The Dominance of Intracellular Maturation of Brain-Derived Neurotrophic Factor Ensures Its Retrograde Effect in Newly Formed Mouse Motor Synapses

included 35 studies with a total of 2238 patients with BD, and 1560 healthy controls. Levels of BDNF were lower in crude blood samples from BD patients (P = 0.02), as well as in the serum of manic (P = 0.01) and depressed patients (P = 0.002), compared with healthy control subjects. No differences in peripheral BDNF levels were observed in any of the affective states. Furthermore, a longer illness duration was associated with higher BDNF levels in BD patients [6]. The BDNF enzyme-linked immunosorbent assay (ELISA) kits used in early reports recognized both proBDNF and mature BDNF, due to the limited specificity of the BDNF antibody [7]. Using new, commercial human BDNF ELISA kits capable of differentiating between proBDNF and mature BDNF, we reported high concentrations of both BDNF forms in human serum [7, 8] (Table 1). Serum levels of proBDNF in approximately 38 percent of the healthy Japanese control subjects were less than the minimum detectable concentration (0.5 ng/mL) of the kit (Table 1) [8]. Noting the high concentrations and putative opposing functions of proBDNF and mature BDNF, authors have focused their attention on the separate measurements of these factors in human blood [2, 9, 10]. Sodersten et al. [11] reported that serum levels of mature BDNF in mood-stabilized patients with BD were significantly higher than in healthy controls, whereas serum levels of proBDNF in BD patients were significantly lower than those of controls (Swedish samples) [11]. In this study, serum levels of proBDNF could be measured in all healthy control subjects (Table 1) [11]. In contrast, serum levels of mature BDNF in depressed patients were significantly lower than those of healthy controls [8]. It is therefore possible that measuring blood levels of mature BDNF and proBDNF could provide a method for distinguishing between depression and BD, thus reducing the high rates of misdiagnosis between these diseases Brain-derived neurotrophic factor (BDNF), a major neurotrophic factor in the brain, plays an important role in the pathophysiology of mood disorders, such as depression and bipolar disorder (BD) [1–3]. BDNF (mature BDNF) is a 13-kDa polypeptide, synthesized initially as a precursor protein, preproBDNF, in the endoplasmic reticulum. Following cleavage of its signal peptide, proBDNF (~32 kDa) is converted to mature BDNF by intracellular or extracellular proteases. It was first thought that only secreted, mature BDNF possessed biological activity, and that proBDNF, which localizes intracellularly, served as an inactive precursor. However, accumulating evidence demonstrates that both proBDNF and mature BDNF are active, eliciting opposing effects via the p75 and TrkB receptors, respectively, and that both forms play a key role in several physiological functions [2, 3]. In 2003, we reported that serum levels of BDNF in drugnaive patients with depression were significantly lower than those of healthy controls [4]. Since then, a number of studies have replicated our initial finding. A recent meta-analysis of 179 associations (N = 9484 subjects) showed that serum levels of total BDNF (mature BDNF and proBDNF), in antidepressant-free patients with depression were significantly lower (Cohen’s d = −0.71, P < 0.0000001) than those of healthy controls [5]. Furthermore, Munkholm et al. [6] performed a systematic and quantitative metaanalysis of BDNF (mature BDNF and proBDNF) levels in blood samples from patients with BD. This analysis

Plasma levels of mature brain-derived neurotrophic factor (BDNF) and matrix metalloproteinase-9 (MMP-9) in treatment-resistant schizophrenia treated with clozapine

BACKGROUND: Accumulating evidence points to the brain-derived neurotrophic factor (BDNF) as a bio- marker for neuropsychiatric diseases, such as major depression. Mature BDNF is synthesized from its precursor form, proBDNF. Although BDNF levels in human blood can be measured using commercially available human BDNF ELISA kits, due to limited specificity of the BDNF antibody, these kits are unable to distinguish between proBDNF and mature BDNF. In this study, we measured serum levels of proBDNF and mature BDNF in healthy subjects, using human proBDNF and BDNF ELISA kits, respectively. METHODS: Serum levels of proBDNF and mature BDNF in healthy subjects (n = 40) were measured using the sand- wich human proBDNF and BDNF ELISA kits. RESULTS: In healthy subjects, serum levels of mature BDNF were 23.71 ± 5.61 ng/mL (mean ± S.D., n=40). Serum levels of proBDNF in healthy subjects were 7.58 ± 7.68 ng/mL (mean ± S.D., n=25). However in 15 subjects, serum lev- els of proBDNF were less than the minimum detectable concentration (0.5 ng/mL) of the kit. CONCLUSIONS: This study shows that serum levels of proBDNF and mature BDNF are measurable using either the commercially available human proBDNF or BDNF ELISA kits, although the sensitivity of proBDNF kit was unaccepta- bly low. These ELISA kits may be useful for measuring proBDNF and mature BDNF in the body fluids of patients with neuropsychiatric, cardiovascular and other diseases.

Neuroprotection is considered a major therapeutic target in Multiple Sclerosis (MS), a chronic inflammatory demyelinating disease of the central nervous system (CNS). Accordingly, current disease modifying drugs (DMDs) for MS have been revaluated for their ability to stimulate production of neurotrophic factors that may provide support to neural cells against neurodegeneration. Brain-derived neurotrophic factor (BDNF) is considered the best candidate for such neuroprotective effects in MS. In the present study, we explored a potential effects of Glatiramer Acetate (GA), and Interferon-beta (IFN-b), the first two available treatments of MS, on circulating levels of BDNF considering the different BDNF forms. Using ELISA assays, we quantified mature and total BDNF in the serum of 20 relapsing-remitting MS (RR-MS) patients treated with GA and 31 with INF-beta compared with 20 age-matched RR-MS patients without any DMD. Mature BDNF but not total BDNF was significantly increased by treatment with IFN-b in female patients only, while GA had no effect. These results support a gender-specific role of BDNF in the treatment of RR-MS with INF-b. Of note, the present study was carried out with standardized ELISA assays which are commercially available and, prospectively, might be routinely used in the common clinical practice to monitor the individual response to the therapy with IFN-b.

BackgroundMeta-analyses have identified serum levels of brain-derived neurotrophic factor (BDNF) as a potential biomarker for major depressive disorder (MDD). However, at the time, commercially available human ELISA kits are unable to distinguish between proBDNF (precursor of BDNF) and mature BDNF because of limited BDNF antibody specificity. In this study, we examined whether serum levels of proBDNF, mature BDNF, and matrix metalloproteinase-9 (MMP-9), which converts proBDNF to mature BDNF, are altered in patients with MDD.Methodology/Principal FindingsSixty-nine patients with MDD and 78 age- and gender-matched healthy subjects were enrolled. Patients were evaluated using 17 items on the Structured Interview Guide for the Hamilton Depression Rating Scale. Cognitive impairment was evaluated using the CogState battery. Serum levels of proBDNF, mature BDNF, and MMP-9 were measured using ELISA kits. Serum levels of mature BDNF in patients with MDD were significantly lower than those of normal controls. In contrast, there was no difference in the serum levels of proBDNF and MMP-9 between patients and normal controls. While neither proBDNF nor mature BDNF serum levels was associated with clinical variables, there were significant correlations between MMP-9 serum levels and the severity of depression, quality of life scores, and social function scores in patients.Conclusions/SignificanceThese findings suggest that mature BDNF may serve as a biomarker for MDD, and that MMP-9 may play a role in the pathophysiology of MDD. Further studies using larger sample sizes will be needed to investigate these results.

There are two forms of brain-derived neurotrophic factor (BDNF), precursor of BDNF (proBDNF) and mature BDNF, which each exert opposing effects through two different transmembrane receptor signaling systems, consisting of p75 neurotrophin receptor (p75NTR) and tyrosine receptor kinase B (TrkB). Previous studies have demonstrated that proBDNF promotes cell death and inhibits the growth and migration of C6 glioma cells through p75NTR in vitro, while mature BDNF has opposite effects on C6 glioma cells. It is hypothesized that mature BDNF is essential in the development of malignancy in gliomas. However, histological data obtained in previous studies were unable distinguish mature BDNF from proBDNF due to the lack of specific antibodies. The present study investigated the expression of mature BDNF using a specific sheep monoclonal anti-mature BDNF antibody in 42 human glioma tissues of different grades and 10 control tissues. The correlation between mature BDNF and TrkB was analyzed. Mature BDNF expression was significantly increased in high-grade gliomas, and was positively correlated with the malignancy of the tumor and TrkB receptor expression. The present data have demonstrated that increased levels of mature BDNF contribute markedly to the development of malignancy of human gliomas through the primary BDNF receptor TrkB.

Brain-derived neurotrophic factor (BDNF) has a role in the pathophysiology of psychiatric disorders. The precursor proBDNF is converted to mature BDNF and BDNF pro-peptide, the N-terminal fragment of proBDNF; however, the precise function of these proteins in psychiatric disorders is unknown. We sought to determine whether expression of these proteins is altered in the brain and peripheral tissues from patients with psychiatric disorders. We measured protein expression of proBDNF, mature BDNF and BDNF pro-peptide in the parietal cortex, cerebellum, liver and spleen from control, major depressive disorder (MDD), schizophrenia (SZ) and bipolar disorder (BD) groups. The levels of mature BDNF in the parietal cortex from MDD, SZ and BD groups were significantly lower than the control group, whereas the levels of BDNF pro-peptide in this area were significantly higher than controls. In contrast, the levels of proBDNF and BDNF pro-peptide in the cerebellum of MDD, SZ and BD groups were significantly lower than controls. Moreover, the levels of mature BDNF from the livers of MDD, SZ and BD groups were significantly higher than the control group. The levels of mature BDNF in the spleen did not differ among the four groups. Interestingly, there was a negative correlation between mature BDNF in the parietal cortex and mature BDNF in the liver in all the subjects. These findings suggest that abnormalities in the production of mature BDNF and BDNF pro-peptide in the brain and liver might have a role in the pathophysiology of psychiatric disorders, indicating a brain–liver axis in psychiatric disorders.

Brain-derived neurotrophic factor (BDNF) is critical for the function and survival of neurons that degenerate in the late stage of Alzheimer's disease (AD). There are two forms of BDNF, the BDNF precursor (proBDNF) and mature BDNF, in human brain. Previous studies have shown that BDNF mRNA and protein, including proBDNF, are dramatically decreased in end-stage AD brain. To determine whether this BDNF decrease is an early or late event during the progression of cognitive decline, we used western blotting to measure the relative amounts of BDNF proteins in the parietal cortex of subjects clinically classified with no cognitive impairment (NCI), mild cognitive impairment (MCI) or mild to moderate AD. We found that the amount of proBDNF decreased 21 and 30% in MCI and AD groups, respectively, as compared with NCI, consistent with our previous results of a 40% decrease in end-stage AD. Mature BDNF was reduced 34 and 62% in MCI and AD groups, respectively. Thus, the decrease in mature BDNF and proBDNF precedes the decline in choline acetyltransferase activity which occurs later in AD. Both proBDNF and mature BDNF levels were positively correlated with cognitive measures such as the Global Cognitive Score and the Mini Mental State Examination score. These results demonstrate that the reduction of both forms of BDNF occurs early in the course of AD and correlates with loss of cognitive function, suggesting that proBDNF and BDNF play a role in synaptic loss and cellular dysfunction underlying cognitive impairment in AD.

High-grade glioma is incurable and is associated with a short survival time and a poor prognosis. There are two forms of brain-derived neurotrophic factor (BDNF), proBDNF and mature BDNF, which exert opposite effects. Their diverse actions are mediated through two different transmembrane receptor signalling systems: p75NTR and TrkB. The important roles of the BDNF/TrkB signalling system in tumour cell proliferation and survival have been demonstrated. However, few studies have been able to distinguish mature BDNF from proBDNF due to the limitation of specific antibodies. Using specific proBDNF antibodies, we demonstrated that the proBDNF/p75NTR pathway appears to inhibit malignant glioma cell growth and migration. In the present study using specific mature BDNF antibodies, we found that mature BDNF inhibited C6 glioma cell apoptosis and increased cell growth and migration in vitro. Our data suggest that the counterbalance between mature BDNF and proBDNF may regulate tumour growth.

A positive correlation between serum levels of mature brain-derived neurotrophic factor and negative symptoms in schizophrenia

Hippocampal brain derived neurotrophic factor levels are mediated by T cells in response to stress

Maternal obesity alters brain derived neurotrophic factor (BDNF) signaling in the placenta in a sexually dimorphic manner

Exogenous gangliosides increase the release of brain-derived neurotrophic factor

The objective of our pilot clinical, prospective study was to determine the serum levels of mature brain-derived neurotrophic factor, in of women with endometriosis and controls and explore whether mature brain-derived neurotrophic factor is a potential biomarker for the disease. The patients were selected from the Endometriosis Marker Austria prospective cohort study conducted at the tertiary referral certified Endometriosis Center of the Medical University of Vienna. All women underwent laparoscopic surgery because there was a suspicion of endometriosis, or the women had pelvic pain, adnexal cysts, unexplained infertility, or uterine fibroids. Our main outcome parameter was total levels of mature brain-derived neurotrophic factor in serum, measured using ELISA. Our results show that serum levels of mature brain-derived neurotrophic factor are significantly higher in women with endometriosis compared to women without endometriosis. The mean serum protein levels are significantly higher in women with rAFS stage I and II endometriosis, whereas no difference was found in women with stage III and IV endometriosis and controls. Postoperative follow-up at 6-10 weeks revealed that surgical intervention leads to equilibration of the levels of secreted mature brain-derived neurotrophic factor between women with and without endometriosis. The difference between serum mature brain-derived neurotrophic factor levels of women with endometriosis compared to women without endometriosis is independent of menstrual cycle phase and overall self-reported pelvic pain. ROC-curve analysis showed that, the mature brain-derived neurotrophic factor is not a useful biomarker for endometriosis. In conclusion, although women with stage I and II endometriosis have increased levels of mature brain-derived neurotrophic factor in serum compared to controls, the difference is not predictive for the disease. Impact statement Endometriosis is a disease that can have a significant impact on the quality of life of affected women. The gold standard for diagnosis to this day remains visualization through laparoscopic surgery with histological verification. Current studies are attempting to find a biomarker with high sensitivity and specificity, which would bypass the surgery-associated risks and would significantly reduce costs. In an attempt to elucidate whether mature serum BDNF can serve as diagnostic marker for the disease, we compared the levels of the protein in women with endometriosis to endometriosis-free controls. While our results showed that serum concentrations of the mature protein were significantly higher in women with endometriosis, we did not find this marker to have the sensitivity or specificity needed in order to allow a reliable diagnosis.

Microglia are intrinsic immune cells that release factors including pro- and anti-inflammatory cytokines, nitric oxide (NO) and neurotrophins following activation in the brain. Elevation of intracellular Ca2+ concentration ([Ca2+ ]i) is important for microglial functions, such as the release of cytokines or NO from activated microglia. Brain-derived neurotrophic factor (BDNF) is a neurotrophin well known for its roles in the activation of microglia. Interestingly, proBDNF, the precursor form of mature BDNF, and mature BDNF elicit opposing neuronal responses in the brain. Mature BDNF induces sustained intracellular Ca2+ elevation through the upregulation of the surface expression of TRPC3 channels in rodent microglial cells. In addition, TRPC3 channels are important for the BDNF-induced suppression of NO production in activated microglia. In this study, we observed that proBDNF and mature BDNF have opposite effects on the relative expression of surface p75 neurotrophin receptor (p75NTR ) in rodent microglial cells. ProBDNF induces a sustained elevation of [Ca2+ ]i through binding to the p75NTR , which is possibly mediated by Rac 1 activation and TRPM7 channels in rodent microglial cells. Flow cytometry showed that proBDNF increased the relative surface expression of TRPM7. Although proBDNF did not affect either mRNA expression of pro- and anti-inflammatory cytokines or the phagocytic activity, proBDNF potentiates the generation of NO induced by IFN-γ and TRPM7 channels could be involved in the proBDNF-induced potentiation of IFN-γ-mediated production of NO. We show direct evidence that rodent microglial cells are able to respond to proBDNF, which might be important for the regulation of inflammatory responses in the brain.