Small Extracellular Vesicles Secreted by Nigrostriatal Astrocytes Rescue Cell Death and Preserve Mitochondrial Function in Parkinson's Disease.

Extracellular vesicles (EVs) are emerging as powerful players in cell-to-cell communication both in healthy and diseased brain. In Parkinson's disease (PD)-characterized by selective dopaminergic neuron death in ventral midbrain (VMB) and degeneration of their terminals in striatum (STR)-astrocytes exert dual harmful/protective functions, with mechanisms not fully elucidated. Here, this study shows that astrocytes from the VMB-, STR-, and VMB/STR-depleted brains release a population of small EVs  in a region-specific manner. Interestingly, VMB-astrocytes secreted the highest rate of EVs, which is further exclusively increased in response to CCL3, a chemokine that promotes robust dopaminergic neuroprotection in different PD models. The neuroprotective potential of nigrostriatal astrocyte-EVs is investigated in differentiated versus undifferentiated SH-SY5Y cells exposed to oxidative stress and mitochondrial toxicity. EVs from both VMB- and STR-astrocytes counteract H2 O2 -induced caspase-3 activation specifically in differentiated cells, with EVs from CCL3-treated astrocytes showing a higher protective effect. High resolution respirometry further reveals that nigrostriatal astrocyte-EVs rescue neuronal mitochondrial complex I function impaired by the neurotoxin MPP+ . Notably, only EVs from VMB-astrocyte fully restore ATP production, again specifically in differentiated SH-SY5Y. These results highlight a regional diversity in the nigrostriatal system for the secretion and activities of astrocyte-EVs, with neuroprotective implications for PD.

"Reframing" dopamine signaling at the intersection of glial networks in the aged Parkinsonian brain as innate Nrf2/Wnt driver: Therapeutical implications.

Dopamine (DA) signaling via G protein-coupled receptors is a multifunctional neurotransmitter and neuroendocrine-immune modulator. The DA nigrostriatal pathway, which controls the motor coordination, progressively degenerates in Parkinson's disease (PD), a most common neurodegenerative disorder (ND) characterized by a selective, age-dependent loss of substantia nigra pars compacta (SNpc) neurons, where DA itself is a primary source of oxidative stress and mitochondrial impairment, intersecting astrocyte and microglial inflammatory networks. Importantly, glia acts as a preferential neuroendocrine-immune DA target, in turn, counter-modulating inflammatory processes. With a major focus on DA intersection within the astrocyte-microglial inflammatory network in PD vulnerability, we herein first summarize the characteristics of DA signaling systems, the propensity of DA neurons to oxidative stress, and glial inflammatory triggers dictating the vulnerability to PD. Reciprocally, DA modulation of astrocytes and microglial reactivity, coupled to the synergic impact of gene-environment interactions, then constitute a further level of control regulating midbrain DA neuron (mDAn) survival/death. Not surprisingly, within this circuitry, DA converges to modulate nuclear factor erythroid 2-like 2 (Nrf2), the master regulator of cellular defense against oxidative stress and inflammation, and Wingless (Wnt)/ß-catenin signaling, a key pathway for mDAn neurogenesis, neuroprotection, and immunomodulation, adding to the already complex "signaling puzzle," a novel actor in mDAn-glial regulatory machinery. Here, we propose an autoregulatory feedback system allowing DA to act as an endogenous Nrf2/Wnt innate modulator and trace the importance of DA receptor agonists applied to the clinic as immune modifiers.

Extracellular Vesicles as Novel Diagnostic and Prognostic Biomarkers for Parkinson's Disease.

The elderly population will significantly increase in the next decade and, with it, the proportion of people affected by age-related diseases. Among them, one of the most invalidating is Parkinson's disease (PD), characterized by motor- and non-motor dysfunctions which strongly impair the quality of life of affected individuals. PD is characterized by the progressive degeneration of dopaminergic neurons, with consequent dopamine depletion, and the accumulation of misfolded α-synuclein aggregates. Although 150 years have passed since PD first description, no effective therapies are currently available, but only palliative treatments. Importantly, PD is often diagnosed when the neuronal loss is elevated, making difficult any therapeutic intervention. In this context, two key challenges remain unanswered: (i) the early diagnosis to avoid the insurgence of irreversible symptoms; and (ii) the reliable monitoring of therapy efficacy. Research strives to identify novel biomarkers for PD diagnosis, prognosis, and therapeutic follow-up. One of the most promising sources of biomarkers is represented by extracellular vesicles (EVs), a heterogeneous population of nanoparticles, released by all cells in the microenvironment. Brain-derived EVs are able to cross the blood-brain barrier, protecting their payload from enzymatic degradation, and are easily recovered from biofluids. Interestingly, EV content is strongly influenced by the specific pathophysiological status of the donor cell. In this manuscript, the role of EVs as source of novel PD biomarkers is discussed, providing all recent findings concerning relevant proteins and miRNAs carried by PD patient-derived EVs, from several biological specimens. Moreover, the contribution of mitochondria-derived EVs will be dissected. Finally, the promising possibility to use EVs as source of markers to monitor PD therapy efficacy will be also examined. In the future, larger cohort studies will help to validate these EV-associated candidates, that might be effectively used as non-invasive and robust source of biomarkers for PD.

High-Resolution Respirometry Reveals MPP+ Mitochondrial Toxicity Mechanism in a Cellular Model of Parkinson's Disease.

MPP+ is the active metabolite of MPTP, a molecule structurally similar to the herbicide Paraquat, known to injure the dopaminergic neurons of the nigrostriatal system in Parkinson's disease models. Within the cells, MPP+ accumulates in mitochondria where it inhibits complex I of the electron transport chain, resulting in ATP depletion and neuronal impairment/death. So far, MPP+ is recognized as a valuable tool to mimic dopaminergic degeneration in various cell lines. However, despite a large number of studies, a detailed characterization of mitochondrial respiration in neuronal cells upon MPP+ treatment is still missing. By using high-resolution respirometry, we deeply investigated oxygen consumption related to each respiratory state in differentiated neuroblastoma cells exposed to the neurotoxin. Our results indicated the presence of extended mitochondrial damage at the inner membrane level, supported by increased LEAK respiration, and a drastic drop in oxygen flow devoted to ADP phosphorylation in respirometry measurements. Furthermore, prior to complex I inhibition, an enhancement of complex II activity was observed, suggesting the occurrence of some compensatory effect. Overall our findings provide a mechanistic insight on the mitochondrial toxicity mediated by MPP+, relevant for the standardization of studies that employ this neurotoxin as a disease model.

Nrf2/Wnt resilience orchestrates rejuvenation of glia-neuron dialogue in Parkinson's disease.

Oxidative stress and inflammation have long been recognized to contribute to Parkinson's disease (PD), a common movement disorder characterized by the selective loss of midbrain dopaminergic neurons (mDAn) of the substantia nigra pars compacta (SNpc). The causes and mechanisms still remain elusive, but a complex interplay between several genes and a number of interconnected environmental factors, are chiefly involved in mDAn demise, as they intersect the key cellular functions affected in PD, such as the inflammatory response, mitochondrial, lysosomal, proteosomal and autophagic functions. Nuclear factor erythroid 2 -like 2 (NFE2L2/Nrf2), the master regulator of cellular defense against oxidative stress and inflammation, and Wingless (Wnt)/ß-catenin signaling cascade, a vital pathway for mDAn neurogenesis and neuroprotection, emerge as critical intertwinned actors in mDAn physiopathology, as a decline of an Nrf2/Wnt/ß-catenin prosurvival axis with age underlying PD mutations and a variety of noxious environmental exposures drive PD neurodegeneration. Unexpectedly, astrocytes, the so-called "star-shaped" cells, harbouring an arsenal of "beneficial" and "harmful" molecules represent the turning point in the physiopathological and therapeutical scenario of PD. Fascinatingly, "astrocyte's fil rouge" brings back to Nrf2/Wnt resilience, as boosting the Nrf2/Wnt resilience program rejuvenates astrocytes, in turn (i) mitigating nigrostriatal degeneration of aged mice, (ii) reactivating neural stem progenitor cell proliferation and neuron differentiation in the brain and (iii) promoting a beneficial immunomodulation via bidirectional communication with mDAns. Then, through resilience of Nrf2/Wnt/ß-catenin anti-ageing, prosurvival and proregenerative molecular programs, it seems possible to boost the inherent endogenous self-repair mechanisms. Here, the cellular and molecular aspects as well as the therapeutical options for rejuvenating glia-neuron dialogue will be discussed together with major glial-derived mechanisms and therapies that will be fundamental to the identification of novel diagnostic tools and treatments for neurodegenerative diseases (NDs), to fight ageing and nigrostriatal DAergic degeneration and promote functional recovery.

Mastering the Tools: Natural versus Artificial Vesicles in Nanomedicine.

Naturally occurring extracellular vesicles and artificially made vesicles represent important tools in nanomedicine for the efficient delivery of biomolecules and drugs. Since its first appearance in the literature 50 years ago, the research on vesicles is progressing at a fast pace, with the main goal of developing carriers able to protect cargoes from degradation, as well as to deliver them in a time- and space-controlled fashion. While natural occurring vesicles have the advantage of being fully compatible with their host, artificial vesicles can be easily synthetized and functionalized according to the target to reach. Research is striving to merge the advantages of natural and artificial vesicles, in order to provide a new generation of highly performing vesicles, which would improve the therapeutic index of transported molecules. This progress report summarizes current manufacturing techniques used to produce both natural and artificial vesicles, exploring the promises and pitfalls of the different production processes. Finally, pros and cons of natural versus artificial vesicles are discussed and compared, with special regard toward the current applications of both kinds of vesicles in the healthcare field.

Extracellular Vesicles as Nanotherapeutics for Parkinson's Disease.

Extracellular vesicles (EVs) are naturally occurring membranous structures secreted by normal and diseased cells, and carrying a wide range of bioactive molecules. In the central nervous system (CNS), EVs are important in both homeostasis and pathology. Through receptor-ligand interactions, direct fusion, or endocytosis, EVs interact with their target cells. Accumulating evidence indicates that EVs play crucial roles in the pathogenesis of many neurodegenerative disorders (NDs), including Parkinson's disease (PD). PD is the second most common ND, characterized by the progressive loss of dopaminergic (DAergic) neurons within the Substantia Nigra pars compacta (SNpc). In PD, EVs are secreted by both neurons and glial cells, with either beneficial or detrimental effects, via a complex program of cell-to-cell communication. The functions of EVs in PD range from their etiopathogenetic relevance to their use as diagnostic tools and innovative carriers of therapeutics. Because they can cross the blood-brain barrier, EVs can be engineered to deliver bioactive molecules (e.g., small interfering RNAs, catalase) within the CNS. This review summarizes the latest findings regarding the role played by EVs in PD etiology, diagnosis, prognosis, and therapy, with a particular focus on their use as novel PD nanotherapeutics.

Glia-Derived Extracellular Vesicles in Parkinson's Disease.

Glial cells are fundamental players in the central nervous system (CNS) development and homeostasis, both in health and disease states. In Parkinson's disease (PD), a dysfunctional glia-neuron crosstalk represents a common final pathway contributing to the chronic and progressive death of dopaminergic (DAergic) neurons of the substantia nigra pars compacta (SNpc). Notably, glial cells communicating with each other by an array of molecules, can acquire a "beneficial" or "destructive" phenotype, thereby enhancing neuronal death/vulnerability and/or exerting critical neuroprotective and neuroreparative functions, with mechanisms that are actively investigated. An important way of delivering messenger molecules within this glia-neuron cross-talk consists in the secretion of extracellular vesicles (EVs). EVs are nano-sized membranous particles able to convey a wide range of molecular cargoes in a controlled way, depending on the specific donor cell and the microenvironmental milieu. Given the dual role of glia in PD, glia-derived EVs may deliver molecules carrying various messages for the vulnerable/dysfunctional DAergic neurons. Here, we summarize the state-of-the-art of glial-neuron interactions and glia-derived EVs in PD. Also, EVs have the ability to cross the blood brain barrier (BBB), thus acting both within the CNS and outside, in the periphery. In these regards, this review discloses the emerging applications of EVs, with a special focus on glia-derived EVs as potential carriers of new biomarkers and nanotherapeutics for PD.

Boosting Antioxidant Self-defenses by Grafting Astrocytes Rejuvenates the Aged Microenvironment and Mitigates Nigrostriatal Toxicity in Parkinsonian Brain via an Nrf2-Driven Wnt/ß-Catenin Prosurvival Axis.

Astrocyte (As) bidirectional dialog with neurons plays a fundamental role in major homeostatic brain functions, particularly providing metabolic support and antioxidant self-defense against reactive oxygen (ROS) and nitrogen species (RNS) via the activation of NF-E2-related factor 2 (Nrf2), a master regulator of oxidative stress. Disruption of As-neuron crosstalk is chiefly involved in neuronal degeneration observed in Parkinson's disease (PD), the most common movement disorder characterized by the selective degeneration of dopaminergic (DAergic) cell bodies of the substantia nigra (SN) pars compacta (SNpc). Ventral midbrain (VM)-As are recognized to exert an important role in DAergic neuroprotection via the expression of a variety of factors, including wingless-related MMTV integration site 1 (Wnt1), a principal player in DAergic neurogenesis. However, whether As, by themselves, might fulfill the role of chief players in DAergic neurorestoration of aged PD mice is presently unresolved. Here, we used primary postnatal mouse VM-As as a graft source for unilateral transplantation above the SN of aged 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mice after the onset of motor symptoms. Spatio-temporal analyses documented that the engrafted cells promoted: (i) a time-dependent nigrostriatal rescue along with increased high-affinity synaptosomal DA uptake and counteraction of motor deficit, as compared to mock-grafted counterparts; and (ii) a restoration of the impaired microenvironment via upregulation of As antioxidant self-defense through the activation of Nrf2/Wnt/ß-catenin signaling, suggesting that grafting As has the potential to switch the SN neurorescue-unfriendly environment to a beneficial antioxidant/anti-inflammatory prosurvival milieu. These findings highlight As-derived factors/mechanisms as the crucial key for successful therapeutic outcomes in PD.

Parkinson's disease, aging and adult neurogenesis: Wnt/ß-catenin signalling as the key to unlock the mystery of endogenous brain repair.

A common hallmark of age-dependent neurodegenerative diseases is an impairment of adult neurogenesis. Wingless-type mouse mammary tumor virus integration site (Wnt)/ß-catenin (WßC) signalling is a vital pathway for dopaminergic (DAergic) neurogenesis and an essential signalling system during embryonic development and aging, the most critical risk factor for Parkinson's disease (PD). To date, there is no known cause or cure for PD. Here we focus on the potential to reawaken the impaired neurogenic niches to rejuvenate and repair the aged PD brain. Specifically, we highlight WßC-signalling in the plasticity of the subventricular zone (SVZ), the largest germinal region in the mature brain innervated by nigrostriatal DAergic terminals, and the mesencephalic aqueduct-periventricular region (Aq-PVR) Wnt-sensitive niche, which is in proximity to the SNpc and harbors neural stem progenitor cells (NSCs) with DAergic potential. The hallmark of the WßC pathway is the cytosolic accumulation of ß-catenin, which enters the nucleus and associates with T cell factor/lymphoid enhancer binding factor (TCF/LEF) transcription factors, leading to the transcription of Wnt target genes. Here, we underscore the dynamic interplay between DAergic innervation and astroglial-derived factors regulating WßC-dependent transcription of key genes orchestrating NSC proliferation, survival, migration and differentiation. Aging, inflammation and oxidative stress synergize with neurotoxin exposure in "turning off" the WßC neurogenic switch via down-regulation of the nuclear factor erythroid-2-related factor 2/Wnt-regulated signalosome, a key player in the maintenance of antioxidant self-defense mechanisms and NSC homeostasis. Harnessing WßC-signalling in the aged PD brain can thus restore neurogenesis, rejuvenate the microenvironment, and promote neurorescue and regeneration.

Wnt/ß-Catenin Signaling Pathway Governs a Full Program for Dopaminergic Neuron Survival, Neurorescue and Regeneration in the MPTP Mouse Model of Parkinson's Disease.

Wingless-type mouse mammary tumor virus (MMTV) integration site (Wnt) signaling is one of the most critical pathways in developing and adult tissues. In the brain, Wnt signaling contributes to different neurodevelopmental aspects ranging from differentiation to axonal extension, synapse formation, neurogenesis, and neuroprotection. Canonical Wnt signaling is mediated mainly by the multifunctional ß-catenin protein which is a potent co-activator of transcription factors such as lymphoid enhancer factor (LEF) and T-cell factor (TCF). Accumulating evidence points to dysregulation of Wnt/ß-catenin signaling in major neurodegenerative disorders. This review highlights a Wnt/ß-catenin/glial connection in Parkinson's disease (PD), the most common movement disorder characterized by the selective death of midbrain dopaminergic (mDAergic) neuronal cell bodies in the subtantia nigra pars compacta (SNpc) and gliosis. Major findings of the last decade document that Wnt/ß-catenin signaling in partnership with glial cells is critically involved in each step and at every level in the regulation of nigrostriatal DAergic neuronal health, protection, and regeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD, focusing on Wnt/ß-catenin signaling to boost a full neurorestorative program in PD.

Neural Stem Cell Grafts Promote Astroglia-Driven Neurorestoration in the Aged Parkinsonian Brain via Wnt/ß-Catenin Signaling.

During aging-one the most potent risk factors for Parkinson's disease (PD)-both astrocytes and microglia undergo functional changes that ultimately hamper homoeostasis, defense, and repair of substantia nigra pars compacta (SNpc) midbrain dopaminergic (mDA) neurons. We tested the possibility of rejuvenating the host microenvironment and boosting SNpc DA neuronal plasticity via the unilateral transplantation of syngeneic neural stem/progenitor cells (NSCs) in the SNpc of aged mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced experimental PD. Transplanted NSCs within the aged SNpc engrafted and migrated in large proportions to the tegmental aqueduct mDA niche, with 30% acquiring an astroglial phenotype. Both graft-derived exogenous (ex-Astro) and endogenous astrocytes (en-Astro) expressed Wnt1. Both ex-Astro and en-Astro were key triggers of Wnt/ß-catenin signaling in SNpc-mDA neurons and microglia, which was associated with mDA neurorescue and immunomodulation. At the aqueduct-ventral tegmental area level, NSC grafts recapitulated a genetic Wnt1-dependent mDA developmental program, inciting the acquisition of a mature Nurr1+ TH+ neuronal phenotype. Wnt/ß-catenin signaling antagonism abolished mDA neurorestoration and immune modulatory effects of NSC grafts. Our work implicates an unprecedented therapeutic potential for somatic NSC grafts in the restoration of mDA neuronal function in the aged Parkinsonian brain. Stem Cells 2018;36:1179-1197.

Microglia Polarization, Gene-Environment Interactions and Wnt/ß-Catenin Signaling: Emerging Roles of Glia-Neuron and Glia-Stem/Neuroprogenitor Crosstalk for Dopaminergic Neurorestoration in Aged Parkinsonian Brain.

Neuroinflammatory processes are recognized key contributory factors in Parkinson's disease (PD) physiopathology. While the causes responsible for the progressive loss of midbrain dopaminergic (mDA) neuronal cell bodies in the subtantia nigra pars compacta are poorly understood, aging, genetics, environmental toxicity, and particularly inflammation, represent prominent etiological factors in PD development. Especially, reactive astrocytes, microglial cells, and infiltrating monocyte-derived macrophages play dual beneficial/harmful effects, via a panel of pro- or anti-inflammatory cytokines, chemokines, neurotrophic and neurogenic transcription factors. Notably, with age, microglia may adopt a potent neurotoxic, pro-inflammatory "primed" (M1) phenotype when challenged with inflammatory or neurotoxic stimuli that hamper brain's own restorative potential and inhibit endogenous neurorepair mechanisms. In the last decade we have provided evidence for a major role of microglial crosstalk with astrocytes, mDA neurons and neural stem progenitor cells (NSCs) in the MPTP- (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-) mouse model of PD, and identified Wnt/ß-catenin signaling, a pivotal morphogen for mDA neurodevelopment, neuroprotection, and neuroinflammatory modulation, as a critical actor in glia-neuron and glia-NSCs crosstalk. With age however, Wnt signaling and glia-NSC-neuron crosstalk become dysfunctional with harmful consequences for mDA neuron plasticity and repair. These findings are of importance given the deregulation of Wnt signaling in PD and the emerging link between most PD related genes, Wnt signaling and inflammation. Especially, in light of the expanding field of microRNAs and inflammatory PD-related genes as modulators of microglial-proinflammatory status, uncovering the complex molecular circuitry linking PD and neuroinflammation will permit the identification of new druggable targets for the cure of the disease. Here we summarize recent findings unveiling major microglial inflammatory and oxidative stress pathways converging in the regulation of Wnt/ß-catenin signaling, and reciprocally, the ability of Wnt signaling pathways to modulate microglial activation in PD. Unraveling the key factors and conditons promoting the switch of the proinflammatory M1 microglia status into a neuroprotective and regenerative M2 phenotype will have important consequences for neuroimmune interactions and neuronal outcome under inflammatory and/or neurodegenerative conditions.

Wnt3a promotes pro-angiogenic features in macrophages in vitro: Implications for stroke pathology.

Wnt3a is implicated in several key cellular processes and its expression has been reported in different cell types. Here, we report a novel function for Wnt3a in macrophages, whose exposure to this ligand shifts them towards a pro-angiogenic phenotype capable, under oxygen and glucose deprivation, of inducing in vitro tubular pattern structures in endothelial cells resembling capillary-like vasculature. These newly acquired angiogenetic features also include increased proliferation and migration and surprisingly, an increase in cell death. This work provides a new link between Wnt3a and macrophage-mediated angiogenesis under glucose and oxygen deprivation in vitro, which are worth further investigation in pathological conditions including stroke, where the stimulation of the angiogenic process might help to recovery after tissue injury Impact statement This work provides a new link between Wnt3a and macrophage-mediated angiogenesis under glucose and oxygen deprivation in vitro. Our results reveal how Wnt3a shifts macrophages towards a pro-angiogenic phenotype, which is able-in absence of both glucose and oxygen-of inducing angiogenesis in vitro, thus pointing to a synergy between the activation of the pathway and the hypoxia scenario. This work also demonstrates that modulation of cell death is key in order to explain the observed angiogenic effects. We consider all these findings of significant importance, since no connection between Wnt3a, macrophages, and angiogenesis has been established so far. Furthermore, we do believe that this work provides new and interesting results, with Wnt signaling pathway emerging as an interesting target mediating beneficial outcomes during the inflammatory response undoubtedly linked to stroke pathology, where angiogenesis has been already proposed as a potential mechanism to promote recovery after the injury.

microRNAs in Parkinson's Disease: From Pathogenesis to Novel Diagnostic and Therapeutic Approaches.

Parkinson's disease (PD) is the most prevalent central nervous system (CNS) movement disorder and the second most common neurodegenerative disease overall. PD is characterized by the progressive loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc) within the midbrain, accumulation of alpha-synuclein (α-SYN) in Lewy bodies and neurites and excessive neuroinflammation. The neurodegenerative processes typically begin decades before the appearance of clinical symptoms. Therefore, the diagnosis is achievable only when the majority of the relevant DAergic neurons have already died and for that reason available treatments are only palliative at best. The causes and mechanism(s) of this devastating disease are ill-defined but complex interactions between genetic susceptibility and environmental factors are considered major contributors to the etiology of PD. In addition to the role of classical gene mutations in PD, the importance of regulatory elements modulating gene expression has been increasingly recognized. One example is the critical role played by microRNAs (miRNAs) in the development and homeostasis of distinct populations of neurons within the CNS and, in particular, in the context of PD. Recent reports demonstrate how distinct miRNAs are involved in the regulation of PD genes, whereas profiling approaches are unveiling variations in the abundance of certain miRNAs possibly relevant either to the onset or to the progression of the disease. In this review, we provide an overview of the miRNAs recently found to be implicated in PD etiology, with particular focus on their potential relevance as PD biomarkers, as well as their possible use in PD targeted therapy.

The role of the immune system in central nervous system plasticity after acute injury.

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.

Wnt/ß-catenin signaling is required to rescue midbrain dopaminergic progenitors and promote neurorepair in ageing mouse model of Parkinson's disease.

Wnt/ß-catenin signaling is required for specification and neurogenesis of midbrain dopaminergic (mDA) neurons, the pivotal neuronal population that degenerates in Parkinson's disease (PD), and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Wnt/ß-catenin signaling plays a vital role in adult neurogenesis but whether it might engage DA neurogenesis/neurorepair in the affected PD brain is yet unresolved. Recently, the adult midbrain aqueduct periventricular regions (Aq-PVRs) were shown to harbor multipotent clonogenic neural stem/progenitor cells (mNPCs) with DA potential in vitro, but restrictive mechanisms in vivo are believed to limit their DA regenerative capacity. Using in vitro mNPC culture systems we herein demonstrate that aging is one most critical factor restricting mNPC neurogenic potential via dysregulation of Wnt/ß-catenin signaling. Coculture paradigms between young/aged (Y/A) mNPCs and Y/A astrocytes identified glial age and a decline of glial-derived factors including Wnts as key determinants of impaired neurogenic potential, whereas Wnt activation regimens efficiently reversed the diminished proliferative, neuronal, and DA differentiation potential of A-mNPCs. Next, in vivo studies in wild (Wt) and transgenic ß-catenin reporter mice uncovered Wnt/ß-catenin signaling activation and remarkable astrocyte remodeling of Aq-PVR in response to MPTP-induced DA neuron death. Spatio-temporal analyses unveiled ß-catenin signaling in predopaminergic (Nurr1(+)/TH(-)) and imperiled or rescuing DAT(+) neurons during MPTP-induced DA neuron injury and self-repair. Aging inhibited Wnt signaling, whereas ß-catenin activation in situ with a specific GSK-3ß antagonist promoted a significant degree of DA neurorestoration associated with reversal of motor deficit, with implications for neurorestorative approaches in PD.

Targeting Wnt signaling at the neuroimmune interface for dopaminergic neuroprotection/repair in Parkinson's disease.

During the past three decades, the Wingless-type MMTV integration site (Wnt) signaling cascade has emerged as an essential system regulating multiple processes in developing and adult brain. Accumulating evidence points to a dysregulation of Wnt signaling in major neurodegenerative pathologies including Parkinson's disease (PD), a common neurodegenerative disorder characterized by the progressive loss of midbrain dopaminergic (mDA) neurons and deregulated activation of astrocytes and microglia. This review highlights the emerging link between Wnt signaling and key inflammatory pathways during mDA neuron damage/repair in PD progression. In particular, we summarize recent evidence documenting that aging and neurotoxicant exposure strongly antagonize Wnt/ß-catenin signaling in mDA neurons and subventricular zone (SVZ) neuroprogenitors via astrocyte-microglial interactions. Dysregulation of the crosstalk between Wnt/ß-catenin signaling and anti-oxidant/anti-inflammatory pathways delineate novel mechanisms driving the decline of SVZ plasticity with age and the limited nigrostriatal dopaminergic self-repair in PD. These findings hold a promise in developing therapies that target Wnt/ß-catenin signaling to enhance endogenous restoration and neuronal outcome in age-dependent diseases, such as PD.

Reactive astrocytes are key players in nigrostriatal dopaminergic neurorepair in the MPTP mouse model of Parkinson's disease: focus on endogenous neurorestoration.

Parkinsons'disease (PD), a common neurodegenerative disorder, is characterized by progressive loss of dopaminergic (DAergic) neurons in the subtantia nigra pars compacta (SNpc) and gliosis. The cause and mechanisms underlying the demise of nigrostriatal DAergic neurons are not completely clarified, but interactions between genes and environmental factors are recognized to play a critical role in modulating the vulnerability to PD. Current evidence points to reactive glia as a pivotal factor in PD, but whether astroglia activation may protect or exacerbate DAergic neuron loss is presently the subject of much debate. Astrocytes and microglia are the key players in neuroinflammatory responses, by secreting an array of pro- and anti-inflammatory cytokines, anti-oxidant and neurotrophic factors. Here, the contribution of astrocytes and their ability to influence DAergic neurodegeneration, neuroprotection and neurorepair will be discussed. In particular, the dynamic interplay between astrocyte-derived factors and neurogenic signals in MPTP-induced plasticity of nigrostriatal DAergic neurons will be summarized together with recent findings showing that reactive astrocytes may contribute to promote DAergic neurogenesis from midbrain adult neural stem/precursor cells (NPCs). Within a host of astrocyte- derived factors, we unveiled Wingless-type MMTV integration site (Wnt)/ß-catenin signalling was unveiled, as a strong candidate in MPTP-induced DAergic neuroplasticty/neurorepair. Understanding the intrinsic plasticity of nigrostriatal DAergic neurons and decifering the signals facilitating the crosstalk between astrocytes and midbrain neuroprogenitors may have implications for the role of stem cells technology in PD and for identifying potential therapeutic targets to promote endogenous neurorepair.