The microtubule-associated protein Tau is strongly implicated in Alzheimer’s disease (AD) and aggregates into neurofibrillary tangles in AD. Genetic reduction of Tau is protective in several animal models of AD and cell culture models of amyloid-β (Aβ) toxicity, making it an exciting therapeutic target for treating AD. A variety of evidence indicates that Tau’s interactions with Fyn kinase and other SH3 domain–containing proteins, which bind to PxxP motifs in Tau’s proline-rich domain, may contribute to AD deficits and Aβ toxicity. Thus, we sought to determine if inhibiting Tau-SH3 interactions ameliorates Aβ toxicity. We developed a peptide inhibitor of Tau-SH3 interactions and a proximity ligation assay (PLA)-based target engagement assay. Then, we used membrane trafficking and neurite degeneration assays to determine if inhibiting Tau-SH3 interactions ameliorated Aβ oligomer (Aβo)-induced toxicity in primary hippocampal neurons from rats. We verified that Tau reduction ameliorated Aβo toxicity in neurons. Using PLA, we identified a peptide inhibitor that reduced Tau-SH3 interactions in HEK-293 cells and primary neurons. This peptide reduced Tau phosphorylation by Fyn without affecting Fyn’s kinase activity state. In primary neurons, endogenous Tau-Fyn interaction was present primarily in neurites and was reduced by the peptide inhibitor, from which we inferred target engagement. Reducing Tau-SH3 interactions in neurons ameliorated Aβo toxicity by multiple outcome measures, namely Aβo-induced membrane trafficking abnormalities and neurite degeneration. Our results indicate that Tau-SH3 interactions are critical for Aβo toxicity and that inhibiting them is a promising therapeutic target for AD.

Sudden Unexpected Death in Epilepsy (SUDEP) is a leading cause of epilepsy-related mortality, and the analysis of mouse SUDEP models is steadily revealing a spectrum of inherited risk phenotypes based on distinct genetic mechanisms. Serotonin (5-HT) signaling enhances post-ictal cardiorespiratory drive and, when elevated in the brain, reduces death following evoked audiogenic brainstem seizures in inbred mouse models. However, no gene in this pathway has yet been linked to a spontaneous epilepsy phenotype, the defining criterion of SUDEP. Most monogenic models of SUDEP invoke a failure of inhibitory synaptic drive as a critical pathogenic step. Accordingly, the G protein-coupled, membrane serotonin receptor 5-HT2C inhibits forebrain and brainstem networks by exciting GABAergic interneurons, and deletion of this gene lowers the threshold for lethal evoked audiogenic seizures. Here we characterize epileptogenesis throughout the lifespan of mice lacking X-linked, 5-HT2C receptors (loxTB Htr2c). We find that loss of Htr2c generates a complex, adult-onset spontaneous epileptic phenotype with a novel progressive hyperexcitability pattern of absences, non-convulsive, and convulsive behavioral seizures culminating in late onset sudden mortality predominantly in male mice. RNAscope localized Htr2c mRNA in subsets of Gad2+ GABAergic neurons in forebrain and brainstem regions. To evaluate the contribution of 5-HT2C receptor-mediated inhibitory drive, we selectively spared their deletion in GAD2+ GABAergic neurons of pan-deleted loxTB Htr2c mice, yet unexpectedly found no amelioration of survival or epileptic phenotype, indicating that expression of 5-HT2C receptors in GAD2+ inhibitory neurons was not sufficient to prevent hyperexcitability and lethal seizures. Analysis of human SUDEP and epilepsy genetic databases identified an enrichment of HTR2C non-synonymous variants in SUDEP cases. Interestingly, while early lethality is not reflected in the mouse model, we also identified variants mainly among male Sudden Infant Death Syndrome patients. Our findings validate HTR2C as a novel, sex-linked candidate gene modifying SUDEP risk, and demonstrate that the complex epilepsy phenotype does not arise solely from 5-HT2C-mediated synaptic disinhibition. These results strengthen the evidence for the serotonin hypothesis of SUDEP risk in humans, and advance current efforts to develop gene-guided interventions to mitigate premature mortality in epilepsy.

The microtubule-associated protein Tau is strongly implicated in Alzheimer's disease (AD) and aggregates into neurofibrillary tangles in AD. Genetic reduction of Tau is protective in several animal models of AD and cell culture models of amyloid-β (Aβ) toxicity, making it an exciting therapeutic target for treating AD. A variety of evidence indicates that Tau's interactions with Fyn kinase and other SH3 domain-containing proteins, which bind to PxxP motifs in Tau's proline-rich domain, may contribute to AD deficits and Aβ toxicity. Thus, we sought to determine if inhibiting Tau-SH3 interactions ameliorates Aβ toxicity. We developed a peptide inhibitor of Tau-SH3 interactions and a proximity ligation assay (PLA)-based target engagement assay. Then, we used membrane trafficking and neurite degeneration assays to determine if inhibiting Tau-SH3 interactions ameliorated Aβ oligomer (Aβo)-induced toxicity in primary hippocampal neurons from rats. We verified that Tau reduction ameliorated Aβo toxicity in neurons. Using PLA, we identified a peptide inhibitor that reduced Tau-SH3 interactions in HEK-293 cells and primary neurons. This peptide reduced Tau phosphorylation by Fyn without affecting Fyn's kinase activity state. In primary neurons, endogenous Tau-Fyn interaction was present primarily in neurites and was reduced by the peptide inhibitor, from which we inferred target engagement. Reducing Tau-SH3 interactions in neurons ameliorated Aβo toxicity by multiple outcome measures, namely Aβo-induced membrane trafficking abnormalities and neurite degeneration. Our results indicate that Tau-SH3 interactions are critical for Aβo toxicity and that inhibiting them is a promising therapeutic target for AD.

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We present here SPECULOOS, a new exoplanet transit search based on a network of 1m-class robotic telescopes targeting the ∼1200 ultracool (spectral type M7 and later) dwarfs bright enough in the infrared (K-mag ≤ 12.5) to possibly enable the atmospheric characterization of temperate terrestrial planets with next-generation facilities like the James Webb Space Telescope. The ultimate goals of the project are to reveal the frequency of temperate terrestrial planets around the lowest-mass stars and brown dwarfs, to probe the diversity of their bulk compositions, atmospheres and surface conditions, and to assess their potential habitability.

Background: Alzheimer's disease (AD) is the leading cause of dementia and lacks disease-modifying treatments. Tau-based therapies are attractive and Tau reduction prevents amyloid-induced dysfunction in preclinical AD models. Tau reduction also prevents amyloid-independent dysfunction in diverse disease contexts, suggesting that strategies exploiting the mechanisms underlying Tau reduction may extend beyond AD. Tau's interaction with SH3 domain containing proteins likely underlie mechanisms of amyloid-induced dysfunction, so we targeted their interaction as a therapeutic strategy. Method:We previously designed a peptide Tau-SH3 interaction inhibitor based on the region of Tau that binds FynSH3, and determined that it prevented amyloid-induced dysfunction in primary neurons. We next completed a high-throughput screen to identify compounds that inhibit Tau-Fyn interaction. Here, we studied a top hit from that screen, generated and characterized a series of daughter compounds, and tested whether the compounds prevented amyloid-induced dysfunction in primary neurons. Result:The hit compound, SR31627, prevented amyloid-β toxicity in primary neurons.The medicinal chemistry program resulted in lead compound SR42667, which had fivefold improved potency and improved drug-like properties. We found that SR42667 binds Tau, is cell-permeable, and prevents amyloid-induced dysfunction. Conclusion:We demonstrate that Tau-SH3 interactions can be targeted using small molecule inhibitors and that these inhibitors have efficacy for blocking amyloidinduced dysfunction.