CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice

Neuroinflammation and microglial activation are significant processes in Alzheimer's disease pathology. Recent genome-wide association studies have highlighted multiple immune-related genes in association with Alzheimer's disease, and experimental data have demonstrated microglial proliferation as a significant component of the neuropathology. In this study, we tested the efficacy of the selective CSF1R inhibitor JNJ-40346527 (JNJ-527) in the P301S mouse tauopathy model. We first demonstrated the anti-proliferative effects of JNJ-527 on microglia in the ME7 prion model, and its impact on the inflammatory profile, and provided potential CNS biomarkers for clinical investigation with the compound, including pharmacokinetic/pharmacodynamics and efficacy assessment by TSPO autoradiography and CSF proteomics. Then, we showed for the first time that blockade of microglial proliferation and modification of microglial phenotype leads to an attenuation of tau-induced neurodegeneration and results in functional improvement in P301S mice. Overall, this work strongly supports the potential for inhibition of CSF1R as a target for the treatment of Alzheimer's disease and other tau-mediated neurodegenerative diseases

Inflammatory biomarkers in Alzheimer's disease plasma

Introduction: Plasma biomarkers for Alzheimer's disease (AD) diagnosis/stratification are a \u201cHoly Grail\u201d of AD research and intensively sought; however, there are no well-established plasma markers. Methods: A hypothesis-led plasma biomarker search was conducted in the context of international multicenter studies. The discovery phase measured 53 inflammatory proteins in elderly control (CTL; 259), mild cognitive impairment (MCI; 199), and AD (262) subjects from AddNeuroMed. Results: Ten analytes showed significant intergroup differences. Logistic regression identified five (FB, FH, sCR1, MCP-1, eotaxin-1) that, age/APO\u3b54 adjusted, optimally differentiated AD and CTL (AUC: 0.79), and three (sCR1, MCP-1, eotaxin-1) that optimally differentiated AD and MCI (AUC: 0.74). These models replicated in an independent cohort (EMIF; AUC 0.81 and 0.67). Two analytes (FB, FH) plus age predicted MCI progression to AD (AUC: 0.71). Discussion: Plasma markers of inflammation and complement dysregulation support diagnosis and outcome prediction in AD and MCI. Further replication is needed before clinical translation

Chemical and optical studies of heat transfer fluids containing solar energy absorbers

The purpose of the present study is to enhance the absorptivities of potential heat transfer fluids to solar radiation. Quantitative measurements were made of the increase in absorptivity of the fluids to dissolved chromophoric materials. Some previous studies have been made of soluble and insoluble chromophores in aqueous solution. The heat transfer fluids chosen for this study had the following properties: liquid at ambient temperature, transparent to most of the solar spectrum, and low vapor pressure above the boiling point of water. Such liquids are generally commercially available organic and inorganic heat transfer fluids with potential application to mid-range solar thermal devices (T/sub max-/ < 350/sup 0/). Only chromophoric materials were considered which were soluble in the liquid

Tritium Systems Test Facility

This TSTF proposal has two principal objectives. The first objective is to provide by mid-FY 1981 a demonstration of the fuel cycle and tritium containment systems which could be used in a Tokamak Experimental Power Reactor for operation in the mid-1980's. The second objective is to provide a capability for further optimization of tritium fuel cycle and environmental control systems beyond that which is required for the EPR. The scale and flow rates in TSTF are close to those which have been projected for a prototype experimental power reactor (PEPR/ITR) and will permit reliable extrapolation to the conditions found in an EPR. The fuel concentrations will be the same as in an EPR. Demonstrations of individual components of the deuterium-tritium fuel cycle and of monitoring, accountability and containment systems and of a maintenance methodology will be achieved at various times in the FY 1979-80 time span. Subsequent to the individual component demonstrations--which will proceed from tests with hydrogen (and/or deuterium) through tracer levels of tritium to full operational concentrations--a complete test and demonstration of the integrated fuel processing and tritium containment facility will be performed. This will occur near the middle of FY 1981. Two options were considered for the TSTF: (1) The modification of an existing building and (2) the construction of a new facility