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Abstract BackgroundNeuronal polarity and synaptic connectivity are compromised in Alzheimer’s disease (AD) and other tauopathies. The axon initial segment (AIS) is a key structure for regulating polarity and functions of neurons. It occupies the first 20‐60 µm of the axon, comprises a diffusion barrier that segregates axon‐enriched from somatodendritic‐enriched molecules, and has a high concentration of voltage‐gated ion channels that generate action potentials. Extracellular amyloid‐β oligomers compromise AIS integrity. However, effects on the AIS of toxic tau species, including extracellular oligomers (xcTauOs) that spread tau pathology from neuron to neuron by a prion‐like process, whereas unknown. Therefore, we wanted to test the hypothesis that AIS structure is sensitive to xcTauOs. MethodPrimary cortical neurons derived from either wild type (WT), or tau knockout (KO) mice were exposed to xcTauOs or vehicle. Quantitative western blotting and immunofluorescence microscopy with an antibody against the AIS‐enriched protein TRIM46 was used to monitor effects on the AIS. The same methods were also used to compare TRIM46 and two other AIS proteins, ankyrin‐G and neurofascin‐186 in human hippocampal tissue obtained from AD and age‐matched non‐AD donors. ResultIn cultured WT, but not TKO neurons, xcTauOs cause a trend toward AIS shortening and reduce the concentration of the resident AIS protein, TRIM46, without affecting total TRIM46 levels. Lentiviral‐driven human tau expression in tau KO neurons rescues TRIM46 sensitivity to xcTauOs. In human AD hippocampus, AIS length and TRIM46 concentration within the AIS are reduced in neurons containing neurofibrillary tangles (NFTs), without affecting the overall protein levels of multiple resident AIS proteins. ConclusionThese collective findings demonstrate that in cultured neurons, xcTauOs cause partial AIS damage by a mechanism dependent on intracellular tau, thereby raising the possibility that AIS reduction in AD is caused by xcTauOs working in concert with endogenous neuronal tau. 

Abstract The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) plays a key role in tumor progression and response to therapy. The dense PDAC stroma causes hypovascularity, which leads to hypoxia. Here, we showed that hypoxia drives long-lasting epithelial–mesenchymal transition (EMT) in PDAC primarily through a positive-feedback histone methylation–MAPK signaling axis. Transformed cells preferentially underwent EMT in hypoxic tumor regions in multiple model systems. Hypoxia drove a cell autonomous EMT in PDAC cells, which, unlike EMT in response to growth factors, could last for weeks. Furthermore, hypoxia reduced histone demethylase KDM2A activity, suppressed PP2 family phosphatase expression, and activated MAPKs to post-translationally stabilize histone methyltransferase NSD2, leading to an H3K36me2-dependent EMT in which hypoxia-inducible factors played only a supporting role. Hypoxia-driven EMT could be antagonized in vivo by combinations of MAPK inhibitors. Collectively, these results suggest that hypoxia promotes durable EMT in PDAC by inducing a histone methylation–MAPK axis that can be effectively targeted with multidrug therapies, providing a potential strategy for overcoming chemoresistance. Significance:Integrated regulation of histone methylation and MAPK signaling by the low-oxygen environment of pancreatic cancer drives long-lasting EMT that promotes chemoresistance and shortens patient survival and that can be pharmacologically inhibited.See related commentary by Wirth and Schneider, p. 1739 

Background: In Alzheimer’s disease (AD) brain, neuronal polarity and synaptic connectivity are compromised. A key structure for regulating polarity and functions of neurons is the axon initial segment (AIS), which segregates somatodendritic from axonal proteins and initiates action potentials. Toxic tau species, including extracellular oligomers (xcTauOs), spread tau pathology from neuron to neuron by a prion-like process, but few other cell biological effects of xcTauOs have been described. Objective: Test the hypothesis that AIS structure is sensitive to xcTauOs. Methods: Cultured wild type (WT) and tau knockout (KO) mouse cortical neurons were exposed to xcTauOs, and quantitative western blotting and immunofluorescence microscopy with anti-TRIM46 monitored effects on the AIS. The same methods were used to compare TRIM46 and two other resident AIS proteins in human hippocampal tissue obtained from AD and age-matched non-AD donors. Results: Without affecting total TRIM46 levels, xcTauOs reduce the concentration of TRIM46 within the AIS and cause AIS shortening in cultured WT, but not TKO neurons. Lentiviral-driven tau expression in tau KO neurons rescues AIS length sensitivity to xcTauOs. In human AD hippocampus, the overall protein levels of multiple resident AIS proteins are unchanged compared to non-AD brain, but TRIM46 concentration within the AIS and AIS length are reduced in neurons containing neurofibrillary tangles. Conclusion: xcTauOs cause partial AIS damage in cultured neurons by a mechanism dependent on intracellular tau, thereby raising the possibility that the observed AIS reduction in AD neurons in vivo is caused by xcTauOs working in concert with endogenous neuronal tau.