BDNF Reduces Toxic Extrasynaptic NMDA Receptor Signaling via Synaptic NMDA Receptors and Nuclear-Calcium-Induced Transcription of inhba/Activin A

Lau, David Tai-Wai; Bengtson, C. Peter; Buchthal, Bettina; Bading, Hilmar

doi:10.1016/j.celrep.2015.07.038

Cited by 85 publications

(60 citation statements)

References 49 publications

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“…Using neocortical cultures (neurons and glial cells), we have confirmed previous observations demonstrating that BDNF fails to protect neurons from excitotoxicity produced by necrotic mechanisms (Koh et al , ). In contrast, BDNF could attenuate apoptotic neuronal death induced in these same cultures by different stimulus (Gawg et al , ) or in an alternative cellular paradigm of excitotoxicity (semi‐pure hippocampal neurons; Gomes et al , ; Lau et al , ) where NMDA activates apoptosis (Almeida et al , ). Since both types of neuronal death occur in the ischemic brain, the in vivo efficacy of BDNF administration might be limited to a subpopulation of the degenerating neurons.…”

Section: Discussionmentioning

confidence: 99%

Prevention of excitotoxicity‐induced processing of BDNF receptor TrkB‐FL leads to stroke neuroprotection

et al. 2019

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Neuroprotective strategies aimed to pharmacologically treat stroke, a prominent cause of death, disability, and dementia, have remained elusive. A promising approach is restriction of excitotoxic neuronal death in the infarct penumbra through enhancement of survival pathways initiated by brain‐derived neurotrophic factor (BDNF). However, boosting of neurotrophic signaling after ischemia is challenged by downregulation of BDNF high‐affinity receptor, full‐length tropomyosin‐related kinase B (TrkB‐FL), due to calpain‐degradation, and, secondarily, regulated intramembrane proteolysis. Here, we have designed a blood–brain barrier (BBB) permeable peptide containing TrkB‐FL sequences (TFL 457 ) which prevents receptor disappearance from the neuronal surface, early induced after excitotoxicity. In this way, TFL 457 interferes TrkB‐FL cleavage by both proteolytic systems and increases neuronal viability via a PLCγ‐dependent mechanism. By preserving downstream CREB and MEF2 promoter activities, TFL 457 initiates a feedback mechanism favoring increased levels in excitotoxic neurons of critical prosurvival mRNAs and proteins. This neuroprotective peptide could be highly relevant for stroke therapy since, in a mouse ischemia model, it counteracts TrkB‐FL downregulation in the infarcted brain, efficiently decreases infarct size, and improves neurological outcome.

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Section: Discussionmentioning

confidence: 99%

Prevention of excitotoxicity‐induced processing of BDNF receptor TrkB‐FL leads to stroke neuroprotection

et al. 2019

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“…The corresponding process, providing protection against ischemic brain damage, could be altered in AD, or aging-related neurodegenerative conditions (Lau et al, 2015). The NIN gene encodes ninein ( GSK3B interacting protein), and variants of GSK3B have been shown to be linked with AD and interacted with the APOE genotype (Izzo et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association and interaction studies of CSF T-tau/Aβ42 ratio in ADNI cohort

Zhang

Chen

et al. 2017

Neurobiology of Aging

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The pathogenic relevance in Alzheimer’s disease (AD) presents a decrease of cerebrospinal fluid (CSF) amyloid-β42 (Aβ42) burden and an increase in CSF total-tau (T-tau) levels. In this work, we performed genome-wide association study (GWAS) and genome-wide interaction study (GWIS) of T-tau/Aβ42 ratio as an AD imaging quantitative trait (QT) on 843 subjects and 563,980 single nucleotide polymorphisms (SNPs) in ADNI cohort. We aim to identify not only SNPs with significant main effects but also SNPs with interaction effects to help explain “missing heritability”. Linear regression method was used to detect SNP-SNP interactions among SNPs with uncorrected p-value≤0.01 from the GWAS. Age, gender and diagnosis were considered as covariates in both studies. The GWAS results replicated the previously reported AD-related genes APOE, APOC1 and TOMM40, as well as identified 14 novel genes, which showed genome-wide statistical significance. GWIS revealed 7 pairs of SNPs meeting the cell-size criteria and with bonferroni-corrected p-value≤0.05. As we expect, these interaction pairs all had marginal main effects but explained a relatively high-level variance of T-tau/Aβ42, demonstrating their potential association with AD pathology.

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“…S3). Expression of an inactive form of CaMBP4 (mut-CaMBP4.mCherry; Lau et al, 2015) did not block IL-2 production in T cells ( Fig. S2 B).…”

Section: Nuclear Calcium Induces the Expression Of Activation Markersmentioning

confidence: 95%

Nuclear calcium is required for human T cell activation

Monaco

Jahraus

Samstag

et al. 2016

Journal of Cell Biology

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BDNF Reduces Toxic Extrasynaptic NMDA Receptor Signaling via Synaptic NMDA Receptors and Nuclear-Calcium-Induced Transcription of inhba/Activin A

Cited by 85 publications

References 49 publications

Prevention of excitotoxicity‐induced processing of BDNF receptor TrkB‐FL leads to stroke neuroprotection

Prevention of excitotoxicity‐induced processing of BDNF receptor TrkB‐FL leads to stroke neuroprotection

Genome-wide association and interaction studies of CSF T-tau/Aβ42 ratio in ADNI cohort

Nuclear calcium is required for human T cell activation

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