. The effects of transcranial direct current stimulation on hippocampal function may be predictive of altered plasticity in animal models of alzheimer's disease
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Claudio Grassi, Maria Vittoria Podda, Saviana Antonella Barbati, Sara Cocco, and Cristian Ripoli
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Neurology ,Transcranial direct-current stimulation ,business.industry ,medicine.medical_treatment ,Medicine ,Neurology (clinical) ,Hippocampal function ,Disease ,Plasticity ,business ,Neuroscience - Published
- 2017
23. NO-donor thiacarbocyanines as multifunctional agents for Alzheimer's disease
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Claudio Grassi, Michela Morbin, Valeria Fugnanesi, Roberta Fruttero, Elisabetta Marini, Mario Salmona, Antonella Federico, Sara Cocco, Laura Gasparini, Nahuai Badiola, Konstantin Chegaev, Cristian Ripoli, Antonio Bastone, Alberto Gasco, Giacomina Rossi, and Barbara Rolando
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Amyloid ,Settore BIO/09 - FISIOLOGIA ,Clinical Biochemistry ,Tau protein ,Pharmaceutical Science ,Hippocampal formation ,Biochemistry ,law.invention ,chemistry.chemical_compound ,law ,Alzheimer Disease ,Drug Discovery ,medicine ,Tau proteins ,Humans ,Nitric Oxide Donors ,Alzheimer disease, Nitric oxide, β-Amyloid, Tau proteins, Thiacarbocyanines, Long term potentiation ,Molecular Biology ,biology ,Chemistry ,Organic Chemistry ,Furoxan ,Nitric oxide ,Long-term potentiation ,Human brain ,Long term potentiation ,Carbocyanines ,medicine.anatomical_structure ,Synaptic plasticity ,biology.protein ,Recombinant DNA ,Molecular Medicine ,β-Amyloid ,Thiacarbocyanines - Abstract
Some symmetrical and unsymmetrical thiacarbocyanines bearing NO-donor nitrooxy and furoxan moieties were synthesized and studied as candidate anti-Alzheimer's drugs. All products activated soluble guanylate cyclase (sGC) in a dose-dependent manner, depending on the presence in their structures of NO-donor groups. None displayed toxicity when tested at concentrations below 10 μM on human brain microvascular endothelial cells (hCMEC/D3). Some products were capable of inhibiting amyloid β-protein (Aβ) aggregation, with a potency in the low μM concentration range, and of inhibiting aggregation of human recombinant tau protein in amyloid fibrils when incubated with the protein at 1 μM concentration. Nitrooxy derivative 21 and furoxan derivative 22 were selected to investigate synaptic plasticity. Both products, tested at 2 μM concentration, counteracted the inhibition of long-term potentiation (LTP) induced by Aβ42 in hippocampal brain slices.
- Published
- 2015
24. Intracellular accumulation of amyloid-β (Aβ) protein plays a major role in Aβ-induced alterations of glutamatergic synaptic transmission and plasticity
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Marcello D'Ascenzo, Federico Scala, Claudio Grassi, Alessia Mastrodonato, Roberto Piacentini, Domenica Donatella Li Puma, Sara Cocco, Cristian Ripoli, and Daniela Puzzo
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Male ,Microinjections ,Settore BIO/09 - FISIOLOGIA ,Long-Term Potentiation ,Primary Cell Culture ,Intracellular Space ,Glutamic Acid ,Biology ,Neurotransmission ,Hippocampus ,Mice ,Glutamatergic ,Synaptic augmentation ,medicine ,Extracellular ,Animals ,synaptic transmission ,6E10 ,Amyloid beta-Peptides ,Neuronal Plasticity ,intraneuronal accumulation ,synaptic plasticity ,General Neuroscience ,beta-amyloid ,Alzheimer's disease ,Excitatory Postsynaptic Potentials ,Long-term potentiation ,Articles ,Peptide Fragments ,autaptic hippocampal neurons ,Synaptic fatigue ,medicine.anatomical_structure ,whole-cell LTP ,Neuron ,amyloid-β protein ,Neuroscience ,Intracellular - Abstract
Intracellular accumulation of amyloid-β (Aβ) protein has been proposed as an early event in AD pathogenesis. In patients with mild cognitive impairment, intraneuronal Aβ immunoreactivity was found especially in brain regions critically involved in the cognitive deficits of AD. Although a large body of evidence demonstrates that Aβ42 accumulates intraneuronally ((in)Aβ), the action and the role of Aβ42 buildup on synaptic function have been poorly investigated. Here, we demonstrate that basal synaptic transmission and LTP were markedly depressed following Aβ42 injection into the neuron through the patch pipette. Control experiments performed with the reverse peptide (Aβ42-1) allowed us to exclude that the effects of (in)Aβ depended on changes in oncotic pressure. To further investigate (in)Aβ synaptotoxicity we used an Aβ variant harboring oxidized methionine in position 35 that does not cross the neuronal plasma membrane and is not uploaded from the extracellular space. This Aβ42 variant had no effects on synaptic transmission and plasticity when applied extracellularly, but induced synaptic depression and LTP inhibition after patch-pipette dialysis. Finally, the injection of an antibody raised against human Aβ42 (6E10) in CA1 pyramidal neurons of mouse hippocampal brain slices and autaptic microcultures did not, per se, significantly affect LTP and basal synaptic transmission, but it protected against the toxic effects of extracellular Aβ42. Collectively, these findings suggest that Aβ42-induced impairment of glutamatergic synaptic function depends on its internalization and intracellular accumulation thus paving the way to a systemic proteomic analysis of intracellular targets/partners of Aβ42.
- Published
- 2014
25. Comparison between optimized GRE and RARE sequences for 19F MRI studies
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Matteo Caffini, Giuseppe Baselli, Sara Cocco, Ileana Zucca, Alfonso Mastropietro, Chiara Dolores Soffientini, Alessandro Scotti, and Maria Grazia Bruzzone
- Subjects
Physics ,Nuclear magnetic resonance ,Steady state (electronics) ,Signal-to-noise ratio (imaging) ,Pulse (signal processing) ,Relaxation (iterative method) ,Pulse sequence ,Sensitivity (control systems) ,Independence (probability theory) ,Sequence (medicine) - Abstract
In 19 F-MRI studies limiting factors are the presence of a low signal due to the low concentration of 19 F-nuclei, necessary for biological applications, and the inherent low sensitivity of MRI. Hence, acquiring images using the pulse sequence with the best signal to noise ratio (SNR) by optimizing the acquisition parameters specifically to a 19 F compound is a core issue. In 19 F-MRI, multiple-spin-echo (RARE) and gradient-echo (GRE) are the two most frequently used pulse sequence families; therefore we performed an optimization study of GRE pulse sequences based on numerical simulations and experimental acquisitions on fluorinated compounds. We compared GRE performance to an optimized RARE sequence. Images were acquired on a 7T MRI preclinical scanner on phantoms containing different fluorinated compounds. Actual relaxation times (T 1 , T 2 , T 2 *) were evaluated in order to predict SNR dependence on sequence parameters. Experimental comparisons between spoiled GRE and RARE, obtained at a fixed acquisition time and in steady state condition, showed RARE sequence outperforming the spoiled GRE (up to 406% higher). Conversely, the use of the unbalanced-SSFP showed a significant increase in SNR compared to RARE (up to 28% higher). Moreover, this sequence (as GRE in general) was confirmed to be virtually insensitive to T 1 and T 2 relaxation times, after proper optimization, thus improving marker independence from the biological environment. These results confirm the efficacy of the proposed optimization tool and foster further investigation addressing in-vivo applicability.
- Published
- 2014
26. The Neurogenic Effects of Exogenous Neuropeptide Y: Early Molecular Events and Long-Lasting Effects in the Hippocampus of Trimethyltin-Treated Rats
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Valentina Corvino, Fabrizio Michetti, Maria Vittoria Podda, Wanda Lattanzi, Elisa Marchese, Maria Concetta Geloso, Claudio Grassi, Stefano Giannetti, Sara Cocco, and Valentina Di Maria
- Subjects
Long-Term Potentiation ,lcsh:Medicine ,Hippocampus ,Hippocampal formation ,Toxicology ,TRIMETHYLTIN ,Neural Stem Cells ,Molecular Cell Biology ,lcsh:Science ,Multidisciplinary ,Trimethyltin Compounds ,Stem Cells ,Pyramidal Cells ,Neurogenesis ,Neurodegeneration ,NEURODEGENERATION ,Neurochemistry ,Neuropeptide Y receptor ,humanities ,LONG TERM POTENTIATION ,Adult Stem Cells ,Neuroprotective Agents ,medicine.anatomical_structure ,Female ,Dendrite extension ,Cellular Types ,Neurochemicals ,Pyramidal cell ,Research Article ,Signal Transduction ,Neurotoxicology ,medicine.medical_specialty ,Kruppel-Like Transcription Factors ,NEUROPEPTIDE Y ,Neurophysiology ,Biology ,Internal medicine ,mental disorders ,medicine ,Animals ,Hedgehog Proteins ,Rats, Wistar ,Settore BIO/16 - ANATOMIA UMANA ,Dentate gyrus ,Neuropeptides ,lcsh:R ,medicine.disease ,Rats ,Neuroanatomy ,Endocrinology ,Cellular Neuroscience ,ENDOGENOUS NEUROGENESIS ,HIPPOCAMPUS ,TEMPORAL LOBE EPILEPSY ,lcsh:Q ,Molecular Neuroscience ,Neuroscience - Abstract
Modulation of endogenous neurogenesis is regarded as a promising challenge in neuroprotection. In the rat model of hippocampal neurodegeneration obtained by Trimethyltin (TMT) administration (8 mg/kg), characterised by selective pyramidal cell loss, enhanced neurogenesis, seizures and cognitive impairment, we previously demonstrated a proliferative role of exogenous neuropeptide Y (NPY), on dentate progenitors in the early phases of neurodegeneration. To investigate the functional integration of newly-born neurons, here we studied in adult rats the long-term effects of intracerebroventricular administration of NPY (2 µg/2 µl, 4 days after TMT-treatment), which plays an adjuvant role in neurodegeneration and epilepsy. Our results indicate that 30 days after NPY administration the number of new neurons was still higher in TMT+NPY-treated rats than in control+saline group. As a functional correlate of the integration of new neurons into the hippocampal network, long-term potentiation recorded in Dentate Gyrus (DG) in the absence of GABAA receptor blockade was higher in the TMT+NPY-treated group than in all other groups. Furthermore, qPCR analysis of Kruppel-like factor 9, a transcription factor essential for late-phase maturation of neurons in the DG, and of the cyclin-dependent kinase 5, critically involved in the maturation and dendrite extension of newly-born neurons, revealed a significant up-regulation of both genes in TMT+NPY-treated rats compared with all other groups. To explore the early molecular events activated by NPY administration, the Sonic Hedgehog (Shh) signalling pathway, which participates in the maintenance of the neurogenic hippocampal niche, was evaluated by qPCR 1, 3 and 5 days after NPY-treatment. An early significant up-regulation of Shh expression was detected in TMT+NPY-treated rats compared with all other groups, associated with a modulation of downstream genes. Our data indicate that the neurogenic effect of NPY administration during TMT-induced neurodegeneration involves early Shh pathway activation and results in a functional integration of newly-generated neurons into the local circuit.
- Published
- 2014
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