Nerve growth factor (NGF) and pro-NGF increase low-density lipoprotein (LDL) receptors in neuronal cells partly by different mechanisms: role of LDL in neurite outgrowth.

Low-density lipoprotein receptors (LDLRs) mediate the uptake of lipoprotein particles into cells, as studied mainly in peripheral tissues. Here, we show that nerve growth factor (NGF) increases LDLR levels in PC6.3 cells and in cultured septal neurons from embryonic rat brain. Study of the mechanisms showed that NGF enhanced transcription of the LDLR gene, acting mainly via Tropomyosin receptor kinase A receptors. Simvastatin, a cholesterol-lowering drug, also increased the LDLR expression in PC6.3 cells. In addition, pro-NGF and pro-brain-derived neurotrophic factor, acting via the p75 neurotrophin receptor (p75NTR) also increased LDLRs. We further observed that Myosin Regulatory Light Chain-Interacting Protein/Inducible Degrader of the LDLR (Mylip/Idol) was down-regulated by pro-NGF, whereas the other LDLR regulator, proprotein convertase subtilisin kexin 9 (PCSK9) was not significantly changed. On the functional side, NGF and pro-NGF increased lipoprotein uptake by neuronal cells as shown using diacetyl-labeled LDL. The addition of serum-derived lipoprotein particles in conjunction with NGF or simvastatin enhanced neurite outgrowth. Collectively, these results show that NGF and simvastatin are able to stimulate lipoprotein uptake by neurons with a positive effect on neurite outgrowth. Increases in LDLRs and lipoprotein particles in neurons could play a functional role during brain development, in neuroregeneration and after brain injuries. Nerve growth factor (NGF) and pro-NGF induce the expression of low-density lipoprotein receptors (LDLRs) in neuronal cells leading to increased LDLR levels. Pro-NGF also down-regulated myosin regulatory light chain-interacting protein/inducible degrader of the LDLR (Mylip/Idol) that is involved in the degradation of LDLRs. NGF acts mainly via Tropomyosin receptor kinase A (TrkA) receptors, whereas pro-NGF stimulates p75 neurotrophin receptor (p75NTR). Elevated LDLRs upon NGF and pro-NGF treatments enhanced lipoprotein uptake by neurons. Addition of LDL particles further led to the stimulation of neurite outgrowth in PC6.3 cells after NGF or simvastatin treatments, suggesting a stimulatory role of lipoproteins on neuronal differentiation. In contrast, pro-NGF had no effect on neurite outgrowth either in the absence or presence of LDL particles. The precise mechanisms by which increased lipoproteins uptake can affect neurite outgrowth warrant further studies.

Exploring peripheral biomarkers in psychostimulant use: A systematic review on neurotrophins, stress-related hormones, oxidative stress molecules and genetic factors.

BACKGROUND: This systematic review aims to comprehensively explore the impact of psychostimulant substances on neurotrophic and inflammatory pathways, including brain-derived neurotrophic factor (BDNF), pro-BDNF, cortisol, dehydroepiandrosterone sulfate (DHEAS), thiobarbituric acid reactive substances (TBARS), interleukins, and the role of genetic factors. The study seeks to address existing gaps in the literature by providing a thorough evaluation of neurotrophic and inflammatory system alterations associated with different stages of psychostimulant dependence for a more nuanced understanding of substance use disorder (SUD) neurobiology. METHODS: A systematic review was conducted in PubMed, Scopus, and Web of Science databases following the PRISMA guidelines. The research encompasses 50 studies with a participant pool totaling 6792 individuals using psychostimulant substances. RESULTS: Key findings include diverse impacts of cocaine on BDNF levels, mainly consisting of their significant increase during withdrawal. In contrast, NGF showed an opposite behavior, reducing during withdrawal. Cortisol and DHEAS levels exhibited relevant increases after psychostimulant use, while TBARS showed conflicting results. Genetic investigations predominantly focused on the Val66Met polymorphism of the BDNF gene, revealing associations with susceptibility to stimulant addiction. CONCLUSIONS: Neurotrophins and inflammatory molecules play a significant role in the pathophysiological mechanisms following psychostimulant use. A better understanding of their complex interplay could aid clinicians in identifying biomarkers of different disease stages. Moreover, clinical interventions designed to interfere with neurotrophic and inflammatory pathways could possibly lead to craving-modulatory strategies and reduce pathological neuronal and systemic consequences of psychostimulant use.

Serum BDNF and pro-BDNF levels in alcohol use disorders according to depression status: An exploratory study of their evolution two months after withdrawal.

Background: Alcohol use disorders (AUDs) are complex pathologies with a myriad of molecular actors involved in both disease progression and remission. Brain-derived neurotrophic factor (BDNF) is suspected to be one such actor due to its neurotrophic effects. The BDNF precursor, pro-BDNF, has different effects, as it mainly promotes neuronal apoptosis. Both forms also play a role in depression and depressive episodes (DE). The aim of this exploratory study was to compare serum BDNF and pro-BDNF levels in patients with AUDs after withdrawal and according to DE status with those of controls without AUDs or DE. Materials and methods: Ninety-nine AUD patients and 40 controls were included. Questionnaires were used to assess both alcohol and psychiatric domains: the severity of hazardous alcohol consumption was assessed using Alcohol Use Disorders Identification Test (AUDIT), craving was assessed using Obsessive and Compulsive Drinking Scale (OCDS), anxiety was assessed with Hamilton Anxiety Rating Scale (HAM-A) and depression with Montgomery-Åsberg Depression Rating Scale (MADRS). Blood samples were collected during two visits: at the time of alcohol withdrawal (M0) and two months later (M2). ELISAs to measure serum BDNF and pro-BDNF levels were performed. AUD patients were categorized according to depression status at M2. Forty-five patients remained abstinent whereas 54 relapsed. BDNF serum levels rose after alcohol withdrawal, but pro-BDNF levels did not vary between M0 and M2. Results: AUD subjects without DE at M2 had higher BDNF levels at both M0 and M2 than AUD subjects with DE at M2. AUD subjects showed lower MADRS and OCD scores at M2 than at M0. AUD subjects without DE had lower BDNF levels at M0 than controls but not at M2, regardless of abstinence maintenance. Conclusion: BDNF serum levels were reduced in AUD patients compared to controls and were further reduced in patients with both AUDs and DE. Alcohol withdrawal treatment was sufficient to induce an increase in serum BDNF levels after 2 months, regardless of whether abstinence was maintained during this time period.

Morin improves learning and memory in healthy adult mice.

BACKGROUND: Morin is a flavonoid found in many edible fruits. The hippocampus and entorhinal cortex play crucial roles in memory formation and consolidation. This study aimed to characterize the effect of morin on recognition and space memory in healthy C57BL/6 adult mice and explore the underlying molecular mechanism. METHODS: Morin was administered i.p. at 1, 2.5, and 5 mg/kg/24 h for 10 days. The Morris water maze (MWM), novel object recognition, novel context recognition, and tasks were conducted 1 day after the last administration. The mice's brains underwent histological characterization, and their protein expression was examined using immunohistochemistry and Western blot techniques. RESULTS: In the MWM and novel object recognition tests, mice treated with 1 mg/kg of morin exhibited a significant recognition index increase compared to the control group. Besides, they demonstrated faster memory acquisition during MWM training. Additionally, the expression of pro-brain-derived neurotrophic factor (BDNF), BDNF, and postsynaptic density protein 95 proteins in the hippocampus of treated mice showed a significant increase. In the entorhinal cortex, only the pro-BDNF increased. Morin-treated mice exhibited a significant increase in the hippocampus's number and length of dendrites. CONCLUSION: This study shows that morin improves recognition memory and spatial memory in healthy adult mice.

BDNF, proBDNF and proBDNF/BDNF ratio with electroencephalographic abnormalities in children with attention deficit hyperactivity disorder: Possible relations to cognition and severity.

Attention deficit hyperactivity disorder (ADHD) with and without subclinical epileptogenic discharges (SED) have been suggested to negatively affect cognitive abilities of children with ADHD. The role of brain-derived neurotrophic factor (BDNF) and its precursor proBDNF in ADHD is in need of being investigated. The aims were to evaluate the levels of serum BDNF, proBDNF and the proBDNF/BDNF ratio in addition to the potential impacts of SED on the children's cognitive abilities and the severity of ADHD. The included participants with ADHD were 30 children with normal electroencephalogram (EEG) (G1) and 30 children with SED (G2), together with 30 healthy children (G3). The cognitive abilities and severity of the disorder were evaluated. The biochemical measures were determined by ELISA. The presence of coexisting SED and nocturnal enuresis has led to a deleterious effect on cognitive processes but not on the severity. The focal epileptogenic discharge was the most common among children in G2. The levels of BDNF in Groups 1 and 2 were less than those in G3. The higher proBDNF/BDNF ratio could be related to the low BDNF levels rather than high proBDNF levels. The findings of this study highlight the importance of investigating the presence of SED and nocturnal enuresis in children with ADHD. Targeting strengthening of cognitive abilities in children with coexisting ADHD and SED is advised. The role of proBDNF in the pathophysiology of ADHD needs further investigation.

BDNF and KISS-1 Levels in Maternal Serum, Umbilical Cord, and Placenta: The Potential Role of Maternal Levels as Effect Biomarker.

Brain-derived neurotrophic factor (BDNF) and kisspeptin-1 (KISS-1) regulate placental development and fetal growth. The predictive value of maternal serum BDNF and KISS-1 concentrations for placental and umbilical cord levels has not yet been explored. The influence of prenatal lead (Pb) and cadmium (Cd) exposure and maternal iron status on BDNF and KISS-1 levels is also unclarified and of concern. In a pilot cross-sectional study with 65 mother-newborn pairs, we analyzed maternal and cord serum levels of pro-BDNF, mature BDNF, and KISS-1, BDNF, and KISS-1 gene expression in placenta, Pb and Cd in maternal and umbilical cord blood (erythrocytes), and placenta. We conducted a series of in vitro experiments using human primary trophoblast cells (hTCs) and BeWo cells to verify main findings of the epidemiological analysis. Strong and consistent correlations were observed between maternal serum levels of pro-BDNF, mature BDNF, and KISS-1 and corresponding levels in umbilical serum and placental tissue. Maternal red blood cell Pb levels were inversely correlated with serum and placental KISS-1 levels. Lower expression and release of KISS-1 was also observed in Pb-exposed BeWo cells. In vitro Pb exposure also reduced cellular BDNF levels. Cd-treated BeWo cells showed increased pro-BDNF levels. Low maternal iron status was positively associated with low BDNF levels. Iron-deficient hTCs and BeWo cells showed a consistent decrease in the release of mature BDNF. The correlations between maternal BDNF and KISS-1 levels, placental gene expression, and umbilical cord serum levels, respectively, indicate the strong potential of maternal serum as predictive matrix for BDNF and KISS-1 levels in placentas and fetal sera. Pb exposure and iron status modulate BDNF and KISS-1 levels, but a clear direction of modulations was not evident. The associations need to be confirmed in a larger sample and validated in terms of placental and neurodevelopmental function. Supplementary Information: The online version contains supplementary material available at 10.1007/s12403-023-00565-w.

A Three-Fold Integrated Perspective on Healthy Development: An Opinion Paper.

Mental health and wellbeing are increasingly threatened in the current post-pandemic times, with stress, especially in students, reaching preoccupying levels. In addition, while many educational programs are unidimensional (i.e., lacking integration between physical, emotional and cognitive elements), there are ways to promote physical, social and mental health in children and adolescents. In this opinion paper, we will discuss the importance of an integrative approach for health development and examine relevant factors, such as awareness and emotional intelligence. We will highlight evidence ranging from behavioral to electrophysiological, structural and molecular, and report several recent studies supporting the effectiveness of a holistic approach in supporting wellbeing and creativity in children and adults, and detailing a specific paradigm named the Quadrato Motor Training (QMT). QMT is a specifically structured movement meditation, involving cognitive, motor and affective components. Finally, we will support a holistic view on education, integrating motion, emotion and cognition to develop a person-centered, or in this case student-centered, approach to wellbeing and health.

BDNF and Pro-BDNF in Amyotrophic Lateral Sclerosis: A New Perspective for Biomarkers of Neurodegeneration.

Amyotrophic Lateral Sclerosis (ALS) is characterized by the progressive degeneration of upper or lower motor neurons, leading to muscle wasting and paralysis, resulting in respiratory failure and death. The precise ALS aetiology is poorly understood, mainly due to clinical and genetic heterogeneity. Thus, the identification of reliable biomarkers of disease could be helpful in clinical practice. In this study, we investigated whether the levels of brain-derived neurotrophic factor (BDNF) and its precursor Pro-BDNF in serum and cerebrospinal fluid (CSF) may reflect the pathological changes related to ALS. We found higher BDNF and lower Pro-BDNF levels in ALS sera compared to healthy controls. BDNF/Pro-BDNF ratio turned out to be accurate in distinguishing ALS patients from controls. Then, the correlations of these markers with several ALS clinical variables were evaluated. This analysis revealed three statistically significant associations: (1) Patients carrying the C9orf72 expansion significantly differed from non-carrier patients and showed serum BDNF levels comparable to control subjects; (2) BDNF levels in CSF were significantly higher in ALS patients with faster disease progression; (3) lower serum levels of Pro-BDNF were associated with a shorter survival. Therefore, we suggest that BDNF and Pro-BDNF, alone or in combination, might be used as ALS prognostic biomarkers.

The BDNF Val66Met Polymorphism is a Relevant, But not Determinant, Risk Factor in the Etiology of Neuropsychiatric Disorders - Current Advances in Human Studies: A Systematic Review.

Brain-derived neurotrophic factor (BDNF) is the brain's most-produced neurotrophin during the lifespan, essentially involved in multiple mechanisms of nervous system development and function. The production/release of BDNF requires multi-stage processing that appears to be regulated at various stages in which the presence of a polymorphism "Val66Met" can exert a critical influence. Aim: To synthesize the knowledge on the BDNF Val66Met polymorphism on intracellular processing and function of BDNF. Methods: We performed a systematic review and collected all available studies on the post-translation processes of BDNF, regarding the Val66Met polymorphism. Searches were performed up to 21st March 2021. Results: Out of 129 eligible papers, 18 studies addressed or had findings relating to BDNF post-translation processes and were included in this review. Discussion: Compilation of experimental findings reveals that the Val66Met polymorphism affects BDNF function by slightly altering the processing, distribution, and regulated release of BDNF. Regarding the critical role of pro-BDNF as a pro-apoptotic factor, such alteration might represent a risk for the development of neuropsychiatric disorders.

Neuroimmune crosstalk through brain-derived neurotrophic factor and its precursor pro-BDNF: New insights into mood disorders.

Mood disorders are the most common mental disorders, affecting approximately 350 million people globally. Recent studies have shown that neuroimmune interaction regulates mood disorders. Brain-derived neurotrophic factor (BDNF) and its precursor pro-BDNF, are involved in the neuroimmune crosstalk during the development of mood disorders. BDNF is implicated in the pathophysiology of psychiatric and neurological disorders especially in antidepressant pharmacotherapy. In this review, we describe the functions of BDNF/pro-BDNF signaling in the central nervous system in the context of mood disorders. In addition, we summarize the developments for BDNF and pro-BDNF functions in mood disorders. This review aims to provide new insights into the impact of neuroimmune interaction on mood disorders and reveal a new basis for further development of diagnostic targets and mood disorders.

Necroptotic astrocytes induced neuronal apoptosis partially through EVs-derived pro-BDNF.

Our previous study showed that neuronal apoptosis was significantly increased upon treatment of conditioned medium (CM) from necroptotic astrocytes (NAS), leaving the underlying mechanism unclear. Considering the nutritive and supportive roles of astrocytes, we first examined the neurotrophic phenotype of necroptotic astrocytes with focus on glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), two important neurotrophic factors, and it was unexpectedly found that the expression of GDNF and BDNF were up-regulated in necroptotic astrocytes in vitro. A question was raised as to whether the functional secreted forms of neurotrophic factors were increased. Considering that extracellular vesicles (EVs) were carriers of secreted substances and their roles in cellular interaction, we isolated EVs from astrocytes and found EVs from normal and necroptotic astrocytes (EVs-NAS) had characteristics of exosomes. We then examined GDNF and BDNF in EVs-NAS, and BDNF was interestingly found as an immature form of pro-BDNF. The expression of pro-BDNF was found to be increased in EVs-NAS, and EVs-NAS had a negative effect on neuronal survival. To verify that whether pro-BDNF was involved in the detrimental effect of EVs-NAS, anti-pro-BDNF antibody was applied, and we found that neuronal apoptosis-induced by EVs-NAS could be significantly attenuated by blocking pro-BDNF, which suggested that necroptotic astrocytes induced neuronal apoptosis partially through EVs-derived pro-BDNF. The data expand our understanding in neurotrophic phenotype of necroptotic astrocytes, and may provide us new strategies targeting on EVs-NAS in treatment of neurological diseases.

BDNF and pro-BDNF in serum and exosomes in major depression: Evolution after antidepressant treatment.

BACKGROUND: The study of clinically related biological indicators in Major Depression (MD) is important. The Brain Derived Neurotrophic Factor (BDNF) appears to play an important role in MD, through its neurotrophic effect, and its levels are significantly decreased. The variation in the serum levels of its precursor proBDNF, which has opposite effects, is not known. Their distribution between serum and exosomes and their evolution during antidepressant treatment is also not known, and may be important in modulating their effects. The aim of this study is to evaluate whether serum and exosome mBDNF and proBDNF levels are altered in patients with MD during antidepressant treatment compared to controls, and their association with clinical improvement and clinical variables. MATERIALS AND METHODS: 42 MD subjects and 40 controls were included. Questionnaires to assess the severity of depression and cognitive impairment and blood samples were collected during the three visits at D0 (inclusion) and 3 and 7 weeks after the start of antidepressant treatment. Assays for mBDNF and proBDNF levels were performed in serum and exosomes by ELISA. RESULTS: MD subjects had decreased serum and exosomal BDNF levels and increased proBDNF levels at D0 compared to controls. BDNF and pro-BDNF vary in an inverse manner in both serum and exosomes during antidepressant treatment. No relationship of BDNF and proBDNF levels to clinical improvement and depression scales was found. CONCLUSION: We demonstrated an evolution of those molecules either in serum or in exosomes after MD treatment. These transport vesicles could have a role in the regulation of BDNF.

Platelets Selectively Regulate the Release of BDNF, But Not That of Its Precursor Protein, proBDNF.

Background: Brain-derived neurotrophic factor (BDNF) plays a role in synaptic plasticity and neuroprotection. BDNF has well-established pro-survival effects, whereas its precursor protein, proBDNF, induces apoptosis. Thus, it has been suggested that the proBDNF/BDNF ratio could be an indicator of neuronal health. Access to neurons is, understandably, limited. Because of their similarities, platelets have been put forward as a non-invasive biomarker of neuronal health; indeed, they store large quantities of BDNF and can release it into circulation upon activation, similarly to neurons. However, whether platelets also express the precursor proBDNF protein remains unknown. We therefore sought to characterize proBDNF levels in human platelets and plasma. Methods: The presence of proBDNF was assessed by immunoblotting, cell fractionation, flow cytometry, and confocal microscopy in washed platelets from 10 healthy volunteers. Platelets from 20 independent healthy volunteers were activated with several classical agonists and the release of BDNF and proBDNF into plasma was quantified by ELISA. Results: Platelets expressed detectable levels of proBDNF (21 ± 13 fmol/250 x 106 platelets). ProBDNF expression was mainly localized in the intracellular compartment. The proBDNF to BDNF molar ratio was ~1:5 in platelets and 10:1 in plasma. In stark contrast to the release of BDNF during platelet activation, intraplatelet and plasma concentrations of proBDNF remained stable following stimulation with classical platelet agonists, consistent with non-granular expression. Conclusions: Platelets express both the mature and the precursor form of BDNF. Whether the intraplatelet proBDNF to BDNF ratio could be used as a non-invasive biomarker of cognitive health warrants further investigation.

Pro-BDNF Knockout Causes Abnormal Motor Behaviours and Early Death in Mice.

Brain derived neurotrophic factor (BDNF) is a member of the neurotrophin family, best characterized for its survival and differentiative effects in the central nervous system. Pro-BDNF, known as the precursor of BDNF, is believed to have opposite functions to mature BDNF (mBDNF). The opposing effects of Pro-BDNF and mBDNF have led researchers to propose a 'yin' (Pro-BDNF) and 'yang' (mBDNF) model of which, the specific mechanism of its opposing functions is unclear and requires further investigation. In order to elucidate pro-BDNF's explicit role, we established a pro-BDNF knockout (KO) mouse model. This BDNF pro-domain KO mouse model showed significant weight loss, impaired righting reflex, abnormal motor behaviours and short lifespan (less than 22 days), mimicking a Huntington's disease (HD)-like phenotype. ELISA results showed BDNF pro-domain KO not only blocked pro-BDNF, but also significantly affected the level of mBDNF. Abnormal morphologic changes were found in the dentate gyrus (DG) of the hippocampus in pro-BDNF KO mice, and western blot confirmed significant cell apoptosis in pro-BDNF KO mice brains. Furthermore, the expression of glutamic acid decarboxylase 65/67 (GAD65/67) was significantly reduced in pro-BDNF KO mice, indicating impaired inhibitory neurotransmission. Heterozygous (Het) mice showed impaired learning and memory capability and depressive-like behaviours, compared with wild type (WT) mice. Overall, these results support that pro-domain of BDNF is an indispensable part of the BDNF gene; without the proper formation of pro-BDNF, mBDNF cannot be produced successfully and function correctly on its own. Our study also supports the BDNF hypothesis in the pathogenesis of HD.

Serum pro-BDNF levels correlate with phospho-tau staining in Alzheimer's disease.

Disruption of brain-derived neurotrophic factor (BDNF) biosynthesis and/or signaling has been implicated in the pathogenesis of Alzheimer's disease (AD). We used postmortem brain and fluid samples from 20 patients with variable severity of AD and 11 controls to investigate whether BDNF levels in serum and brain tissue correlated with hippocampal pathology. Total BDNF, precursor BDNF (pro-BDNF), and mature BDNF were measured in cerebrospinal fluid, serum, and 3 postmortem brain regions. Histological markers for AD pathology, the BDNF cognate receptor (TrkB), and glia were measured in the hippocampus (HIP). Lower pro-BDNF levels were observed in the entorhinal and frontal cortices in AD cases compared with controls. AD cases also exhibited significantly lower staining densities of the cognate BDNF receptor TrkB in the HIP compared with controls, and TrkB staining was inversely correlated with both Amylo-Glo and pTau staining in the same region, suggesting a relationship between the density of the cognate BDNF receptor and accumulation of AD pathology. In addition, higher serum pro-BDNF levels correlated with lower HIP pro-BDNF levels and higher pTau staining in the HIP. Total BDNF levels in cortical regions were also negatively correlated with Amylo-Glo staining in the HIP suggesting that reduced BDNF cortical levels might influence hippocampal amyloid accumulation. These results strongly suggest that altered BDNF and TrkB receptors are involved in AD pathology and therefore warrant investigations into therapies involving the BDNF pathway.

Opioid and neuroHIV Comorbidity - Current and Future Perspectives.

With the current national opioid crisis, it is critical to examine the mechanisms underlying pathophysiologic interactions between human immunodeficiency virus (HIV) and opioids in the central nervous system (CNS). Recent advances in experimental models, methodology, and our understanding of disease processes at the molecular and cellular levels reveal opioid-HIV interactions with increasing clarity. However, despite the substantial new insight, the unique impact of opioids on the severity, progression, and prognosis of neuroHIV and HIV-associated neurocognitive disorders (HAND) are not fully understood. In this review, we explore, in detail, what is currently known about mechanisms underlying opioid interactions with HIV, with emphasis on individual HIV-1-expressed gene products at the molecular, cellular and systems levels. Furthermore, we review preclinical and clinical studies with a focus on key considerations when addressing questions of whether opioid-HIV interactive pathogenesis results in unique structural or functional deficits not seen with either disease alone. These considerations include, understanding the combined consequences of HIV-1 genetic variants, host variants, and µ-opioid receptor (MOR) and HIV chemokine co-receptor interactions on the comorbidity. Lastly, we present topics that need to be considered in the future to better understand the unique contributions of opioids to the pathophysiology of neuroHIV. Graphical Abstract Blood-brain barrier and the neurovascular unit. With HIV and opiate co-exposure (represented below the dotted line), there is breakdown of tight junction proteins and increased leakage of paracellular compounds into the brain. Despite this, opiate exposure selectively increases the expression of some efflux transporters, thereby restricting brain penetration of specific drugs.

Mechanisms That Modulate and Diversify BDNF Functions: Implications for Hippocampal Synaptic Plasticity.

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that has pleiotropic effects on neuronal morphology and synaptic plasticity that underlie hippocampal circuit development and cognition. Recent advances established that BDNF function is controlled and diversified by molecular and cellular mechanisms including trafficking and subcellular compartmentalization of different Bdnf mRNA species, pre- vs. postsynaptic release of BDNF, control of BDNF signaling by tropomyosin receptor kinase B (TrkB) receptor interactors and conversion of pro-BDNF to mature BDNF and BDNF-propeptide. Defects in these regulatory mechanisms affect dendritic spine formation and morphology of pyramidal neurons as well as synaptic integration of newborn granule cells (GCs) into preexisting circuits of mature hippocampus, compromising the cognitive function. Here, we review recent findings describing novel dynamic mechanisms that diversify and locally control the function of BDNF in hippocampal neurons.

Poly-l-lysine-coated superparamagnetic nanoparticles: a novel method for the transfection of pro-BDNF into neural stem cells.

Poly-l-lysine-coated superparamagnetic iron oxide nanoparticles (SPIONs-PLL) were prepared and used as a novel-carrier for the transfer of brain-derived neurotrophic factor (BDNF) into neural stem cells (NSCs) under the beneficial influence of an external magnetic field. Pro-BDNF, a gene from human brain cDNA libraries, was obtained by polymerase chain reaction and constructed in a mammalian expression vector (PSecTag2/HygroB). The nanoparticles (NPs) were examined using Fourier transform infrared spectroscopy, zeta potential, and Transmission electron microscopy. From the results, the levels of BDNF among the transfected and untransfected cells were 30.326 ± 5.9 and 5.85 ± 3.11 pg/mL, respectively, as detected by an ELISA method. Moreover, the enhanced green fluorescent protein vector was used to evaluate the gene expression efficiency for SPIONs-PLL as a non-viral carrier in NSCs. This was performed under the influence of a magnetic field and the transfection reagents (such as Lipofectamine 2000), which served as a positive control. The histological analysis revealed that the concentration of intracellular NPs was significantly higher than intercellular NPs. These results suggest that SPIONs-PLL can serve as a novel alternative for the transfection of BDNF-NSCs and could be used in gene therapy.

Beyond good and evil: A putative continuum-sorting hypothesis for the functional role of proBDNF/BDNF-propeptide/mBDNF in antidepressant treatment.

Depression and posttraumatic stress disorder are assumed to be maladaptive responses to stress and antidepressants are thought to counteract such responses by increasing BDNF (brain-derived neurotrophic factor) levels. BDNF acts through TrkB (tropomyosin-related receptor kinase B) and plays a central role in neuroplasticity. In contrast, both precursor proBDNF and BDNF propeptide (another metabolic product from proBDNF cleavage) have a high affinity to p75 receptor (p75R) and usually convey apoptosis and neuronal shrinkage. Although BDNF and proBDNF/propeptide apparently act in opposite ways, neuronal turnover and remodeling might be a final common way that both act to promote more effective neuronal networking, avoiding neuronal redundancy and the misleading effects of environmental contingencies. This review aims to provide a brief overview about the BDNF functional role in antidepressant action and about p75R and TrkB signaling to introduce the "continuum-sorting hypothesis." The resulting hypothesis suggests that both BDNF/proBDNF and BDNF/propeptide act as protagonists to fine-tune antidepressant-dependent neuroplasticity in crucial brain structures to modulate behavioral responses to stress.

p75 neurotrophin receptor and pro-BDNF promote cell survival and migration in clear cell renal cell carcinoma.

p75NTR, a member of TNF receptor family, is the low affinity receptor common to several mature neurotrophins and the high affinity receptor for pro-neurotrophins. Brain-Derived Neurotrophic Factor (BDNF), a member of neurotrophin family has been described to play an important role in development and progression of several cancers, through its binding to a high affinity tyrosine kinase receptor B (TrkB) and/or p75NTR. However, the functions of these two receptors in renal cell carcinoma (RCC) have never been investigated. An overexpression of p75NTR, pro-BDNF, and to a lesser extent for TrkB and sortilin, was detected by immunohistochemistry in a cohort of 83 clear cell RCC tumors. p75NTR, mainly expressed in tumor tissues, was significantly associated with higher Fuhrman grade in multivariate analysis. In two derived-RCC lines, 786-O and ACHN cells, we demonstrated that pro-BDNF induced cell survival and migration, through p75NTR as provided by p75NTR RNA silencing or blocking anti-p75NTR antibody. This mechanism is independent of TrkB activation as demonstrated by k252a, a tyrosine kinase inhibitor for Trk neurotrophin receptors. Taken together, these data highlight for the first time an important role for p75NTR in renal cancer and indicate a putative novel target therapy in RCC.