Deficiency in BDNF/TrkB Neurotrophic Activity Stimulates δ-Secretase by Upregulating C/EBPβ in Alzheimer’s Disease

Wang, Zhi-Hao; Xiang, Jie; Liu, Xia; Yu, Shan Ping; Manfredsson, Fredric P.; Sandoval, Ivette M.; Wu, Shengxi; Wang, Jian‐Zhi; Ye, Keqiang

doi:10.1016/j.celrep.2019.06.054

Cited by 159 publications

(117 citation statements)

References 57 publications

(73 reference statements)

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“…In support, we showed that microglia and astrocyte-induced neuroinflammation plays a crucial role in the development of POCD. Moreover, alteration in BDNF signaling can result in synaptic dysfunction that is associated with memory deficits observed in AD [48], Parkinson's disease (PD) [41], stroke [49], and sepsisassociated encephalopathy [50]. In the present study, we showed that anesthesia and surgery induced decreased levels of BDNF, which could be reversed by memantine and MDL-28170.…”

Section: Discussionmentioning

confidence: 47%

Dysregulation of BDNF/TrkB signaling mediated by NMDAR/Ca2+/calpain might contribute to postoperative cognitive dysfunction in aging mice

Qiu

Pan

Luo

et al. 2020

J Neuroinflammation

155

117

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Background: Postoperative cognitive decline (POCD) is a recognized clinical phenomenon characterized by cognitive impairments in patients following anesthesia and surgery, yet its underlying mechanism remains unclear. Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity, learning, and memory via activation of TrkB-full length (TrkB-FL) receptors. It has been reported that an abnormal truncation of TrkB mediated by calpain results in dysregulation of BDNF/TrkB signaling and is associated with cognitive impairments in several neurodegenerative disorders. Calpains are Ca 2+ -dependent proteases, and overactivation of calpain is linked to neuronal death. Since one source of intracellular Ca 2+ is N-methyl-d-aspartate receptors (NMDARs) related and the function of NMDARs can be regulated by neuroinflammation, we therefore hypothesized that dysregulation of BDNF/TrkB signaling mediated by NMDAR/Ca 2+ /calpain might be involved in the pathogenesis of POCD.Methods: In the present study, 16-month-old C57BL/6 mice were subjected to exploratory laparotomy with isoflurane anesthesia to establish the POCD animal model. For the interventional study, mice were treated with either NMDAR antagonist memantine or calpain inhibitor MDL-28170. Behavioral tests were performed by open field, Y maze, and fear conditioning tests from 5 to 8 days post-surgery. The levels of Iba-1, GFAP, interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), NMDARs, calpain, BDNF, TrkB, bax, bcl-2, caspase-3, and dendritic spine density were determined in the hippocampus.Results: Anesthesia and surgery-induced neuroinflammation overactivated NMDARs and then triggered overactivation of calpain, which subsequently led to the truncation of TrkB-FL, BDNF/TrkB signaling dysregulation, dendritic spine loss, and cell apoptosis, contributing to cognitive impairments in aging mice. These abnormities were prevented by memantine or MDL-28170 treatment. Conclusion: Collectively, our study supports the notion that NMDAR/Ca2+/calpain is mechanistically involved in anesthesia and surgery-induced BDNF/TrkB signaling disruption and cognitive impairments in aging mice, which provides one possible therapeutic target for POCD.

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Section: Discussionmentioning

confidence: 47%

Dysregulation of BDNF/TrkB signaling mediated by NMDAR/Ca2+/calpain might contribute to postoperative cognitive dysfunction in aging mice

Qiu

Pan

Luo

et al. 2020

J Neuroinflammation

155

117

View full text Add to dashboard Cite

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“…4 , 5 , and 7 ). Our previous study demonstrated that BDNF and C/EBPβ inversely regulate each other, providing a mechanistic link between BDNF/TrkB reduction, C/EBPβ up-regulation, δ-secretase (AEP) activation, and Aβ and Tau alterations in the murine brains ( 39 ). In the current study, we found that R13 (7,8-DHF) also functions as antioxidant in the murine colon, leading to proinflammatory cytokine IL-6 decrease and suppression of C/EBPβ.…”

Section: Discussionmentioning

confidence: 99%

Gut dysbiosis contributes to amyloid pathology, associated with C/EBPβ/AEP signaling activation in Alzheimer’s disease mouse model

et al. 2020

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The gut-brain axis is bidirectional, and gut microbiota influence brain disorders including Alzheimer’s disease (AD). CCAAT/enhancer binding protein β/asparagine endopeptidase (C/EBPβ/AEP) signaling spatiotemporally mediates AD pathologies in the brain via cleaving both β-amyloid precursor protein and Tau. We show that gut dysbiosis occurs in 5xFAD mice, and is associated with escalation of the C/EBPβ/AEP pathway in the gut with age. Unlike that of aged wild-type mice, the microbiota of aged 3xTg mice accelerate AD pathology in young 3xTg mice, accompanied by active C/EBPβ/AEP signaling in the brain. Antibiotic treatment diminishes this signaling and attenuates amyloidogenic processes in 5xFAD, improving cognitive functions. The prebiotic R13 inhibits this pathway and suppresses amyloid aggregates in the gut. R13-induced Lactobacillus salivarius antagonizes the C/EBPβ/AEP axis, mitigating gut leakage and oxidative stress. Our findings support the hypothesis that C/EBPβ/AEP signaling is activated by gut dysbiosis, implicated in AD pathologies in the gut.

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“…TrkB-expressing neurons in the dorsomedial hypothalamus act as critical regulators of energy expenditure and body weight through appetite suppression and an increase in satiety [9]. Furthermore, the downregulation of TrkB expression is associated with the pathogenesis of Alzheimer's [10,11], Huntington's [12,13], and Parkinson's [14,15] diseases. Conversely, TrkB is aberrantly overexpressed in a variety of human cancers [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

TrkB-Induced Inhibition of R-SMAD/SMAD4 Activation is Essential for TGF-β-Mediated Tumor Suppressor Activity

Kim

Jin

2020

Cancers

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TrkB-mediated activation of the IL6/JAK2/STAT3 signaling pathway is associated with the induction of the epithelial–mesenchymal transition (EMT) program and the acquisition of metastatic potential by tumors. Conversely, the transforming of growth factor-β (TGF-β) is implicated in tumor suppression through the canonical SMAD-dependent signaling pathway. Hence, TrkB could play a role in disrupting the potent TGF-β-mediated growth inhibition, a concept that has not been fully explored. Here, we identified TrkB to be a crucial regulator of the TGF-β signaling pathway as it inhibits the TGF-β-mediated tumor suppression and the activation of TrkB kinase. We further show that the interactions between TrkB and SMADs inhibit TGF-β-mediated R-SMAD/SMAD4 complex formation and suppress TGF-β-induced nuclear translocation and target gene expression. Additionally, the knockdown of TrkB restored the tumor inhibitory activity of TGF-β signaling. These observations suggest that interactions between TrkB and SMADs are critical for the inhibition of TGF-β tumor suppressor activity in cancer cells.

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Deficiency in BDNF/TrkB Neurotrophic Activity Stimulates δ-Secretase by Upregulating C/EBPβ in Alzheimer’s Disease

Cited by 159 publications

References 57 publications

Dysregulation of BDNF/TrkB signaling mediated by NMDAR/Ca2+/calpain might contribute to postoperative cognitive dysfunction in aging mice

Dysregulation of BDNF/TrkB signaling mediated by NMDAR/Ca2+/calpain might contribute to postoperative cognitive dysfunction in aging mice

Gut dysbiosis contributes to amyloid pathology, associated with C/EBPβ/AEP signaling activation in Alzheimer’s disease mouse model

TrkB-Induced Inhibition of R-SMAD/SMAD4 Activation is Essential for TGF-β-Mediated Tumor Suppressor Activity

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