Serum brain-derived neurotrophic factor, nerve growth factor and neurotrophin-3 levels in dementia

The aim of this study is to measure serum levels of neurotropic factor (NF) in patients with dementia. Brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin-3 (NT-3) were determined in Alzheimer's dementia patients without medication (AD; n: 22), Alzheimer's dementia patients receiving cholinesterase inhibitor (CEI) treatment (AD?+?CEI; n: 32) and vascular dementia patients receiving CEI treatment (VaD?+?CEI; n: 27) and the age-matched control group (n: 20). NGF levels were detected to be significantly higher in the control group than in AD group (P?相似文献   

阿尔茨海默病患者血清脑源性神经营养因子水平的改变及意义

目的研究阿尔茨海默病(AD)患者血清脑源性神经营养因子(BDNF)水平的改变及意义。方法对40例AD患者(AD组)用酶联免疫吸附法检测血清BDNF水平、聚合酶链反应-限制性片段长度多态性对APOE基因进行分型及神经心理评估,并与遗忘型轻度认知障碍(a MCI组)患者和正常对照者(正常对照组)进行比较,分析AD患者血清BDNF水平及与临床指标的相关性。结果与正常对照组相比,AD和a MCI血清BDNF水平差异无统计学意义(F=1.21,P=0.33);a MCI、轻度AD、中重度AD组间BDNF水平差异无统计学意义(F=2.31,P=0.08);相关分析发现是否携带APOEε4等位基因和简易精神状态检查(MMSE)评分不能影响血清BDNF水平(P>0.05)。结论血清BDNF水平既不能作为AD早期诊断的外周标志物,也不能反映AD病情的严重程度。     

Differential sorting of nerve growth factor and brain-derived neurotrophic factor in hippocampal neurons.

Nerve growth factor (NGF) is released through the constitutive secretory pathway from cells in peripheral tissues and nerves where it can act as a target-derived survival factor. In contrast, brain-derived neurotrophic factor (BDNF) appears to be processed in the regulated secretory pathway of brain neurons and secreted in an activity-dependent manner to play a role in synaptic plasticity. To determine whether sorting differences are intrinsic to the neurotrophins or reflect differences between cell types, we compared NGF and BDNF processing in cultured hippocampal neurons using a Vaccinia virus expression system. Three independent criteria (retention or release from cells after pulse-chase labeling, depolarization-dependent release, and immunocytochemical localization) suggest that the bulk of newly synthesized NGF is sorted into the constitutive pathway, whereas BDNF is primarily sorted into the regulated secretory pathway. Similar results occurred with AtT 20 cells, including those transfected with cDNAs encoding neurotrophin precursor-green fluorescent protein fusions. The NGF precursor, but not the BDNF precursor, is efficiently cleaved by the endoprotease furin in the trans-Golgi network (TGN). Blocking furin activity in AtT 20 cells with alpha1-PDX as well as increasing the expression of NGF precursor partially directed NGF into the regulated secretory pathway. Therefore, neurotrophins can be sorted into either the constitutive or regulated secretory pathways, and sorting may be regulated by the efficiency of furin cleavage in the TGN. This mechanism may explain how neuron-generated neurotrophins can act both as survival factors and as neuropeptides.     

Physical activity increases mRNA for brain-derived neurotrophic factor and nerve growth factor in rat brain

Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) support the viability and function of many types of neurons, and are likely mediators of activity-dependent changes in the CNS. We examined BDNF and NGF mRNA levels in several brain areas of adult male rats following 0, 2, 4, or 7 nights with ad libitum access to running wheels. BDNF mRNA was significantly increased in several brain areas, most notably in the hippocampus and caudal13 of cerebral cortex following 2, 4, and 7 nights with exercise. Significant elevations in BDNF mRNA were localized in Ammon's horn areas 1 (CAI) and 4 (CA4) of the hippocampus, and layers II–III of the caudal neocortex and retrosplenial cortex. NGF mRNA was also significantly elevated in the hippocampus and caudal13 of the cortex, affecting primarily the dentate gyrus granular layer (DG) and CA4 of the hippocampus and layers II–III in caudal neocortex.     

Expression of nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 in the somatosensory cortex of the mature rat: coexpression with high-affinity neurotrophin receptors

Neurotrophins, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3), are critical for the maintenance and plasticity of central nervous system (CNS) neurons. We tested the hypothesis that cortical neurons participate in redundant autocrine/paracrine systems. Three sets of studies determined the distribution of NGF-, BDNF-, and NT-3-expressing neurons, the frequency of neurons coexpressing NGF and BDNF, and the frequency of neurons expressing a neurotrophin and its associated high-affinity receptor. The distribution of NGF-, BDNF, and NT-3-immunoreactive neurons was identical. Neurotrophin-positive cells were parceled throughout the cortex, although the labeling frequency was not the same in all layers. More than 30% of the neurons in layers II/III, V, and VI were labeled, whereas only 5-10% of the neurons in layer IV was immunopositive for a neurotrophin. Some glia were also neurotrophin positive, particularly BDNF-positive glia. About 70% of the neurons in layers II/III and V coexpressed NGF and BDNF or coexpressed NGF and NT-3. Ligand-receptor colabeling was also common among cortical neurons. For example, nearly 70% of the NGF-, BDNF-, and NT-3-positive neurons in layer V colabeled with their respective high-affinity receptors, i.e., trkA, trkB, and trkC, respectively. Thus, (a) neurons express multiple neurotrophins and (b) cortical neurons (e.g., layer V neurons) contain the components required for autocrine/paracrine and/or anterograde communication (e.g., neurons in layer II/III support layer V neurons). These systems mean that the cortex is capable of regulating itself autonomously.     

Early social enrichment shapes social behavior and nerve growth factor and brain-derived neurotrophic factor levels in the adult mouse brain.

BACKGROUND: Early experiences produce persistent changes in brain and behavioral function. We investigate whether being reared in a communal nest (CN), a form of early social enrichment that characterizes the natural ecological niche of many rodent species including the mouse, has effects on adult social/aggressive behavior and nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) levels in mice. METHODS: The CN consisted of a single nest where three mothers kept their pups together and shared care-giving behavior from birth to weaning (postnatal day 25). RESULTS: Compared to standard laboratory conditions, in CN condition, mouse mothers displayed higher levels of maternal care. At adulthood, CN mice displayed higher propensity to interact socially and achieved more promptly the behavioral profile of either dominant or subordinate male. Furthermore, CN adult mice showed higher NGF levels, which were further affected by social status, and higher BDNF levels in the brain. CONCLUSIONS: Our findings indicate that CN, a highly stimulating early social environment, produces differences in social behavior later in life associated with marked changes of neurotrophin levels in selected brain areas, including hippocampus and hypothalamus.     

Basal serum levels and reactivity of nerve growth factor and brain-derived neurotrophic factor to standardized acute exercise in multiple sclerosis and controls

Neurotrophins like brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are thought to play an important role in neuronal repair and plasticity. Recent experimental evidence suggests neuroprotective effects of these proteins in multiple sclerosis (MS). We investigated the response of serum NGF and BDNF concentrations to standardized acute exercise in MS patients and controls. Basal NGF levels were significantly elevated in MS. Thirty minutes of moderate exercise significantly induced BDNF production in MS patients and controls, but no differential effects were seen. We conclude that moderate exercise can be used to induce neutrophin production in humans. This may mediate beneficial effects of physical exercise in MS reported recently.     

Low serum levels of brain-derived neurotrophic factor and epidermal growth factor in patients with chronic schizophrenia

Neurotrophic factors (NFs) play a pivotal role in the development of the central nervous system. They are thus also suspected of being involved in the etiology of schizophrenia. Previous studies reported a decreased level of serum brain-derived neurotrophic factor (BDNF) in schizophrenia, whereas the association of epidermal growth factor (EGF) with this illness remains controversial. Using a two-site enzyme immunoassay, we conducted the simultaneous measurement of serum BDNF and EGF levels in a group of patients with chronic schizophrenia (N = 74) and a group of normal controls matched in age, body mass index, smoking habit and sex (N = 87). We found that, compared to normal controls, patients with chronic schizophrenia exhibited lower serum levels of both BDNF and EGF across all ages examined (21–59 years). The serum levels of BDNF and EGF were negatively correlated in the controls (r = − 0.387, P = 0.0002) but not in the patients. Clinical parameters such as duration of illness and psychiatric rating scale also showed no robust correlations with the NF levels. Collectively, these results suggest that pervasive, abnormal signaling of NFs underlies the pathophysiology of chronic schizophrenia.     

Differential regulation of nerve growth factor and brain-derived neurotrophic factor in a mouse model of learned helplessness

Stress-induced helplessness in rodents constitutes a well-defined model to investigate neurobiological mechanisms of depression. Neurotrophins like nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have both been shown to be involved in neurobiological changes of physiological and pathological reactions to stress. In this study we investigated NGF and BDNF protein levels in the frontal cortex and hippocampus in mice treated with an established model of inducible helplessness via electric footshocks compared to untreated controls at various times (0 h up to 14 days after treatment). NGF levels were transiently decreased by one forth in the frontal cortex of shocked mice at 6 h after the stress treatment, whereas BDNF levels remained unchanged in the brain areas investigated throughout the time course. In addition, frontal cortex BDNF levels showed a significantly higher concentration in the right compared to the left hemisphere (up to 3-fold). This effect was detectable independently of treatment, namely in shocked and control mice at any time point measured. In conclusion, a transient decrease of frontal NGF constitutes the most striking correlate of neurobiological changes in this animal model of stress-induced change of behaviour. Interhemispherical differences of BDNF content in the frontal cortex are a new finding that might reflect intracerebral side dominance. Thus, subsequent studies of frontal cortex BDNF expression should carefully consider an interhemispherical variance to avoid misinterpretation.     

Nerve growth factor and brain-derived neurotrophic factor in human paediatric hemimegalencephaly

Paediatric hemimegalencephaly (HME) is a congenital central nervous system (CNS) disorder, characterized by monolateral cerebral hemisphere enlargement, intractable seizures starting in the post-neonatal period, and mental retardation associated with neuropathological anomalies (mainly cortical thickness and lack of lamination). Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are two neurotrophic factors produced in the mammalian CNS that are involved in the survival, development, and function of a variety of brain cells. In the present study, we found increased cerebral tissue levels of NGF and BDNF in 4 infants with HME; these changes appear to be also associated with abnormal NGF-receptor expression in subcortical blood vessels. Moreover, the marked reduction of cortical choline acetyltransferase immunoreactivity is strongly suggestive of a dysregulation in the NGF differentiative activity in this site that could lead to the pathogenesis of HME.     

Delayed neurotrophin treatment following deafness rescues spiral ganglion cells from death and promotes regrowth of auditory nerve peripheral processes: effects of brain-derived neurotrophic factor and fibroblast growth factor

The extent to which neurotrophic factors are able to not only rescue the auditory nerve from deafferentation-induced degeneration but also promote process regrowth is of basic and clinical interest, as regrowth may enhance the therapeutic efficacy of cochlear prostheses. The use of neurotrophic factors is also relevant to interventions to promote regrowth and repair at other sites of nerve trauma. Therefore, auditory nerve survival and peripheral process regrowth were assessed in the guinea pig cochlea following chronic infusion of BDNF + FGF(1) into scala tympani, with treatment initiated 4 days, 3 weeks, or 6 weeks after deafferentation from deafening. Survival of auditory nerve somata (spiral ganglion neurons) was assessed from midmodiolar sections. Peripheral process regrowth was assessed using pan-Trk immunostaining to selectively label afferent fibers. Significantly enhanced survival was seen in each of the treatment groups compared to controls receiving artificial perilymph. A large increase in peripheral processes was found with BDNF + FGF(1) treatment after a 3-week delay compared to the artificial perilymph controls and a smaller enhancement after a 6-week delay. Neurotrophic factor treatment therefore has the potential to improve the benefits of cochlear implants by maintaining a larger excitable population of neurons and inducing neural regrowth.     

Expression of neurotrophin genes in human fibroblasts: Differential regulation of the brain-derived neurotrophic factor gene

Brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and neurotrophin-3 (NT-3) are structurally related survival and differentiation factors for distinct sets of peripheral and central neurons. We previously reported that BDNF and NGF gene expression are differentially regulated in mouse L929 fibroblasts. Here we examine expression of these three neurotrophins in human fibroblasts. Northern blots detected BDNF and NT-3 mRNAs in fibroblasts derived from lung (WI-38), calvarium and foreskin. WI-38 cells and foreskin fibroblasts expressed 1.6 kb as well as 4 kb BDNF mRNAs whereas only the smaller BDNF mRNA was detected in calvarium fibroblasts. NGF mRNA was present in foreskin and calvarium but not lung fibroblasts. In WI-38 cells serum treatment increased levels of BDNF mRNA within 2 hr. Cycloheximide did not inhibit the increase. Treatment with 12-O-tetradecanoyl phorbol-13-acetate (TPA) transiently suppressed BDNF mRNA. Treatment with both serum and TPA first stimulated and then transiently suppressed BDNF mRNA. TPA and/or serum did not significantly affect BDNF mRNA in calvarium fibroblasts. These results show that human fibroblasts derived from different tissues express and regulate neurotrophin genes differentially.     

Serum concentrations of nerve growth factor and brain-derived neurotrophic factor in depressed patients before and after antidepressant treatment

INTRODUCTION: Stress, glucocorticoids and anti-depressant treatment have been found to modulate the expression of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Recent research suggests that serum BDNF concentration is reduced in depression and that successful antidepressant treatment leads to an increase in serum BDNF concentration. METHODS: We studied depressed patients receiving a standardized antidepressant treatment with either 150 mg amitriptyline (n=20) or 40 mg paroxetine (n=20) for 36 days in a prospective design. Changes in the concentrations of serum neurotrophins and salivary cortisol in response to antidepressant treatment were assessed. RESULTS: Independent of clinical efficacy there was a significant 'treatment' by 'medication' interaction effect on BDNF serum concentrations that indicated a decline of BDNF by 12% in paroxetine-treated patients while there was an increase by 13% in amitriptyline-treated patients. Neither antidepressant altered NGF concentrations. The changes in cortisol and neurotrophin concentrations were not related. DISCUSSION: Changes in BDNF serum concentrations as a result of antidepressant therapy depend on the antidepressant instead of being a general characteristic of response to antidepressant treatment.     

gamma-Glutamyltransferase: normal cortical levels in Alzheimer disease

gamma-Glutamyltransferase (EC 2.3.2.2; gamma-GT) may be important in the transport of amino acids or peptides across the blood-brain barrier. Gamma-GT activities were the same in cortical samples from Alzheimer and age-matched control brains, and there was no correlation between gamma-GT and choline acetyltransferase (ChAT) or acetylcholinesterase (AChE) levels, both of which were significantly reduced in the Alzheimer samples. ChAT and AChE activities were significantly correlated in both groups. ChAT showed a negative correlation with age in the controls and a positive correlation in the Alzheimer group. The opposite was true for gamma-GT, although the correlations were of low significance. The results do not lend any support to the hypothesis of a defect in the blood-brain barrier in Alzheimer disease.     

Overexpression of brain-derived neurotrophic factor in the hippocampus protects against post-stroke depression

Post-stroke depression is associated with reduced expression of brain-derived neurotrophic factor(BDNF). In this study, we evaluated whether BDNF overexpression affects depression-like behavior in a rat model of post-stroke depression. The middle cerebral artery was occluded to produce a model of focal cerebral ischemia. These rats were then subjected to isolation-housing combined with chronic unpredictable mild stress to generate a model of post-stroke depression. A BDNF gene lentiviral vector was injected into the hippocampus. At 7 days after injection, western blot assay and real-time quantitative PCR revealed that BDNF expression in the hippocampus was increased in depressive rats injected with BDNF lentivirus compared with depressive rats injected with control vector. Furthermore, sucrose solution consumption was higher, and horizontal and vertical movement scores were increased in the open field test in these rats as well. These findings suggest that BDNF overexpression in the hippocampus of post-stroke depressive rats alleviates depression-like behaviors.     

Effects of brain-derived neurotrophic factor and nerve growth factor on remaining neurons in the lesioned nucleus basalis magnocellularis

Rats received a unilateral lesion of the nucleus basalis magnocellularis (NBM) by infusion of ibotenic acid. Starting 2 weeks after the lesion, the animals were treated with nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF) by intraparenchymal infusion of 3 μg per day for 4 weeks. Lesioned control animals received a similar amount of cytochromec. The activity of cholone acethyltransferase (ChAT) in the frontal neocortex was signigicantly reduced by the lesion (−39%). However, the intraparenchymal treatment with NGF or BDNF did not affect cortical ChAT activity. The number of p75 NGF receptor-immunoreactive neurons in the NBM was significantly decreased (−49%) by the lesion and was not affected by NGF or BDNF. The size of the remaining neurons was significantly increased by NGF (+32%), but not by BDNF (+12%). Similarly, in situ hybridization showed enhanced expression of the p75 NGF receptor following treatment with NGF, but not with BDNF. These results suggest that although BDNF occurs in the target area of cholinergic NBM neurons, its effects on these neurons are less pronounced than those of NGF.