Mitochondrial ROS control neuronal excitability and cell fate in frontotemporal dementia.

INTRODUCTION: The second most common form of early-onset dementia-frontotemporal dementia (FTD)-is often characterized by the aggregation of the microtubule-associated protein tau. Here we studied the mechanism of tau-induced neuronal dysfunction in neurons with the FTD-related 10+16 MAPT mutation. METHODS: Live imaging, electrophysiology, and redox proteomics were used in 10+16 induced pluripotent stem cell-derived neurons and a model of tau spreading in primary cultures. RESULTS: Overproduction of mitochondrial reactive oxygen species (ROS) in 10+16 neurons alters the trafficking of specific glutamate receptor subunits via redox regulation. Increased surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors containing GluA1 and NR2B subunits leads to impaired glutamatergic signaling, calcium overload, and excitotoxicity. Mitochondrial antioxidants restore the altered response and prevent neuronal death. Importantly, extracellular 4R tau induces the same pathological response in healthy neurons, thus proposing a mechanism for disease propagation. DISCUSSION: These results demonstrate mitochondrial ROS modulate glutamatergic signaling in FTD, and suggest a new therapeutic strategy

Synaptic proximity enables NMDAR signalling to promote brain metastasis.

Metastasis-the disseminated growth of tumours in distant organs-underlies cancer mortality. Breast-to-brain metastasis (B2BM) is a common and disruptive form of cancer and is prevalent in the aggressive basal-like subtype, but is also found at varying frequencies in all cancer subtypes. Previous studies revealed parameters of breast cancer metastasis to the brain, but its preference for this site remains an enigma. Here we show that B2BM cells co-opt a neuronal signalling pathway that was recently implicated in invasive tumour growth, involving activation by glutamate ligands of N-methyl-D-aspartate receptors (NMDARs), which is key in model systems for metastatic colonization of the brain and is associated with poor prognosis. Whereas NMDAR activation is autocrine in some primary tumour types, human and mouse B2BM cells express receptors but secrete insufficient glutamate to induce signalling, which is instead achieved by the formation of pseudo-tripartite synapses between cancer cells and glutamatergic neurons, presenting a rationale for brain metastasis.This work was principally supported by grants from the Swiss National Science Foundation and the European Research Council, and by a gift from the Biltema Foundation that was administered by the ISREC Foundation, Lausanne, Switzerland

Indobufen is a potent inhibitor of whole blood aggregation in patients with a high atherosclerotic risk

The newly developed method, based on the quantitation of changes in electrical impedance, to determine platelet aggregation in whole blood was applied to the evaluation of the effects of Indobufen, a well known inhibitor of platelet rich plasma aggregation. The platelet antiaggregatory activity of the drug after single (200 or 400 mg) and repeated doses (200 mg or 200 mg b.i.d. for 1 week) was determined on whole blood aggregation and thromboxane B2 formation by platelet rich plasma of 16 patients with high risk of atherosclerosis. At 2 hr after the single dose treatments, Indobufen significantly reduced the whole blood aggregation induced by 0.5-2 micrograms/ml collagen. At 24 hr from the intake of the drug the aggregation was significantly inhibited in patients who ingested the 400 mg dose only. As far as the repeated administrations are concerned, it appears that the inhibition of whole blood aggregation and thromboxane B2 formation by platelets reached 12 hr after the last drug administration was comparable to the degree of inhibition achieved 2 hr after Indobufen intake. It is concluded that Indobufen orally administered to patients with high risk of atherosclerosis is a potent inhibitor of whole blood aggregation