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

Evaluation of fuel resources and requirements for the magnetic fusion energy program

Information is given for each of the following topics: (1) requirements for experimental fusion power reactors, (2) tritium requirements, (3) sources of T, (4) T availability from DOE production reactors, (5) T availability from heavy-water reactors, (6) T availability from light-water reactors, (7) T availability from fuel reprocessing plants, (8) natural Li requirements and availability, (9) /sup 6/Li requirements and availability, and (10) availability of /sup 3/He or /sup 4/He. (MOW

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