European Brain Research Institute EBRI

Rome, Italy

European Brain Research Institute EBRI

Rome, Italy
SEARCH FILTERS
Time filter
Source Type

Bobba A.,CNR Institute of Biomembrane and Bioenergetics | Amadoro G.,CNR Institute of Neuroscience | Valenti D.,CNR Institute of Biomembrane and Bioenergetics | Corsetti V.,European Brain Research Institute EBRI | And 2 more authors.
Mitochondrion | Year: 2013

Here we investigate the effect of β-amyloid on mitochondrial respiratory function, i.e.mitochondrial oxygen consumption and membrane potential generation as well as the individual activities of both the mitochondrial Complexes I-IV, that compose mitochondrial electron transport chain, and the ATP synthase, by using homogenate from cerebellar granule cells, treated with low concentrations of β-amyloid, and Alzheimer synaptic-enriched brain samples. We found that β-amyloid caused both a selective defect in Complex I activity associated with an increase (5 fold) of intracellular reactive oxygen species and an impairment of Complex IV likely due to membrane lipid peroxidation. In addition, a 130% increase of the GSSG/GSH ratio was measured in Alzheimer brains with respect to age-matched controls. Knowing the mechanisms of action of β-amyloid could allow to mitigate or even to interrupt the toxic cascade that leads a cell to death. The results of this study represent an important innovation because they offer the possibility to act at mitochondrial level and on specific sites to protect cells, for example by preventing the interaction of β-amyloid with the identified targets, by stabilizing or by restoring mitochondrial function or by interfering with the energy metabolism. © 2013 Elsevier B.V. and Mitochondria Research Society.


Antonelli R.,International School for Advanced Studies | Pizzarelli R.,International School for Advanced Studies | Pedroni A.,International School for Advanced Studies | Fritschy J.-M.,University of Zürich | And 5 more authors.
Nature Communications | Year: 2014

The cell adhesion molecule Neuroligin2 (NL2) is localized selectively at GABAergic synapses, where it interacts with the scaffolding protein gephyrin in the post-synaptic density. However, the role of this interaction for formation and plasticity of GABAergic synapses is unclear. Here, we demonstrate that endogenous NL2 undergoes proline-directed phosphorylation at its unique S714-P consensus site, leading to the recruitment of the peptidyl-prolyl cis-trans isomerase Pin1. This signalling cascade negatively regulates NL2' s ability to interact with gephyrin at GABAergic post-synaptic sites. As a consequence, enhanced accumulation of NL2, gephyrin and GABA A receptors was detected at GABAergic synapses in the hippocampus of Pin1-knockout mice (Pin1â '/â ') associated with an increase in amplitude of spontaneous GABA A -mediated post-synaptic currents. Our results suggest that Pin1-dependent signalling represents a mechanism to modulate GABAergic transmission by regulating NL2/gephyrin interaction. © 2014 Macmillan Publishers Limited. All rights reserved.


Bobba A.,CNR Institute of Neuroscience | Amadoro G.,CNR Institute of Neuroscience | La Piana G.,University of Bari | Calissano P.,European Brain Research Institute EBRI | Atlante A.,CNR Institute of Neuroscience
Apoptosis | Year: 2015

Alzheimer's disease (AD) and cancer proceed via one or more common molecular mechanisms: a metabolic shift from oxidative phosphorylation to glycolysis - corresponding to the activation of the Warburg effect - occurs in both diseases. The findings reported in this paper demonstrate that, in the early phase of apoptosis, glucose metabolism is enhanced, i.e. key proteins which internalize and metabolize glucose - glucose transporter, hexokinase and phosphofructokinase - are up-regulated, in concomitance with a parallel decrease in oxygen consumption by mitochondria and increase of l-lactate accumulation. Reversal of the glycolytic phenotype occurs in the presence of dichloroacetate, inhibitor of the pyruvate dehydrogenase kinase enzyme, which speeds up apoptosis of cerebellar granule cells, reawakening mitochondria and then modulating glycolytic enzymes. Loss of the adaptive advantage afforded by aerobic glycolysis, which occurs in the late phase of apoptosis, exacerbates the pathological processes underlying neurodegeneration, leading inevitably the cell to death. In conclusion, the data propose that both aerobic, i.e. Warburg effect, essentially due to the protective numbness of mitochondria, and anaerobic glycolysis, rather due to the mitochondrial impairment, characterize the entire time frame of apoptosis, from the early to the late phase, which mimics the development of AD. © 2014 Springer Science+Business Media New York.


East D.A.,Royal Veterinary College University of London | Campanella M.,Royal Veterinary College University of London | Campanella M.,University College London | Campanella M.,European Brain Research Institute EBRi
Autophagy | Year: 2013

Calcium (Ca2+) has long been known as a ubiquitous intracellular second messenger, exploited by cells to control processes as diverse as development, proliferation, learning, muscle contraction and secretion. The spatial and temporal patterns of these Ca2+-associated signals, as well as their amplitude, is precisely controlled to create gradients of the ion, varying considerably depending on cell type and function. Tuning of intracellular Ca2+ is achieved in part by the buffering role of mitochondria, whose unperturbed function is essential for maintaining cellular energy balance. Quality of mitochondria is ensured by the process of targeted autophagy or mitophagy, which depends on a molecular cascade driving the catabolic process of autophagy toward damaged or deficient organelles for elimination via the lysosomal pathway. Nonspecific and targeted autophagy are highly regulated processes fundamental to cell growth and tissue homeostasis, allowing resources to be reallocated in nutrient-deprived cells as well as being instrumental in the repair of damaged organelles or the elimination of those in excess. Given the role of Ca2+ signaling in many fundamental cellular processes requiring precise regulation, the involvement of Ca 2+ in autophagy is still somewhat ill-defined, and only in the past few years has evidence emerged linking the two. This minireview aims to summarize recent work implicating Ca2+ as an important regulator of autophagy, outlining a role for Ca2+ that may be even more critical in the regulation of targeted mitochondrial autophagy. © 2013 Landes Bioscience.


Faccenda D.,Royal Veterinary College University of London | Tan C.H.,University College London | Seraphim A.,University College London | Duchen M.R.,University College London | And 3 more authors.
Cell Death and Differentiation | Year: 2013

Mitochondrial structure has a central role both in energy conversion and in the regulation of cell death. We have previously shown that IF 1 protects cells from necrotic cell death and supports cristae structure by promoting the oligomerisation of the F 1 F o-ATPsynthase. As IF 1 is upregulated in a large proportion of human cancers, we have here explored its contribution to the progression of apoptosis and report that an increased expression of IF 1, relative to the F 1 F o-ATPsynthase, protects cells from apoptotic death. We show that IF 1 expression serves as a checkpoint for the release of Cytochrome c (Cyt c) and hence the completion of the apoptotic program. We show that the progression of apoptosis engages an amplification pathway mediated by: (i) Cyt c-dependent release of ER Ca 2+, (ii) Ca 2+-dependent recruitment of the GTPase Dynamin-related protein 1 (Drp1), (iii) Bax insertion into the outer mitochondrial membrane and (iv) further release of Cyt c. This pathway is accelerated by suppression of IF 1 and delayed by its overexpression. IF 1 overexpression is associated with the preservation of mitochondrial morphology and ultrastructure, consistent with a central role for IF 1 as a determinant of the inner membrane architecture and with the role of mitochondrial ultrastructure in the regulation of Cyt c release. These data suggest that IF 1 is an antiapoptotic and potentially tumorigenic factor and may be a valuable predictor of responsiveness to chemotherapy. © 2013 Macmillan Publishers Limited All rights reserved.


Meli G.,European Brain Research Institute EBRI | Lecci A.,European Brain Research Institute EBRI | Manca A.,European Brain Research Institute EBRI | Krako N.,European Brain Research Institute EBRI | And 6 more authors.
Nature Communications | Year: 2014

A' 2 oligomers (A' 2Os) are crucially involved in Alzheimer's Disease (AD). However, the lack of selective approaches for targeting these polymorphic A' 2 assemblies represents a major hurdle in understanding their biosynthesis, traffic and actions in living cells. Here, we established a subcellularly localized conformational-selective interference (CSI) approach, based on the expression of a recombinant antibody fragment against A' 2Os in the endoplasmic reticulum (ER). By CSI, we can control extra- and intracellular pools of A' 2Os produced in an AD-relevant cell model, without interfering with the maturation and processing of the A' 2 precursor protein. The anti-A' 2Os intrabody selectively intercepts critical A' 2O conformers in the ER, modulating their assembly and controlling their actions in pathways of cellular homeostasis and synaptic signalling. Our results demonstrate that intracellular A' 2 undergoes pathological oligomerization through critical conformations formed inside the ER. This establishes intracellular A' 2Os as key targets for AD treatment and presents CSI as a potential targeting strategy. © 2014 Macmillan Publishers Limited. All rights reserved.


Amadoro G.,CNR Institute of Neuroscience | Corsetti V.,University of Rome Tor Vergata | Atlante A.,CNR Institute of Biomembrane and Bioenergetics | Florenzano F.,IRCSS Fondazione Santa Lucia | And 5 more authors.
Neurobiology of Aging | Year: 2012

Although amyloid beta (Aβ) peptide can promote tau pathology and its toxicity is concurrently tau-dependent, the underlying mechanisms of the in vivo interplay of these proteins remain unsolved. Structural and functional mitochondrial alterations play an early, precipitating role in synaptic failure of Alzheimer's disease (AD) pathogenesis and an aggravated mitochondrial impairment has been described in triple APP/PS/tau transgenic mice carrying both plaques and tangles, if compared with mice overexpressing tau or amyloid precursor protein (APP) alone. Here, we show that a neurotoxic aminoterminal (NH 2)-derived tau fragment mapping between 26 and 230 amino acids of the human tau40 isoform (441 amino acids)-but not the physiological full-length protein-preferentially interacts with Aβ peptide(s) in human AD synapses in association with mitochondrial adenine nucleotide translocator-1 (ANT-1) and cyclophilin D. The two peptides-Aβ 1-42 and the smaller and more potent NH 2-26-44 peptide of the longest 20-22 kDa NH 2-tau fragment-inhibit the ANT-1-dependent adenosine diphosphate-adenosine triphosphate (ADP/ATP) exchange in a noncompetitive and competitive manner, respectively, and together further aggravate the mitochondrial dysfunction by exacerbating the ANT-1 impairment. Taken together, these data establish a common, direct and synergistic toxicity of pathological APP and tau products on synaptic mitochondria and suggest potential, new pathway(s) and target(s) for a combined, more efficient therapeutic intervention of early synaptic dysfunction in AD. © 2012 Elsevier Inc.


Bobba A.,CNR Institute of Neuroscience | Amadoro G.,CNR Institute of Neuroscience | Petragallo V.A.,CNR Institute of Neuroscience | Calissano P.,European Brain Research Institute EBRI | Atlante A.,CNR Institute of Neuroscience
Biochimica et Biophysica Acta - Bioenergetics | Year: 2013

To find out whether and how the adenine nucleotide translocator-1 (ANT-1) inhibition due to NH2htau and Aβ1-42 is due to an interplay between these two Alzheimer's peptides, ROS and ANT-1 thiols, use was made of mersalyl, a reversible alkylating agent of thiol groups that are oriented toward the external hydrophilic phase, to selectively block and protect, in a reversible manner, the -SH groups of ANT-1. The rate of ATP appearance outside mitochondria was measured as the increase in NADPH absorbance which occurs, following external addition of ADP, when ATP is produced by oxidative phosphorylation and exported from mitochondria in the presence of glucose, hexokinase and glucose-6-phosphate dehydrogenase. We found that the mitochondrial superoxide anions, whose production is induced at the level of Complex I by externally added Aβ1-42 and whose release from mitochondria is significantly reduced by the addition of the VDAC inhibitor DIDS, modify the thiol group/s present at the active site of mitochondrial ANT-1, impair ANT-1 in a mersalyl-prevented manner and abrogate the toxic effect of NH2htau on ANT-1 when Aβ1-42 is already present. A molecular mechanism is proposed in which the pathological Aβ-NH2htau interplay on ANT-1 in Alzheimer's neurons involves the thiol redox state of ANT-1 and the Aβ1-42-induced ROS increase. This result represents an important innovation because it suggests the possibility of using various strategies to protect cells at the mitochondrial level, by stabilizing or restoring mitochondrial function or by interfering with the energy metabolism providing a promising tool for treating or preventing AD. © 2013 Elsevier B.V.


Mendez P.,European Brain Research Institute EBRI
Neural plasticity | Year: 2011

Cortical structures of the adult mammalian brain are characterized by a spectacular diversity of inhibitory interneurons, which use GABA as neurotransmitter. GABAergic neurotransmission is fundamental for integrating and filtering incoming information and dictating postsynaptic neuronal spike timing, therefore providing a tight temporal code used by each neuron, or ensemble of neurons, to perform sophisticated computational operations. However, the heterogeneity of cortical GABAergic cells is associated to equally diverse properties governing intrinsic excitability as well as strength, dynamic range, spatial extent, anatomical localization, and molecular components of inhibitory synaptic connections that they form with pyramidal neurons. Recent studies showed that similarly to their excitatory (glutamatergic) counterparts, also inhibitory synapses can undergo activity-dependent changes in their strength. Here, some aspects related to plasticity and modulation of adult cortical and hippocampal GABAergic synaptic transmission will be reviewed, aiming at providing a fresh perspective towards the elucidation of the role played by specific cellular elements of cortical microcircuits during both physiological and pathological operations.


Mendez P.,European Brain Research Institute EBRI | Bacci A.,European Brain Research Institute EBRI
Neural Plasticity | Year: 2011

Cortical structures of the adult mammalian brain are characterized by a spectacular diversity of inhibitory interneurons, which use GABA as neurotransmitter. GABAergic neurotransmission is fundamental for integrating and filtering incoming information and dictating postsynaptic neuronal spike timing, therefore providing a tight temporal code used by each neuron, or ensemble of neurons, to perform sophisticated computational operations. However, the heterogeneity of cortical GABAergic cells is associated to equally diverse properties governing intrinsic excitability as well as strength, dynamic range, spatial extent, anatomical localization, and molecular components of inhibitory synaptic connections that they form with pyramidal neurons. Recent studies showed that similarly to their excitatory (glutamatergic) counterparts, also inhibitory synapses can undergo activity-dependent changes in their strength. Here, some aspects related to plasticity and modulation of adult cortical and hippocampal GABAergic synaptic transmission will be reviewed, aiming at providing a fresh perspective towards the elucidation of the role played by specific cellular elements of cortical microcircuits during both physiological and pathological operations. Copyright 2011 Pablo Méndez and Alberto Bacci.

Loading European Brain Research Institute EBRI collaborators
Loading European Brain Research Institute EBRI collaborators