Effects of APOE4 allelic dosage on lipidomic signatures in the entorhinal cortex of aged mice

Apolipoprotein E ε4 (APOE4) is the primary genetic risk factor for the late-onset form of Alzheimer's disease (AD). Although the reason for this association is not completely understood, researchers have uncovered numerous effects of APOE4 expression on AD-relevant brain processes, including amyloid beta (Aβ) accumulation, lipid metabolism, endosomal-lysosomal trafficking, and bioenergetics. In this study, we aimed to determine the effect of APOE4 allelic dosage on regional brain lipid composition in aged mice, as well as in cultured neurons. We performed a targeted lipidomic analysis on an AD-vulnerable brain region (entorhinal cortex; EC) and an AD-resistant brain region (primary visual cortex; PVC) from 14-15 month-old APOE3/3, APOE3/4, and APOE4/4 targeted replacement mice, as well as on neurons cultured with conditioned media from APOE3/3 or APOE4/4 astrocytes. Our results reveal that the EC possesses increased susceptibility to APOE4-associated lipid alterations compared to the PVC. In the EC, APOE4 expression showed a dominant effect in decreasing diacylglycerol (DAG) levels, and a semi-dominant, additive effect in the upregulation of multiple ceramide, glycosylated sphingolipid, and bis(monoacylglycerol)phosphate (BMP) species, lipids known to accumulate as a result of endosomal-lysosomal dysfunction. Neurons treated with conditioned media from APOE4/4 vs. APOE3/3 astrocytes showed similar alterations of DAG and BMP species to those observed in the mouse EC. Our results suggest that APOE4 expression differentially modulates regional neuronal lipid signatures, which may underlie the increased susceptibility of EC-localized neurons to AD pathology

Kinematics of Mass Transport Deposits revealed by magnetic fabrics

This study was supported by the Israel Science Foundation (ISF grants No. 1245/11 and 1436/14). We thank the Editor A. V. Newman and the reviewers M. Jackson and B. Almqvist, whose comments and suggestions improved the quality of our manuscript. The laboratory assistance of Ran Issachar and Daniel Zvi is highly acknowledged. All data used in this analysis is presented in Figures 1-4 and Table 1. Correspondence and requests for materials should be addressed to R.W. ([email protected]).Peer reviewedPublisher PD

Brain energy rescue:an emerging therapeutic concept for neurodegenerative disorders of ageing

The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner — a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes

A co-condensation model for in-flight synthesis of metal-carbide nanoparticles in thermal plasma jet

We present a theoretical analysis of the formation, growth, and transport of two-component nanoparticles in thermal plasma jet. The approach of the aerosol science and the idea of multicomponent co-condensation are employed for the analysis. The processes of homogeneous nucleation, heterogeneous growth, and coagulations due to Brownian collisions are considered in combination with the convective and diffusive transport of particles and the reacting gases within an axisymmetric domain. As a particular example, the authors study multicomponent co-condensation of metal-carbide nanoparticles from various precursors in a DC plasma gun operating in an argon atmosphere