OASI Institute for Research and Care on Mental Retardation and Brain Aging

Troina, Italy

OASI Institute for Research and Care on Mental Retardation and Brain Aging

Troina, Italy

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Peruzzotti-Jametti L.,University of Cambridge | Donega M.,University of Cambridge | Giusto E.,University of Cambridge | Mallucci G.,University of Cambridge | And 4 more authors.
Neuroscience | Year: 2014

Acute brain injuries cause rapid cell death that activates bidirectional crosstalk between the injured brain and the immune system.In the acute phase, the damaged CNS activates resident and circulating immune cells via the local and systemic release of soluble mediators. This early immune activation is necessary to confine the injured tissue and foster the clearance of cellular debris, thus bringing the inflammatory reaction to a close. In the chronic phase, a sustained immune activation has been described in many CNS disorders, and the degree of this prolonged response has variable effects on spontaneous brain regenerative processes. The challenge for treating acute CNS damage is to understand how to optimally engage and modify these immune responses, thus providing new strategies that will compensate for tissue lost to injury.Herein we have reviewed the available information regarding the role and function of the innate and adaptive immune responses in influencing CNS plasticity during the acute and chronic phases of after injury. We have examined how CNS damage evolves along the activation of main cellular and molecular pathways that are associated with intrinsic repair, neuronal functional plasticity and facilitation of tissue reorganization. © 2014 IBRO.


L'Episcopo F.,OASI Institute for Research and Care on Mental Retardation and Brain Aging | L'Episcopo F.,University of Catania | Drouin-Ouellet J.,Lund University | Tirolo C.,OASI Institute for Research and Care on Mental Retardation and Brain Aging | And 10 more authors.
Cell Death and Disease | Year: 2016

Glycogen synthase kinase-3β (GSK-3β) has emerged as a critical factor in several pathways involved in hippocampal neuronal maintenance and function. In Huntington's disease (HD), there are early hippocampal deficits both in patients and transgenic mouse models, which prompted us to investigate whether disease-specific changes in GSK-3β expression may underlie these abnormalities. Thirty-three postmortem hippocampal samples from HD patients (neuropathological grades 2-4) and age- and sex-matched normal control cases were analyzed using real-time quantitative reverse transcription PCRs (qPCRs) and immunohistochemistry. In vitro and in vivo studies looking at hippocampal pathology and GSK-3β were also undertaken in transgenic R6/2 and wild-type mice. We identified a disease and stage-dependent upregulation of GSK-3β mRNA and protein levels in the HD hippocampus, with the active isoform pGSK-3β-Tyr216 being strongly expressed in dentate gyrus (DG) neurons and astrocytes at a time when phosphorylation of Tau at the AT8 epitope was also present in these same neurons. This upregulation of pGSK-3β-Tyr216 was also found in the R6/2 hippocampus in vivo and linked to the increased vulnerability of primary hippocampal neurons in vitro. In addition, the increased expression of GSK-3β in the astrocytes of R6/2 mice appeared to be the main driver of Tau phosphorylation and caspase3 activation-induced neuronal death, at least in part via an exacerbated production of major proinflammatory mediators. This stage-dependent overactivation of GSK-3β in HD-affected hippocampal neurons and astrocytes therefore points to GSK-3β as being a critical factor in the pathological development of this condition. As such, therapeutic targeting of this pathway may help ameliorate neuronal dysfunction in HD. © 2016 Macmillan Publishers Limited All rights reserved.


PubMed | University of Catania, Lund University and OASI Institute for Research and Care on Mental Retardation and Brain Aging
Type: | Journal: Cell death & disease | Year: 2016

Glycogen synthase kinase-3 (GSK-3) has emerged as a critical factor in several pathways involved in hippocampal neuronal maintenance and function. In Huntingtons disease (HD), there are early hippocampal deficits both in patients and transgenic mouse models, which prompted us to investigate whether disease-specific changes in GSK-3 expression may underlie these abnormalities. Thirty-three postmortem hippocampal samples from HD patients (neuropathological grades 2-4) and age- and sex-matched normal control cases were analyzed using real-time quantitative reverse transcription PCRs (qPCRs) and immunohistochemistry. In vitro and in vivo studies looking at hippocampal pathology and GSK-3 were also undertaken in transgenic R6/2 and wild-type mice. We identified a disease and stage-dependent upregulation of GSK-3 mRNA and protein levels in the HD hippocampus, with the active isoform pGSK-3-Tyr(216) being strongly expressed in dentate gyrus (DG) neurons and astrocytes at a time when phosphorylation of Tau at the AT8 epitope was also present in these same neurons. This upregulation of pGSK-3-Tyr(216) was also found in the R6/2 hippocampus in vivo and linked to the increased vulnerability of primary hippocampal neurons in vitro. In addition, the increased expression of GSK-3 in the astrocytes of R6/2 mice appeared to be the main driver of Tau phosphorylation and caspase3 activation-induced neuronal death, at least in part via an exacerbated production of major proinflammatory mediators. This stage-dependent overactivation of GSK-3 in HD-affected hippocampal neurons and astrocytes therefore points to GSK-3 as being a critical factor in the pathological development of this condition. As such, therapeutic targeting of this pathway may help ameliorate neuronal dysfunction in HD.


L'Episcopo F.,OASI Institute for Research and Care on Mental Retardation and Brain Aging | Serapide M.F.,University of Catania | Tirolo C.,OASI Institute for Research and Care on Mental Retardation and Brain Aging | Testa N.,OASI Institute for Research and Care on Mental Retardation and Brain Aging | And 5 more authors.
Molecular Neurodegeneration | Year: 2011

Background: Dopamine-synthesizing (dopaminergic, DA) neurons in the ventral midbrain (VM) constitute a pivotal neuronal population controlling motor behaviors, cognitive and affective brain functions, which generation critically relies on the activation of Wingless-type MMTV integration site (Wnt)/β-catenin pathway in their progenitors. In Parkinson's disease, DA cell bodies within the substantia nigra pars compacta (SNpc) progressively degenerate, with causes and mechanisms poorly understood. Emerging evidence suggests that Wnt signaling via Frizzled (Fzd) receptors may play a role in different degenerative states, but little is known about Wnt signaling in the adult midbrain. Using in vitro and in vivo model systems of DA degeneration, along with functional studies in both intact and SN lesioned mice, we herein highlight an intrinsic Wnt1/Fzd-1/β-catenin tone critically contributing to the survival and protection of adult midbrain DA neurons. Results: In vitro experiments identifie Fzd-1 receptor expression at a mRNA and protein levels in dopamine transporter (DAT) expressing neurons, and demonstrate the ability of exogenous Wnt1 to exert robust neuroprotective effects against Caspase-3 activation, the loss of tyrosine hydroxylase-positive (TH +) neurons and [ 3H] dopamine uptake induced by different DA-specific insults, including serum and growth factor deprivation, 6-hydroxydopamine and MPTP/MPP +. Co-culture of DA neurons with midbrain astrocytes phenocopies Wnt1 neuroprotective effects, whereas RNA interference-mediated knockdown of Wnt1 in midbrain astrocytes markedly reduces astrocyte-induced TH + neuroprotection. Likewise, silencing β-catenin mRNA or knocking down Fzd-1 receptor expression in mesencephalic neurons counteract astrocyte-induced TH + neuroprotection. In vivo experiments document Fzd-1 co-localization with TH + neurons within the intact SNpc and blockade of Fzd/β-catenin signaling by unilateral infusion of a Fzd/β-catenin antagonist within the SN induces reactive astrocytosis and acutely inhibits TH + neuron survival in ipsilateral SNpc, an effect efficiently prevented by pharmacological activation of β-catenin signaling within the SNpc. Conclusion: These results defining a novel Wnt1/Fzd-1/β- catenin astrocyte-DA autoprotective loop provide a new mechanistic inside into the regulation of pro-survival processes, with potentially relevant consequences for drug design or drug action in Parkinson's disease. © 2011 L'Episcopo et al; licensee BioMed Central Ltd.


Marchetti B.,University of Catania | Marchetti B.,OASI Institute for Research and Care on Mental Retardation and Brain Aging | Pluchino S.,University of Cambridge | Pluchino S.,Cambridge Biomedical Research Center
Trends in Molecular Medicine | Year: 2013

The roles of Wnts in neural development, synaptogenesis, and cancer are generally well characterized. Nonetheless, evidence exists that interactions between the immune and nervous systems control major brain regenerative processes ranging from physiological or pathological (reparative) regeneration to neurogenesis and synaptic plasticity. Recent studies describe deregulated Wnt-Fzd signaling in degenerative and inflammatory central nervous system (CNS) disorders, and the expression of Wnt signaling components in the immune system, and in immune-like cells of the mammalian CNS. This would suggest a likely involvement of Wnts in inflammation-driven brain damage and inflammation-directed brain repair. Here, we review how Wnts modulate neuroimmune interactions and offer a perspective on the most challenging therapeutic opportunities for those CNS diseases where injury-reactive Wnt-flavored inflammation precedes secondary neurodegeneration. © 2012 Elsevier Ltd.


PubMed | OASI Institute for Research and Care on Mental Retardation and Brain Aging
Type: Journal Article | Journal: Neurobiology of disease | Year: 2011

Emerging evidence points to reactive glia as a pivotal factor in Parkinsons disease (PD) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse model of basal ganglia injury, but whether astrocytes and microglia activation may exacerbate dopaminergic (DAergic) neuron demise and/or contribute to DAergic repair is presently the subject of much debate. Here, we have correlated the loss and recovery of the nigrostriatal DAergic functionality upon acute MPTP exposure with extensive gene expression analysis at the level of the ventral midbrain (VM) and striata (Str) and found a major upregulation of pro-inflammatory chemokines and wingless-type MMTV integration site1 (Wnt1), a key transcript involved in midbrain DAergic neurodevelopment. Wnt signaling components (including Frizzled-1 [Fzd-1] and -catenin) were dynamically regulated during MPTP-induced DAergic degeneration and reactive glial activation. Activated astrocytes of the ventral midbrain were identified as candidate source of Wnt1 by in situ hybridization and real-time PCR in vitro. Blocking Wnt/Fzd signaling with Dickkopf-1 (Dkk1) counteracted astrocyte-induced neuroprotection against MPP(+) toxicity in primary mesencephalic astrocyte-neuron cultures, in vitro. Moreover, astroglial-derived factors, including Wnt1, promoted neurogenesis and DAergic neurogenesis from adult midbrain stem/neuroprogenitor cells, in vitro. Conversely, lack of Wnt1 transcription in response to MPTP in middle-aged mice and failure of DAergic neurons to recover were reversed by pharmacological activation of Wnt/-catenin signaling, in vivo, thus suggesting MPTP-reactive astrocytes in situ and Wnt1 as candidate components of neuroprotective/neurorescue pathways in MPTP-induced nigrostriatal DAergic plasticity.


PubMed | OASI Institute for Research and Care on Mental Retardation and Brain Aging
Type: Journal Article | Journal: Rejuvenation research | Year: 2011

Aging represents a major risk factor for the development and progression of Parkinson disease (PD), a chronic degenerative disorder characterized by the selective loss of dopaminergic (DAergic) neurons in the subtantia nigra pars compacta (SNpc). Emerging evidence highlights the glia as a pivotal factor in PD etiology, and epidemiological studies indicate that certain nonsteroidal antiinflammatory drugs (NSAIDs) may prevent or delay the progression of PD. Given that the exaggerated inflammatory response observed in old age may play a critical role in exacerbating DAergic vulnerability, we hypothesize here that switching the harmful glial response to inflammation and oxidative stress might increase the ability of the SN to resist inflammatory attacks. To this end, we developed a treatment in which we combined the effects of nitric oxide (NO) with nonsteroidal antiinflammatory activity by using HCT1026, a NO-donating derivative of flurbiprofen that has a safe profile and additional immunomodulatory properties. Young and aged mice fed with control or HCT1026 (30 mg kg(-1) day(-1)) diet were exposed to a single systemic injection of a subtoxic dose (0.2 mg kg(-1)) of lipopolysaccharide (LPS), one of the most extensively used glial activators. HCT1026 efficiently reversed the age-dependent increase of microglial activation in response to LPS to levels measured in younger mice. In aged mice, LPS induced a progressive loss of DAergic neurons with no recovery for their entire life span, whereas younger mice or aged mice fed with HCT1026 were resistant to systemic LPS-induced DAergic neurodegeneration, underscoring glia as a key pharmacological target for DAergic neuroprotection.


Dopamine-synthesizing (dopaminergic, DA) neurons in the ventral midbrain (VM) constitute a pivotal neuronal population controlling motor behaviors, cognitive and affective brain functions, which generation critically relies on the activation of Wingless-type MMTV integration site (Wnt)/-catenin pathway in their progenitors. In Parkinsons disease, DA cell bodies within the substantia nigra pars compacta (SNpc) progressively degenerate, with causes and mechanisms poorly understood. Emerging evidence suggests that Wnt signaling via Frizzled (Fzd) receptors may play a role in different degenerative states, but little is known about Wnt signaling in the adult midbrain. Using in vitro and in vivo model systems of DA degeneration, along with functional studies in both intact and SN lesioned mice, we herein highlight an intrinsic Wnt1/Fzd-1/-catenin tone critically contributing to the survival and protection of adult midbrain DA neurons.In vitro experiments identifie Fzd-1 receptor expression at a mRNA and protein levels in dopamine transporter (DAT) expressing neurons, and demonstrate the ability of exogenous Wnt1 to exert robust neuroprotective effects against Caspase-3 activation, the loss of tyrosine hydroxylase-positive (TH+) neurons and [3H] dopamine uptake induced by different DA-specific insults, including serum and growth factor deprivation, 6-hydroxydopamine and MPTP/MPP+. Co-culture of DA neurons with midbrain astrocytes phenocopies Wnt1 neuroprotective effects, whereas RNA interference-mediated knockdown of Wnt1 in midbrain astrocytes markedly reduces astrocyte-induced TH+ neuroprotection. Likewise, silencing -catenin mRNA or knocking down Fzd-1 receptor expression in mesencephalic neurons counteract astrocyte-induced TH+ neuroprotection. In vivo experiments document Fzd-1 co-localization with TH+ neurons within the intact SNpc and blockade of Fzd/-catenin signaling by unilateral infusion of a Fzd/-catenin antagonist within the SN induces reactive astrocytosis and acutely inhibits TH+ neuron survival in ipsilateral SNpc, an effect efficiently prevented by pharmacological activation of -catenin signaling within the SNpc.These results defining a novel Wnt1/Fzd-1/-catenin astrocyte-DA autoprotective loop provide a new mechanistic inside into the regulation of pro-survival processes, with potentially relevant consequences for drug design or drug action in Parkinsons disease.

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