Currently, there are no available approaches to cure or slow down the progression of Alzheimer’s disease (AD), which is characterized by the accumulation of extracellular amyloid-β (Aβ) deposits and intraneuronal tangles composed of hyperphosphorylated tau. β2 adrenergic receptors (β2ARs) are expressed throughout the cortex and hippocampus and play a key role in cognitive functions. Alterations in the function of these receptors have been linked to Alzheimer’s disease; however these data remain controversial as apparent contradicting reports have been published. Given the current demographics of growing elderly population and the high likelihood of concurrent beta-blocker use for other chronic conditions, more studies into the role of this receptor in AD animal models are needed. Here we show that administration of ICI 118,551, a selective β2AR antagonist, exacerbates cognitive deficits in a mouse model of AD, the 3xTg-AD mice. Neuropathologically, ICI 118,551 increased Aβ levels and Aβ plaque burden. Concomitantly, ICI 118,551-treated 3xTg-AD mice showed an increase in tau phosphorylation and accumulation. Mechanistically, these changes were linked to an increase in amyloidogenic APP processing. These results suggest that under the conditions used here, selective pharmacological inhibition of β2ARs has detrimental effects on AD-like pathology in mice. Overall, these studies strengthen the notion that the link between β2ARs and AD is likely highly complex and suggest caution in generalizing the beneficial effects of beta-blockers on AD.
The survival of patients diagnosed with glioblastoma (GBM), the most deadly form of brain cancer, is compromised by the proclivity for local invasion into the surrounding normal brain, which prevents complete surgical resection and contributes to therapeutic resistance. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor (TNF) superfamily, can stimulate glioma cell invasion and survival via binding to fibroblast growth factor-inducible 14 (Fn14) and subsequent activation of the transcription factor NF-κB. To discover small molecule inhibitors that disrupt the TWEAK-Fn14 signaling axis, we utilized a cell-based drug-screening assay using HEK293 cells engineered to express both Fn14 and a NF-κB-driven firefly luciferase reporter protein. Focusing on the LOPAC1280 library of 1280 pharmacologically active compounds, we identified aurintricarboxylic acid (ATA) as an agent that suppressed TWEAK-Fn14-NF-κB dependent signaling, but not TNFα-TNFR-NF-κB driven signaling. We demonstrated that ATA repressed TWEAK-induced glioma cell chemotactic migration and invasion via inhibition of Rac1 activation but had no effect on cell viability or Fn14 expression. In addition, ATA treatment enhanced glioma cell sensitivity to both the chemotherapeutic agent temozolomide (TMZ) and radiation-induced cell death. In summary, this work reports a repurposed use of a small molecule inhibitor that targets the TWEAK-Fn14 signaling axis, which could potentially be developed as a new therapeutic agent for treatment of GBM patients.
Background Neddylation inhibition, affecting posttranslational protein function and turnover, is a promising therapeutic approach to cancer. We report vulnerability to MLN4924 or pevonedistat (a neddylation inhibitor) in a subset of glioblastoma (GBM) preclinical models and identify biomarkers, mechanisms, and signatures of differential response. Methods GBM sequencing data was queried for genes associated with MLN4924 response status; candidates were validated by molecular techniques. Time-course transcriptomics and proteomics revealed processes implicated in MLN4924 response. Results Vulnerability to MLN4924 is associated with elevated S-phase populations, re-replication, and DNA damage. Transcriptomics and shotgun proteomics depict PTEN signaling, DNA replication, and chromatin instability pathways as significant differentiators between sensitive and resistant models. Loss of PTEN and its nuclear functions is associated with resistance to MLN4924. Time-course proteomics identified elevated TOP2A in resistant models through treatment. TOP2A inhibitors combined with MLN4924 prove synergistic. Conclusions We show that PTEN status serves as both a novel biomarker for MLN4924 response in GBM and reveals a vulnerability to TOP2A inhibitors in combination with MLN4924.
We present a case of metastatic neuroblastoma to the mandible in an 11-month-old patient presenting with worsening right-sided proptosis and scalp swelling after a fall 2 weeks prior. Initial evaluation with computed tomography of the head demonstrated soft tissue masses centered at the right sphenoid and right mandible. These masses proved to be metastatic lesions from an intra-abdominal neuroblastoma. Review of the literature revealed 20 cases of neuroblastoma metastasis to the mandible over the past 70 years. To our knowledge, our patient is the youngest reported case with asymptomatic mandibular metastasis related to neuroblastoma and the first to be characterized with magnetic resonance imaging.
Alzheimer's Disease (AD) is characterized by decreased levels of acetylcholine and formation of neurotoxic β‐amyloid plaque. The result is a loss of cognitive function. Both effects correlate with elevated levels of butyrylcholinesterase (BuChE) activity. Reversible cholinesterase inhibitors have been shown to decrease β‐amyloid peptide formation in animal models. We have shown that aryl dialkyl phosphates are potent and highly selective irreversible inhibitors of BuChE. In this study, the toxicity of di‐n‐butyl 2‐chlorophenyl phosphate (DB2ClPP) was determined in cultured human SK‐N‐SH neuroblastoma cells. Cells were exposed to increasing concentrations of DB2ClPP for 24 hrs and then assayed for changes in cell proliferation, membrane integrity, and induction of apoptosis. Concentrations of DB2ClPP as high as 10 μM had no effect on any of these parameters. Incubation of whole blood with DB2ClPP revealed that the compound is present at detectable levels in plasma after 1 hr. These studies suggest that there is a significant potential for this class of compounds as a therapeutic to treat the symptoms of AD.
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