Iron and Ferroptosis More than a Suspect: Beyond the Most Common Mechanisms of Neurodegeneration for New Therapeutic Approaches to Cognitive Decline and Dementia.

Neurodegeneration is a multifactorial process that involves multiple mechanisms. Examples of neurodegenerative diseases are Parkinson's disease, multiple sclerosis, Alzheimer's disease, prion diseases such as Creutzfeldt-Jakob's disease, and amyotrophic lateral sclerosis. These are progressive and irreversible pathologies, characterized by neuron vulnerability, loss of structure or function of neurons, and even neuron demise in the brain, leading to clinical, functional, and cognitive dysfunction and movement disorders. However, iron overload can cause neurodegeneration. Dysregulation of iron metabolism associated with cellular damage and oxidative stress is reported as a common event in several neurodegenerative diseases. Uncontrolled oxidation of membrane fatty acids triggers a programmed cell death involving iron, ROS, and ferroptosis, promoting cell death. In Alzheimer's disease, the iron content in the brain is significantly increased in vulnerable regions, resulting in a lack of antioxidant defenses and mitochondrial alterations. Iron interacts with glucose metabolism reciprocally. Overall, iron metabolism and accumulation and ferroptosis play a significant role, particularly in the context of diabetes-induced cognitive decline. Iron chelators improve cognitive performance, meaning that brain iron metabolism control reduces neuronal ferroptosis, promising a novel therapeutic approach to cognitive impairment.

Matrix metalloproteinases, purinergic signaling, and epigenetics: hubs in the spinal neuroglial network following peripheral nerve injury.

Activation of glial cells (reactive gliosis) and the purinergic pathway, together with metalloproteinase (MMP)-induced remodeling of the neural extracellular matrix (nECM), drive maladaptive changes in the spinal cord following peripheral nerve injury (PNI). We evaluated the effects on spinal maladaptive plasticity through administration of oxidized ATP (oxATP), an antagonist of P2X receptors (P2XR), and/or GM6001, an inhibitor of MMPs, in rats following spared nerve injury (SNI) of the sciatic nerve. With morpho-molecular techniques, we demonstrated a reduction in spinal reactive gliosis and changes in the neuro-glial-nECM crosstalk via expression remodeling of P2XR, nerve growth factor (NGF) receptors (TrkA and p75), and histone deacetylase 2 (HDAC2) after treatments with oxATP/GM6001. Altogether, our data suggest that MMPs and purinergic inhibition have a modulatory impact on key proteins in the neuro-glial-nECM network, acting at different levels from intracellular signaling to epigenetic modifications.

The Spatiotemporal Coupling: Regional Energy Failure and Aberrant Proteins in Neurodegenerative Diseases.

The spatial and temporal coordination of each element is a pivotal characteristic of systems, and the central nervous system (CNS) is not an exception. Glial elements and the vascular interface have been considered more recently, together with the extracellular matrix and the immune system. However, the knowledge of the single-element configuration is not sufficient to predict physiological or pathological long-lasting changes. Ionic currents, complex molecular cascades, genomic rearrangement, and the regional energy demand can be different even in neighboring cells of the same phenotype, and their differential expression could explain the region-specific progression of the most studied neurodegenerative diseases. We here reviewed the main nodes and edges of the system, which could be studied to develop a comprehensive knowledge of CNS plasticity from the neurovascular unit to the synaptic cleft. The future goal is to redefine the modeling of synaptic plasticity and achieve a better understanding of neurological diseases, pointing out cellular, subcellular, and molecular components that couple in specific neuroanatomical and functional regions.

Neurons, Glia, Extracellular Matrix and Neurovascular Unit: A Systems Biology Approach to the Complexity of Synaptic Plasticity in Health and Disease.

The synaptic cleft has been vastly investigated in the last decades, leading to a novel and fascinating model of the functional and structural modifications linked to synaptic transmission and brain processing. The classic neurocentric model encompassing the neuronal pre- and post-synaptic terminals partly explains the fine-tuned plastic modifications under both pathological and physiological circumstances. Recent experimental evidence has incontrovertibly added oligodendrocytes, astrocytes, and microglia as pivotal elements for synapse formation and remodeling (tripartite synapse) in both the developing and adult brain. Moreover, synaptic plasticity and its pathological counterpart (maladaptive plasticity) have shown a deep connection with other molecular elements of the extracellular matrix (ECM), once considered as a mere extracellular structural scaffold altogether with the cellular glue (i.e., glia). The ECM adds another level of complexity to the modern model of the synapse, particularly, for the long-term plasticity and circuit maintenance. This model, called tetrapartite synapse, can be further implemented by including the neurovascular unit (NVU) and the immune system. Although they were considered so far as tightly separated from the central nervous system (CNS) plasticity, at least in physiological conditions, recent evidence endorsed these elements as structural and paramount actors in synaptic plasticity. This scenario is, as far as speculations and evidence have shown, a consistent model for both adaptive and maladaptive plasticity. However, a comprehensive understanding of brain processes and circuitry complexity is still lacking. Here we propose that a better interpretation of the CNS complexity can be granted by a systems biology approach through the construction of predictive molecular models that enable to enlighten the regulatory logic of the complex molecular networks underlying brain function in health and disease, thus opening the way to more effective treatments.

Roadmap for Stroke: Challenging the Role of the Neuronal Extracellular Matrix.

Stroke is a major challenge in modern medicine and understanding the role of the neuronal extracellular matrix (NECM) in its pathophysiology is fundamental for promoting brain repair. Currently, stroke research is focused on the neurovascular unit (NVU). Impairment of the NVU leads to neuronal loss through post-ischemic and reperfusion injuries, as well as coagulatory and inflammatory processes. The ictal core is produced in a few minutes by the high metabolic demand of the central nervous system. Uncontrolled or prolonged inflammatory response is characterized by leukocyte infiltration of the injured site that is limited by astroglial reaction. The metabolic failure reshapes the NECM through matrix metalloproteinases (MMPs) and novel deposition of structural proteins continues within months of the acute event. These maladaptive reparative processes are responsible for the neurological clinical phenotype. In this review, we aim to provide a systems biology approach to stroke pathophysiology, relating the injury to the NVU with the pervasive metabolic failure, inflammatory response and modifications of the NECM. The available data will be used to build a protein-protein interaction (PPI) map starting with 38 proteins involved in stroke pathophysiology, taking into account the timeline of damage and the co-expression scores of their RNA patterns The application of the proposed network could lead to a more accurate design of translational experiments aiming at improving both the therapy and the rehabilitation processes.

Astrocytes and Microglia-Mediated Immune Response in Maladaptive Plasticity is Differently Modulated by NGF in the Ventral Horn of the Spinal Cord Following Peripheral Nerve Injury.

Reactive astrocytes and activated microglia are the key players in several pathophysiologic modifications of the central nervous system. We used the spared nerve injury (SNI) of the sciatic nerve to induce glial maladaptive response in the ventral horn of lumbar spinal cord and examine its role in the remodeling of the tripartite synapse plasticity. Imaging the ventral horn revealed that SNI was associated with both an early microglial and astrocytic activation, assessed, respectively, by analysis of Iba1 and GFAP expression. Microglia, in particular, localized peculiarly surrounding the motor neurons somata. Perineuronal astrocytes, which play a key role in maintaining the homeostasis of neuronal circuitry, underwent a substantial phenotypic change following peripheral axotomy, producing reactive gliosis. The gliosis was associated with the reduction of glial aminoacid transporters (GLT1 and GlyT1) and increase of neuronal glutamate transporter EAAC1. Although the expression of GABAergic neuronal marker GAD65/67 showed no change, glutamate increase, as demonstrated by HPLC analysis, shifted the excitatory/inhibitory balance as showed by the net increase of the glutamate/GABA ratio. Moreover, endogenous NGF levels were altered in SNI animals and not restored by the intrathecal NGF administration. This treatment reverted phenotypic changes associated with reactive astrocytosis, but failed to modify microglia activation. These findings on one hand confirm the correlation between gliopathy and maladaptive plasticity of the spinal synaptic circuitry, on the other hand add new data concerning the complex peculiar behavior of different glial cells in neuronal degenerative processes, defining a special role of microglia in sustaining the inflammatory response.

Microglia-Induced Maladaptive Plasticity Can Be Modulated by Neuropeptides In Vivo.

Microglia-induced maladaptive plasticity is being recognized as a major cause of deleterious self-sustaining pathological processes that occur in neurodegenerative and neuroinflammatory diseases. Microglia, the primary homeostatic guardian of the central nervous system, exert critical functions both during development, in neural circuit reshaping, and during adult life, in the brain physiological and pathological surveillance. This delicate critical role can be disrupted by neural, but also peripheral, noxious stimuli that can prime microglia to become overreactive to a second noxious stimulus or worsen underlying pathological processes. Among regulators of microglia, neuropeptides can play a major role. Their receptors are widely expressed in microglial cells and neuropeptide challenge can potently influence microglial activity in vitro. More relevantly, this regulator activity has been assessed also in vivo, in experimental models of brain diseases. Neuropeptide action in the central nervous system has been associated with beneficial effects in neurodegenerative and neuroinflammatory pathological experimental models. This review describes some of the mechanisms of the microglia maladaptive plasticity in vivo and how neuropeptide activity can represent a useful therapeutical target in a variety of human brain pathologies.

Fusion-fission-mitophagy cycling and metabolic reprogramming coordinate nerve growth factor (NGF)-dependent neuronal differentiation.

Neuronal differentiation is regulated by nerve growth factor (NGF) and other neurotrophins. We explored the impact of NGF on mitochondrial dynamics and metabolism through time-lapse imaging, metabolomics profiling, and computer modeling studies. We show that NGF may direct differentiation by stimulating fission, thereby causing selective mitochondrial network fragmentation and mitophagy, ultimately leading to increased mitochondrial quality and respiration. Then, we reconstructed the dynamic fusion-fission-mitophagy cycling of mitochondria in a computer model, integrating these processes into a single network mechanism. Both the computational model and the simulations are able to reproduce the proposed mechanism in terms of mitochondrial dynamics, levels of reactive oxygen species (ROS), mitophagy, and mitochondrial quality, thus providing a computational tool for the interpretation of the experimental data and for future studies aiming to detail further the action of NGF on mitochondrial processes. We also show that changes in these mitochondrial processes are intertwined with a metabolic function of NGF in differentiation: NGF directs a profound metabolic rearrangement involving glycolysis, TCA cycle, and the pentose phosphate pathway, altering the redox balance. This metabolic rewiring may ensure: (a) supply of both energy and building blocks for the anabolic processes needed for morphological reorganization, as well as (b) redox homeostasis.

Alzheimer's Disease from the Amyloidogenic Theory to the Puzzling Crossroads between Vascular, Metabolic and Energetic Maladaptive Plasticity.

Alzheimer's disease (AD) is a progressive and degenerative disease producing the most common type of dementia worldwide. The main pathogenetic hypothesis in recent decades has been the well-known amyloidogenic hypothesis based on the involvement of two proteins in AD pathogenesis: amyloid ß (Aß) and tau. Amyloid deposition reported in all AD patients is nowadays considered an independent risk factor for cognitive decline. Vascular damage and blood-brain barrier (BBB) failure in AD is considered a pivotal mechanism for brain injury, with increased deposition of both immunoglobulins and fibrin. Furthermore, BBB dysfunction could be an early sign of cognitive decline and the early stages of clinical AD. Vascular damage generates hypoperfusion and relative hypoxia in areas with high energy demand. Long-term hypoxia and the accumulation within the brain parenchyma of neurotoxic molecules could be seeds of a self-sustaining pathological progression. Cellular dysfunction comprises all the elements of the neurovascular unit (NVU) and neuronal loss, which could be the result of energy failure and mitochondrial impairment. Brain glucose metabolism is compromised, showing a specific region distribution. This energy deficit worsens throughout aging. Mild cognitive impairment has been reported to be associated with a glucose deficit in the entorhinal cortex and in the parietal lobes. The current aim is to understand the complex interactions between amyloid ß (Aß) and tau and elements of the BBB and NVU in the brain. This new approach aimed at the study of metabolic mechanisms and energy insufficiency due to mitochondrial impairment would allow us to define therapies aimed at predicting and slowing down the progression of AD.

Polystyrene micro and nano-particles induce metabolic rewiring in normal human colon cells: A risk factor for human health.

Polystyrene is a thermoplastic polymer widely used in commercial products. Like all plastics, polystyrene can be degraded into microplastic and nanoplastic particles and ingested via food chain contamination. Although the ecological impact due to plastic contamination is well known, there are no studies indicating a carcinogenic potential of polystyrene microplastics (MPs) and nanoplastics (NPs). Here, we evaluated the effects of the MPs and NPs on normal human intestinal CCD-18Co cells. Our results show that internalization of NPs and MPs induces metabolic changes under both acute and chronic exposure by inducing oxidative stress, increasing glycolysis via lactate to sustain energy metabolism and glutamine metabolism to sustain anabolic processes. We also show that this decoupling of nutrients mirrors the effect of the potent carcinogenic agent azoxymethane and HCT15 colon cancer cells, carrying out the typical strategy of cancer cells to optimize nutrients utilization and allowing metabolic adaptation to environmental stress conditions. Taken together our data provide new evidence that chronic NPs and MPs exposure could act as cancer risk factor for human health.

Reactive astrocytosis-induced perturbation of synaptic homeostasis is restored by nerve growth factor.

Reactive gliosis has been implicated in both inflammatory and neurodegenerative diseases. However, mechanisms by which astrocytic activation affects synaptic efficacy have been poorly elucidated. We have used the spared nerve injury (SNI) of the sciatic nerve to induce reactive astrocytosis in the lumbar spinal cord and investigate its potential role in disrupting the neuro-glial circuitry. Analysis of spinal cord sections revealed that SNI was associated with an increase of microglial (Iba1) and astrocytic (GFAP) markers. These changes, indicative of reactive gliosis, were paralleled by (i) a decrease of glial amino acid transporters (GLT1 and GlyT1) and increased levels of (ii) neuronal glutamate transporter EAAC1, (iii) neuronal vesicular GABA transporter (vGAT) and (iv) the GABAergic neuron marker GAD65/67. Besides the increase of Glutamate/GABA ratio, indicative of the perturbation of synaptic circuitry homeostasis, the boost of glutamate also compromised glial function in neuroprotection by up-regulating the xCT subunit of the glutamate-cystine antiport system and reducing glutathione (GSH) production. Finally, this study also shows that all these structural changes were linked to an alteration of endogenous NGF metabolism, as demonstrated by the decrease of endogenous NGF expression levels and increased activity of the NGF-degrading metalloproteinases. All the changes displayed by SNI-animals were reversed by a 7-days i.t. administration of NGF or GM6001, a generic metalloproteinase inhibitor, as compared to vehicle (ACSF)-treated animals. All together, these data strongly support the correlation between reactive astrogliosis and mechanisms underlying the perturbation of the synaptic circuitry in the SNI model of peripheral nerve injury, and the essential role of NGF in restoring both synaptic homeostasis and the neuroprotective function of glia.

Cross-talk between cell cycle induction and mitochondrial dysfunction during oxidative stress and nerve growth factor withdrawal in differentiated PC12 cells.

Neuronal death has been reported to involve mitochondrial dysfunction and cell cycle reentry. In this report, we used Nerve Growth Factor (NGF)-differentiated PC12 cells to investigate mechanisms linking mitochondrial dysfunction and cell cycle activation during neuronal death induced by NGF withdrawal and/or oxidative stress. We found that loss of survival following H(2) O(2) -induced oxidative stress or NGF deprivation was preceded by a decrease in mitochondrial membrane potential (ΔΨm), increase in reactive oxygen species (ROS), and up-regulation of cyclin D1 and phosphorylation (Ser-780) of protein retinoblastoma (P-pRb), without an increase of proliferation rates. Treatment with H(2) O(2) , but not NGF deprivation, also induced the phosporylation (Ser-10) of p27(kip1) and the appearance of a cleaved P-p27(kip1) fragment of about 15 kDa. The extent of cell cycle activation appeared to be inversely correlated to the duration of toxic stimuli (pulse/continuous). H(2) O(2) -induced mitogenic responses appeared to be mediated by induction of P-MAPK and P-Akt and were blocked by p38MAPK and JNK inhibitors as well as by the CDK inhibitor flavopiridol (Flav) and by sodium selenite (Sel), a component of selenoproteins, including glutathione peroxidases. Inhibition of p38MAPK and JNK, instead, did not affect cyclin D1 changes following NGF deprivation. Finally, both Flav hydrochloride and Sel partially prevented mitochondrial dysfunction and cell death following NGF withdrawal or H(2) O(2) toxicity, but not during oxidative stress in the absence of NGF. Taken together, these data suggest that H(2) O(2) -induced oxidative stress can determine distinct patterns of mitogenic responses as a function of mitochondrial dysfunction depending on 1) intensity/duration of stress stimuli and/or 2) presence of NGF.

Inhibition of plasminogen/plasmin system retrieves endogenous nerve growth factor and adaptive spinal synaptic plasticity following peripheral nerve injury.

Dysfunctions of the neuronal-glial crosstalk and/or impaired signaling of neurotrophic factors represent key features of the maladaptive changes in the central nervous system (CNS) in neuroinflammatory as neurodegenerative disorders. Tissue plasminogen activator (tPA)/plasminogen (PA)/plasmin system has been involved in either process of maturation and degradation of nerve growth factor (NGF), highlighting multiple potential targets for new therapeutic strategies. We here investigated the role of intrathecal (i.t.) delivery of neuroserpin (NS), an endogenous inhibitor of plasminogen activators, on neuropathic behavior and maladaptive synaptic plasticity in the rat spinal cord following spared nerve injury (SNI) of the sciatic nerve. We demonstrated that SNI reduced spinal NGF expression, induced spinal reactive gliosis, altering the expression of glial and neuronal glutamate and GABA transporters, reduced glutathione (GSH) levels and is associated to neuropathic behavior. Beside the increase of NGF expression, i.t. NS administration reduced reactive gliosis, restored synaptic homeostasis, GSH levels and reduced neuropathic behavior. Our results hereby highlight the essential role of tPA/PA system in the synaptic homeostasis and mechanisms of maladaptive plasticity, sustaining the beneficial effects of NGF-based approach in neurological disorders.

Transcriptomics and Metabolomics Integration Reveals Redox-Dependent Metabolic Rewiring in Breast Cancer Cells.

Rewiring glucose metabolism toward aerobic glycolysis provides cancer cells with a rapid generation of pyruvate, ATP, and NADH, while pyruvate oxidation to lactate guarantees refueling of oxidized NAD+ to sustain glycolysis. CtPB2, an NADH-dependent transcriptional co-regulator, has been proposed to work as an NADH sensor, linking metabolism to epigenetic transcriptional reprogramming. By integrating metabolomics and transcriptomics in a triple-negative human breast cancer cell line, we show that genetic and pharmacological down-regulation of CtBP2 strongly reduces cell proliferation by modulating the redox balance, nucleotide synthesis, ROS generation, and scavenging. Our data highlight the critical role of NADH in controlling the oncogene-dependent crosstalk between metabolism and the epigenetically mediated transcriptional program that sustains energetic and anabolic demands in cancer cells.

Intrathecal NGF administration reduces reactive astrocytosis and changes neurotrophin receptors expression pattern in a rat model of neuropathic pain.

Nerve growth factor (NGF), an essential peptide for sensory neurons, seems to have opposite effects when administered peripherally or directly to the central nervous system. We investigated the effects of 7-days intrathecal (i.t.) infusion of NGF on neuronal and glial spinal markers relevant to neuropathic behavior induced by chronic constriction injury (CCI) of the sciatic nerve. Allodynic and hyperalgesic behaviors were investigated by Von Frey and thermal Plantar tests, respectively. NGF-treated animals showed reduced allodynia and thermal hyperalgesia, compared to control animals. We evaluated on lumbar spinal cord the expression of microglial (ED-1), astrocytic (GFAP and S-100beta), and C- and Adelta-fibers (SubP, IB-4 and Cb) markers. I.t. NGF treatment reduced reactive astrocytosis and the density of SubP, IB4 and Cb positive fibers in the dorsal horn of injured animals. Morphometric parameters of proximal sciatic nerve stump fibers and cells in DRG were also analyzed in CCI rats: myelin thickness was reduced and DRG neurons and satellite cells appeared hypertrophic. I.t. NGF treatment showed a beneficial effect in reversing these molecular and morphological alterations. Finally, we analyzed by immunohistochemistry the expression pattern of neurotrophin receptors TrkA, pTrkA, TrkB and p75(NTR). Substantial alterations in neurotrophin receptors expression were observed in the spinal cord of CCI and NGF-treated animals. Our results indicate that i.t. NGF administration reverses the neuro-glial morphomolecular changes occurring in neuropathic animals paralleled by alterations in neurotrophin receptors ratio, and suggest that NGF is effective in restoring homeostatic conditions in the spinal cord and maintaining analgesia in neuropathic pain.

The Spinal Extracellular Matrix Modulates a Multi-level Protein Net and Epigenetic Inducers Following Peripheral Nerve Injury.

The extracellular matrix (ECM) of the central nervous system (CNS) plays a pivotal role in the pathogenesis of several neurodegenerative and neuroinflammatory disorders. Among the major factors, matrix metalloproteinases (MMPs) are actively involved in ECM remodeling and directly affect neuro-glial interactions. Since disease-related functional alterations mostly rely on the proteome, modulation of MMPs activity may be a strategy to correct mechanisms behind neurological disorders. We here investigated modifications of signaling components related to the central pathways in spinal maladaptive plasticity following spared nerve injury (SNI) of the sciatic nerve, and after treatment with the MMPs inhibitor GM6001 for 3 or 8 days. We found that GM6001 reduced the massive astrocytic and microglial activation indicative of reactive gliosis. Functional activity of GM6001 was paralleled by its significant effect on expression levels of the purinergic P2X4 receptor (P2X4R), the transcription factors NFκB and RPBJ, as well as levels of the nerve growth factor (NGF) receptor TrkA. Moreover, we showed that histone deacetylases 1 and 2 (HDAC1, HDAC2) were differentially modulated after SNI and GM6001 treatments for 3 or 8 days. Our data suggest a multi-level network of interactions across ECM and the neuroglial network involving MMPs, the neurotrophin system, intracellular signaling, and epigenetic modifications.

ROS networks: designs, aging, Parkinson's disease and precision therapies.

How the network around ROS protects against oxidative stress and Parkinson's disease (PD), and how processes at the minutes timescale cause disease and aging after decades, remains enigmatic. Challenging whether the ROS network is as complex as it seems, we built a fairly comprehensive version thereof which we disentangled into a hierarchy of only five simpler subnetworks each delivering one type of robustness. The comprehensive dynamic model described in vitro data sets from two independent laboratories. Notwithstanding its five-fold robustness, it exhibited a relatively sudden breakdown, after some 80 years of virtually steady performance: it predicted aging. PD-related conditions such as lack of DJ-1 protein or increased α-synuclein accelerated the collapse, while antioxidants or caffeine retarded it. Introducing a new concept (aging-time-control coefficient), we found that as many as 25 out of 57 molecular processes controlled aging. We identified new targets for "life-extending interventions": mitochondrial synthesis, KEAP1 degradation, and p62 metabolism.

Disruption of redox homeostasis for combinatorial drug efficacy in K-Ras tumors as revealed by metabolic connectivity profiling.

BACKGROUND: Rewiring of metabolism induced by oncogenic K-Ras in cancer cells involves both glucose and glutamine utilization sustaining enhanced, unrestricted growth. The development of effective anti-cancer treatments targeting metabolism may be facilitated by the identification and rational combinatorial targeting of metabolic pathways. METHODS: We performed mass spectrometric metabolomics analysis in vitro and in vivo experiments to evaluate the efficacy of drugs and identify metabolic connectivity. RESULTS: We show that K-Ras-mutant lung and colon cancer cells exhibit a distinct metabolic rewiring, the latter being more dependent on respiration. Combined treatment with the glutaminase inhibitor CB-839 and the PI3K/aldolase inhibitor NVP-BKM120 more consistently reduces cell growth of tumor xenografts. Maximal growth inhibition correlates with the disruption of redox homeostasis, involving loss of reduced glutathione regeneration, redox cofactors, and a decreased connectivity among metabolites primarily involved in nucleic acid metabolism. CONCLUSIONS: Our findings open the way to develop metabolic connectivity profiling as a tool for a selective strategy of combined drug repositioning in precision oncology.

A new nerve growth factor-mimetic peptide active on neuropathic pain in rats.

Analysis of the structure of nerve growth factor (NGF)-tyrosine kinase receptor A (TrkA) complex, site-directed mutagenesis studies and results from chemical modification of amino acid residues have identified loop 1, loop 4, and the N-terminal region of the NGF molecule as the most relevant for its biological activity. We synthesized several peptides mimicking the two loops (1 and 4) linked together with an appropriate spacer, with or without the N-terminal region. Two peptides named NL1L4 and L1L4 demonstrated good NGF agonist activity at a concentration as low as 3 mum. They induced differentiation of chick dorsal root ganglia and stimulated tyrosine phosphorylation of TrkA, but not TrkB, receptor. In addition L1L4 was able to induce differentiation of PC12 cells. More interestingly, the peptide with the highest "in vitro" activity (L1L4) was shown to reduce neuropathic behavior and restore neuronal function in a rat model of peripheral neuropathic pain, thereby suggesting a potential therapeutic role for this NGF-mimetic peptide.

Neural plasticity and adult neurogenesis: the deep biology perspective.

The recognition that neurogenesis does not stop with adolescence has spun off research towards the reduction of brain disorders by enhancing brain regeneration. Adult neurogenesis is one of the tougher problems of developmental biology as it requires the generation of complex intracellular and pericellular anatomies, amidst the danger of neuroinflammation. We here review how a multitude of regulatory pathways optimized for early neurogenesis has to be revamped into a new choreography of time dependencies. Distinct pathways need to be regulated, ranging from neural growth factor induced differentiation to mitochondrial bioenergetics, reactive oxygen metabolism, and apoptosis. Requiring much Gibbs energy consumption, brain depends on aerobic energy metabolism, hence on mitochondrial activity. Mitochondrial fission and fusion, movement and perhaps even mitoptosis, thereby come into play. All these network processes are interlinked and involve a plethora of molecules. We recommend a deep thinking approach to adult neurobiology.