Cancer cells are critically dependent on ER–mitochondria Ca2+ flux that regulates their bioenergetics. Here, Raturi et al. identify the ER oxidoreductase TMX1 as a thiol-dependent regulator of this intracellular signaling mechanism within cancer cells.

Kainic acid, an analogue of the excitatory neurotransmitter glutamate, can trigger seizures and neurotoxicity in the hippocampus and other limbic structures in a manner that mirrors the neuropathology of human temporal lobe epilepsy (TLE). However, the underlying mechanisms associated with the neurotoxicity remain unclear. Since amyloid-β (Aβ) peptides, which are critical in the development of Alzheimer's disease, can mediate toxicity by activating glutamatergic NMDA receptors, it is likely that the enhanced glutamatergic transmission that renders hippocampal neurons vulnerable to kainic acid treatment may involve Aβ peptides. Thus, we seek to establish what role Aβ plays in kainic acid-induced toxicity using in vivo and in vitro paradigms. Our results show that systemic injection of kainic acid to adult rats triggers seizures, gliosis and loss of hippocampal neurons, along with increased levels/processing of amyloid precursor protein (APP), resulting in the enhanced production of Aβ-related peptides. The changes in APP levels/processing were evident primarily in activated astrocytes, implying a role for astrocytic Aβ in kainic acid-induced toxicity. Accordingly, we showed that treating rat primary cultured astrocytes with kainic acid can lead to increased Aβ production/secretion without any compromise in cell viability. Additionally, we revealed that kainic acid reduces neuronal viability more in neuronal/astrocyte co-cultures than in pure neuronal culture, and this is attenuated by precluding Aβ production. Collectively, these results indicate that increased production/secretion of Aβ-related peptides from activated astrocytes can contribute to neurotoxicity in kainic acid-treated rats. Since kainic acid administration can lead to neuropathological changes resembling TLE, it is likely that APP/Aβ peptides derived from astrocytes may have a role in TLE pathogenesis.

Background: Amyloid-β (Aβ) peptides are a family of proteins that are considered to be a principal aspect of Alzheimer's disease (AD), the most common cause of senile dementia affecting elderly individuals. These peptides result from the proteolytic processing of amyloid precursor protein (APP) by sequential cleavage mediated via β- and γ-secretases. Evidence suggests that an overproduction and/or a lack of degradation may increase brain Aβ levels which, in turn, contribute to neuronal loss and development of AD. Objectives: In this study, we seek to determine what effect Aβ has on APP processing in cultured astrocytes. Methods: Using the human astrocytoma cell line U-373, we investigated the effects induced by oligomeric Aβ_1-42 treatment on the cellular levels/expression of APP and its products, C-terminal fragments αCTF and βCTF, and Aβ_1-40. In conjunction with these experiments, we examined the relative levels and activity of β- and γ-secretases in Aβ-treated astrocytes. Results: We report here that Aβ_1-42 treatment of astrocytes increased the expression of APP and its cleaved products including Aβ_1-40 in a time-dependent manner. Conclusions: These results suggest that activated astrocytes can contribute to the development of AD by enhancing levels and processing of APP leading to an increased production/secretion of Aβ-related peptides.

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