Search

Halipi et al. explored the impact of extracellular vesicles (EVs) on amyloid-β (Aβ) aggregation. They concluded that EVs reduce Aβ aggregation, as seen by shorter and thicker fibrils. While we agree with the complex role of EVs in Alzheimer's disease, we are sceptical of the claim that EVs slow down Aβ aggregation, noting missing key references. Previous literature rather suggests that EVs (derived from neuronal cell lines) accelerate the process of Aβ fibrillation and plaque formation. Halipi et al.'s findings may be skewed due to the lack of essential neuronally expressed Aβ-binding partners, like the prion protein (PrP C ) in their EV samples. The commentary, in the light of included original experiments and cited literature, suggests that membrane proteins like PrP C are crucial to fully understand the role of EVs in Aβ aggregation, and Halipi et al.'s conclusions should be reexamined in light of these factors.

Autophagic flux can be quantified based on the accumulation of lipidated LC3B in the presence of late-stage autophagy inhibitors. This method has been widely applied to identify novel compounds that activate autophagy. Here we scrutinize this approach and show that bafilomycin A1 (BafA) but not chloroquine is suitable for flux quantification due to the stimulating effect of chloroquine on non-canonical LC3B-lipidation. Significant autophagic flux increase by rapamycin could only be observed when combining it with BafA concentrations not affecting basal flux, a condition which created a bottleneck, rather than fully blocking autophagosome-lysosome fusion, concomitant with autophagy stimulation. When rapamycin was combined with saturating concentrations of BafA, no significant further increase of LC3B lipidation could be detected over the levels induced by the late-stage inhibitor. The large assay window obtained by this approach enables an effective discrimination of autophagy activators based on their cellular potency. To demonstrate the validity of this approach, we show that a novel inhibitor of the acetyltransferase EP300 activates autophagy in a mTORC1-dependent manner. We propose that the creation of a sensitized background rather than a full block of autophagosome progression is required to quantitatively capture changes in autophagic flux., (© 2022. The Author(s).)

The influence of a low dose of morphine was investigated on the acquisition and maintenance of consumption of a sweetened ethanol solution with water as the alternative in a two-bottle choice procedure. During acquisition in Experiment 1, morphine failed to significantly increase the consumption of a sweetened ethanol solution compared to either a postinjection period in the same animals or a no-treatment control group. Although morphine significantly increased sweetened ethanol consumption when compared to a saline control group, this appears to be due to a stress response to the injections, which suppressed ethanol consumption in the saline animals. During maintenance in Experiment 2, morphine significantly increased consumption of sweetened ethanol in all groups compared to consumption following saline control injections. There was no difference in this effect among the three groups, suggesting that prior history with morphine was not a factor. In addition, rats that were exposed to morphine during both experiments drank significantly more sweetened ethanol following injections in Experiment 2 than in Experiment 1. This suggests that morphine's potentiation of ethanol consumption is due to its interaction with endogenous opioid receptors that modulate the reward value of ethanol rather than more general mechanisms affecting satiety or taste. The results of these experiments provide support for both the Deficit and Surfeit Hypotheses of ethanol consumption, both of which suggest that endogenous opioid receptors are responsible, in part, for ethanol's reinforcing properties.