The role of brain derived neurotrophic factor in central nervous system

Li, Yiyi; Li, Fang; Qin, Dongdong; Chen, Hongyu; Wang, Jianhao; Wang, Jiabei; Song, Shafei; Wang, Chao; Wang, Yamei; Liu, Songyan; Gao, Dandan; Wang, Zhi-Hao

doi:10.3389/fnagi.2022.986443

Cited by 35 publications

(34 citation statements)

References 127 publications

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“…Furthermore, ABCD1 expression in cALD astrocytes was sufficient to mitigate the basal TLR hyperactivation which is quite intriguing. BDNF and CNTF play essential role in neuronal genesis, differentiation, survival and functional maintenance of sympathetic and parasympathetic neurons (Li et al, 2022; Linnerbauer and Rothhammer, 2020). While AMN-OV astrocytes do not show lowering in glycolysis, BDNF, CNTF, and NGF expressions were increased suggesting that ABCD1 induction can enhance neuroprotection in AMN phenotype.…”

Section: Discussionmentioning

confidence: 99%

iPSC-derived astrocytes to model phenotype-specific differential neuroinflammatory and metabolic responses in X-linked adrenoleukodystrophy

Parasar

Kaur

Poisson

et al. 2022

Preprint

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Objective: The role of astrocytes largely remains to be explored in X-linked adrenoleukodystrophy (X-ALD). Due to limited study models and inaccessibility to patient-tissue samples, we differentiated astrocytes from patient fibroblast-derived induced pluripotent stem cell (iPSCs) which provided a unique system to investigate molecular and etiopathogenetic mechanisms, identify targets, and develop therapeutic agents for X-ALD. Methods: We reprogrammed fibroblasts from adrenomyeloneuropathy (AMN) and cerebral adrenoleukodystrophy (cALD) patients carrying ABCD1 with pathogenic variants and a control patient to generate iPSCs. We differentiated iPSCs into astrocytes and performed transmission electron microscopy, gene expression, immunoblotting, enzyme-linked immunosorbent assay, miRNA-Seq, and lipidomics to characterize phenotypic and molecular features of patient-derived astrocytes. Results: These differentiated astrocytes exhibit diseased phenotypes and replicate biochemical and molecular changes found in patients. We confirmed the deletion of ABCD1 gene-encoded ALD protein and identified ABCD1 variant-driven very long chain fatty acid deposition in AMN and cALD astrocytes. Especially, cALD astrocytes showed increased glycolysis, increased signal transducer and transcription activator (STAT)3 activation, higher miR-9 expression in miRNA-Seq analysis, and reduced expression of anti-inflammatory cytokines such as arginase-1 and mannose receptor C-type-1. Consequently, Toll-like receptor-signaling via myeloid differentiation primary response gene 88 (MyD88) and nuclear factor-kappa B (NF-κB; p52 and p65) induced STAT3 and an altered miR-9 expression is a potential contributor to inflammatory milieu in cALD while interleukin-6 -induced anti-inflammatory cytokine production and increased chemotactic CCL-2 (MCP-1) production in AMN potentially favors microglial recruitment protecting its further progression. Interpretation: We demonstrate for the first time that patient iPSC-derived astrocytes mimic and recapitulate neuroinflammatory and biochemical defects of X-ALD and provide an in vitro cellular system to study X-ALD.

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Section: Discussionmentioning

confidence: 99%

iPSC-derived astrocytes to model phenotype-specific differential neuroinflammatory and metabolic responses in X-linked adrenoleukodystrophy

Parasar

Kaur

Poisson

et al. 2022

Preprint

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“…Interestingly, another finding was the differential expression of the lncRNA AC0008937.2 in the context of SAD, which—as an antisense lncRNA to MAP3K1 —has a potentially regulative role ( 75 ) in the MAPK signaling cascade. Another important gene that can regulate and is regulated by MAPK signaling is the brain-derived neurotrophic factor (BDNF) ( 76 , 77 ), which is an important player in neurogenesis ( 78 ). The neurotrophin BDNF, which is known to be affected by neuroinflammation ( 79 ), is essential for dendritic development in peripheral and central nervous system and regulates dendritic growth ( 80 ).…”

Section: Discussionmentioning

confidence: 99%

Blood transcriptome analysis suggests an indirect molecular association of early life adversities and adult social anxiety disorder by immune-related signal transduction

et al. 2023

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Social anxiety disorder (SAD) is a psychiatric disorder characterized by severe fear in social situations and avoidance of these. Multiple genetic as well as environmental factors contribute to the etiopathology of SAD. One of the main risk factors for SAD is stress, especially during early periods of life (early life adversity; ELA). ELA leads to structural and regulatory alterations contributing to disease vulnerability. This includes the dysregulation of the immune response. However, the molecular link between ELA and the risk for SAD in adulthood remains largely unclear. Evidence is emerging that long-lasting changes of gene expression patterns play an important role in the biological mechanisms linking ELA and SAD. Therefore, we conducted a transcriptome study of SAD and ELA performing RNA sequencing in peripheral blood samples. Analyzing differential gene expression between individuals suffering from SAD with high or low levels of ELA and healthy individuals with high or low levels of ELA, 13 significantly differentially expressed genes (DEGs) were identified with respect to SAD while no significant differences in expression were identified with respect to ELA. The most significantly expressed gene was MAPK3 (p = 0.003) being upregulated in the SAD group compared to control individuals. In contrary, weighted gene co-expression network analysis (WGCNA) identified only modules significantly associated with ELA (p ≤ 0.05), not with SAD. Furthermore, analyzing interaction networks of the genes from the ELA-associated modules and the SAD-related MAPK3 revealed complex interactions of those genes. Gene functional enrichment analyses indicate a role of signal transduction pathways as well as inflammatory responses supporting an involvement of the immune system in the association of ELA and SAD. In conclusion, we did not identify a direct molecular link between ELA and adult SAD by transcriptional changes. However, our data indicate an indirect association of ELA and SAD mediated by the interaction of genes involved in immune-related signal transduction.

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“…Besides its involvement in multiple neurological disorders such as Alzheimer’s, Parkinson’s and Huntington’s disease, BDNF also participated in depression. Moreover, depression patients have lower serum BDNF levels ( Lee et al, 2007 ; Li et al, 2022b ). It is also reported that inflammatory cytokines can decrease BDNF signaling ( Cortese et al, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

Inflammation-activated C/EBPβ mediates high-fat diet-induced depression-like behaviors in mice

Chen

Wang

et al. 2022

Front. Mol. Neurosci.

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Depression, one of the most common causes of disability, has a high prevalence rate in patients with metabolic syndrome. Type 2 diabetes patients are at an increased risk for depression. However, the molecular mechanism coupling diabetes to depressive disorder remains largely unknown. Here we found that the neuroinflammation, associated with high-fat diet (HFD)-induced diabetes and obesity, activated the transcription factor CCAAT/enhancer binding protein β (C/EBPβ) in hippocampal neurons. This factor repressed brain-derived neurotrophic factor (BDNF) expression and caused depression-like behaviors in male mice. Besides, the loss of C/EBPβ expression in C/EBPβ heterozygous knockout male mice attenuated HFD-induced depression-like behaviors, whereas Thy1-C/EBPβ transgenic male mice (overexpressing C/EBPβ) showed depressive behaviors after a short-term HFD. Furthermore, HFD impaired synaptic plasticity and decreased surface expression of glutamate receptors in the hippocampus of wild-type (WT) mice, but not in C/EBPβ heterozygous knockout mice. Remarkably, the anti-inflammatory drug aspirin strongly alleviated HFD-elicited depression-like behaviors in neuronal C/EBPβ transgenic mice. Finally, the genetic delivery of BDNF or the pharmacological activation of the BDNF/TrkB signaling pathway by 7,8-dihydroxyflavone reversed anhedonia in a series of behavioral tests on HFD-fed C/EBPβ transgenic mice. Therefore, our findings aim to demonstrate that the inflammation-activated neuronal C/EBPβ promotes HFD-induced depression by diminishing BDNF expression.

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The role of brain derived neurotrophic factor in central nervous system

Cited by 35 publications

References 127 publications

iPSC-derived astrocytes to model phenotype-specific differential neuroinflammatory and metabolic responses in X-linked adrenoleukodystrophy

iPSC-derived astrocytes to model phenotype-specific differential neuroinflammatory and metabolic responses in X-linked adrenoleukodystrophy

Blood transcriptome analysis suggests an indirect molecular association of early life adversities and adult social anxiety disorder by immune-related signal transduction

Inflammation-activated C/EBPβ mediates high-fat diet-induced depression-like behaviors in mice

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