Identification of an ERK inhibitor as a therapeutic drug against tau aggregation in a new cell-based assay

Formation of Tau aggregates is a common pathological feature of tauopathies and their accumulation directly correlates with cytotoxicity and neuronal degeneration. Great efforts have been made to understand Tau aggregation and to find therapeutics halting or reversing the process, however, progress has been slowed due to the lack of a suitable method for monitoring Tau aggregation. We developed a cell-based assay allowing to detect and quantify Tau aggregation in living cells. The system is based on the FRET biosensor CST able to monitor the molecular dynamic of Tau aggregation in different cellular conditions. We probed candidate compounds that could block Tau hyperphosphorylation. In particular, to foster the drug discovery process, we tested kinase inhibitors approved for the treatment of other diseases. We identified the ERK inhibitor PD-901 as a promising therapeutic molecule since it reduces and prevents Tau aggregation. This evidence establishes the CST cell-based aggregation assay as a reliable tool for drug discovery and suggests that PD-901 might be a promising compound to be tested for further preclinical studies on AD

Candiduria in critically ill children: Risk factors and predictors of mortality

We studied 28 cases of pediatric candiduria for risk factors and predictors for mortality among 101 children admitted within a 2-year period to two pediatric intensive care units in a tertiary hospital. The case-control study, comparing candidemic and noncandiduric children matched for underlying disease, age, APACHE II score, and surgical intervention, revealed several risk factors for candiduria. Urinary tract abnormalities, use of a urinary catheter, prior dialysis, total parenteral nutrition, use of a vascular catheter, artificial ventilation, and duration of therapy with broad-spectrum antibiotics were statistically significantly associated with candiduria (P 21 days, use of more than four antibiotics in therapy for greater than or equal to 10 days, and absence of antifungal therapy were significant predictors of poor outcome (P < .001-.04)

Deletion of murine tau gene increases tau aggregation in a human mutant tau transgenic mouse model.

We have reported previously a tau transgenic mouse model (Tg30tau) overexpressing human 4R1N double-mutant tau (P301S and G272V) and that develops AD (Alzheimer's disease)-like NFTs (neurofibrillary tangles) in an age-dependent manner. Since murine tau might interfere with the toxic effects of human mutant tau, we set out to analyse the phenotype of our Tg30tau model in the absence of endogenous murine tau with the aim to reproduce more faithfully a model of human tauopathy. By crossing the Tg30tau line with TauKO (tau-knockout) mice, we have obtained a new mouse line called Tg30xTauKO that expresses only exogenous human double-mutant 4R1N tau. Whereas Tg30xTauKO mice express fewer tau proteins compared with Tg30tau, they exhibit augmented sarkosyl-insoluble tau in the brain and an increased number of Gallyas-positive NFTs in the hippocampus. Taken together, exclusion of murine tau causes accelerated tau aggregation during aging of this mutant tau transgenic model.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: re.jinfo:eu-repo/semantics/publishe