Elevated Peripheral Brain-Derived Neurotrophic Factor Level Associated With Decreasing Insulin Secretion May Forecast Memory Dysfunction in Patients With Long-Term Type 2 Diabetes

BackgroundWith the progressive course of diabetes and the decline in islet function, the cognitive dysfunction of patients aggravated.ObjectiveWe aimed to investigate the roles of brain-derived neurotrophic factor (BDNF) and the Val66Met polymorphism in mild cognitive impairment (MCI) in patients with type 2 diabetes mellitus (T2DM).MethodsA total of 169 Chinese patients with T2DM were involved and divided into long-term (diabetes duration >10 years) and short-term (diabetes duration ≤10 years) diabetes, and in each group, the patients were separated as MCI and the control. Demographic characteristics, clinical variables, and cognitive performances were assessed. The plasma BDNF level was measured via enzyme-linked immunosorbent assay. The Val66Met polymorphisms were analyzed.ResultsLong-term T2DM have lower 2 h postprandial C-peptide (p < 0.05). The BDNF level was slightly higher in patients with MCI than in the controls in each duration group without statistical significance. The relationship of BDNF to Montreal Cognitive Assessment was not proven either. However, in the long-term diabetes group, BDNF concentration remained as an independent factor of logical memory test (β = −0.27; p < 0.05), and they were negatively correlated (r = −0.267; p = 0.022); BDNF was also negatively correlated with fasting C-peptide (r = −0.260; p = 0.022), 2 h postprandial C-peptide (r = −0.251; p = 0.028), and homeostasis model assessment of insulin resistance (r = −0.312; p = 0.006). In genotypic groups, BDNF Val/Val performed better in logical memory test than Met/Met and Val/Met.ConclusionElevated peripheral BDNF level associated with declined islet function, when combined with its Val66Met polymorphism, may forecast memory dysfunction in patients with long-term T2DM.

The role of brain-derived neurotrophic factor and the neurotrophin receptor p75NTR in age-related brain atrophy and the transition to Alzheimer’s disease

Alzheimer’s disease is a neurodegenerative condition that is potentially mediated by synaptic dysfunction before the onset of cognitive impairments. The disease mostly affects elderly people and there is currently no therapeutic which halts its progression. One therapeutic strategy for Alzheimer’s disease is to regenerate lost synapses by targeting mechanisms involved in synaptic plasticity. This strategy has led to promising drug candidates in clinical trials, but further progress needs to be made. An unresolved problem of Alzheimer’s disease is to identify the molecular mechanisms that render the aged brain susceptible to synaptic dysfunction. Understanding this susceptibility may identify drug targets which could halt, or even reverse, the disease’s progression. Brain derived neurotrophic factor is a neurotrophin expressed in the brain previously implicated in Alzheimer’s disease due to its involvement in synaptic plasticity. Low levels of the protein increase susceptibility to the disease and post-mortem studies consistently show reductions in its expression. A desirable therapeutic approach for Alzheimer’s disease is to stimulate the expression of brain derived neurotrophic factor and potentially regenerate lost synapses. However, synthesis and secretion of the protein are regulated by complex activity-dependent mechanisms within neurons, which makes this approach challenging. Moreover, the protein is synthesised as a precursor which exerts the opposite effect of its mature form through the neurotrophin receptor p75NTR. This review will evaluate current evidence on how age-related alterations in the synthesis, processing and signalling of brain derived neurotrophic factor may increase the risk of Alzheimer’s disease.

Brain-Derived Neurotrophic Factor Suppressed Proinflammatory Cytokines Secretion and Enhanced MicroRNA(miR)-3168 Expression in Macrophages

We investigated the role of brain-derived neurotrophic factor (BDNF) and its signaling pathway in the proinflammatory cytokines production of macrophages. The effects of different concentrations of BDNF on proinflammatory cytokines expression and secretion in U937 cell-differentiated macrophages, and human monocyte-derived macrophages were analyzed using enzyme-linked immunosorbent assay and real-time polymerase chain reaction. The CRISPR-Cas9 system was used to knockout p75 neurotrophin receptor (p75NTR), one of the BDNF receptors. Next-generation sequencing (NGS) was conducted to search for BDNF-regulated microRNA. A very low concentration of BDNF (1 ng/mL) could suppress the secretion of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6 in lipopolysaccharide (LPS)-stimulated macrophages but did not change their mRNA expression. BDNF suppressed IL-1β and IL-6 secretion in human monocyte-derived macrophages. In U937 cells, BDNF suppressed the phosphorylation of JNK and c-Jun. The p75NTR knockout strongly suppressed IL-1β, IL-6, and TNF-α secretion in macrophages and LPS-stimulated macrophages. BDNF regulated the expression of miR-3168 with Ras-related protein Rab-11A as its target. In conclusion, BDNF suppressed proinflammatory cytokines secretion in macrophages and inhibited the phosphorylation of JNK. Knockout of p75NTR suppressed proinflammatory cytokines expression and secretion. BDNF upregulated the expression of miR-3168. The inhibition of p75NTR could be a potential strategy to control inflammation.

Psychological Status, Compliance, Serum Brain-Derived Neurotrophic Factor, and Nerve Growth Factor Levels of Patients with Depression after Augmented Mindfulness-Based Cognitive Therapy

Objective. Mindfulness-based cognitive therapy (MBCT) is a cost-effective psychosocial program that prevents relapse/recurrence in major depression. The present study aimed to analyze the effects of augmented MBCT along with standard treatment dominated by pharmacotherapy on psychological state, compliance, brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) expression levels in patients with depression. Methods. A total of 160 eligible patients with depression in The First Affiliated Hospital of Zhengzhou University were included in this study. The study randomly assigned the patients to the experimental group (n = 80) and control group (n = 80). All participants were assessed with the questionnaires including the 17-item Hamilton Depression Rating Scale (HAMD-17), Rosenberg Self-esteem Scale (RSES), Self-Acceptance Questionnaire (SAQ), and Stigma Scale (Scale of Stigma in People with Mental Illness, SSPM). The serum levels of BDNF and NGF were detected by enzyme-linked immunosorbent assay (ELISA). Results. After 8 weeks of treatment, the experimental group showed significant lower HAMD-17 score, higher RSES, and SAQ score, as well as lower SSPM score compared with the control group ( P < 0.01 ). Furthermore, ELISA revealed that the serum levels of BDNF and NGF remarkably increased in the experimental group after treatment ( P < 0.001 ). Conclusions. Our data showed that augmented MBCT combined with pharmacotherapy contributed to improvement on patients’ psychological state, compliance, and disease recurrence.

The Brain-Derived Neurotrophic Factor Functional Polymorphism and Hand Grip Strength Impact the Association between Brain-Derived Neurotrophic Factor Levels and Cognition in Older Adults in the United States

Introduction Aging is associated with subtle cognitive decline in attention, memory, executive function, processing speed, and reasoning. Although lower brain-derived neurotrophic factor (BDNF) has been linked to cognitive decline among older adults, it is not known if the association differs among individuals with various BDNF Val66Met (rs6265) genotypes. In addition, it is not clear whether these associations vary by hand grip strength or physical activity (PA). Methods A total of 2904 older adults were included in this study using data from the Health and Retirement Study. Associations between serum BDNF and measures of cognitive function were evaluated using multivariable linear regression models stratified by Met allele status. PA and hand grip strength were added to the model to evaluate whether including these variables altered associations between serum BDNF and cognition. Results Mean age was 71.4 years old, and mean body mass index was 28.3 kg/m2. Serum BDNF levels were positively associated with higher total cognitive score (beta = 0.34, p = .07), mental status (beta = 0.16, p = .07), and word recall (beta = 0.22, p =.04) among Met carriers, while serum BDNF levels were negatively associated with mental status (beta = −0.09, p = .07) among non-Met carriers. Furthermore, associations changed when hand grip strength was added to the model but not when PA was added to the model. Conclusions The BDNF Val66Met variant may moderate the association between serum BDNF levels and cognitive function in older adults. Furthermore, such associations differ according to hand grip strength but not PA.