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

Modeling and measurements of generation and recombination currents in thin-film SOi gated-diodes

Generation-recombination (g-r) parameters are of great importance for SOI devices, because they determine junction leakage, bipolar effects, and various floating body effects. On the other hand, g-r parameters are the measure of the material and processing quality. In SOI devices, g-r parameters are generally determined from the transient drain current response of a SOI MOSFET to front- or back-gate pulses [1–3]. These measurements usually allow extracting the carrier lifetime without details as to the origin of g-r mechanisms. In this work, we discuss the gated-diode method based on d. c. measurements, which provides more detailed information about g-r processes [1,4]. The gated-diode method is widely used in a bulk-Si technology, because it enables easily to separate volume- and surface-related component [4]. In thin-film SOI devices, the behavior of g-r currents is more complicated due to interface coupling, the specific free carrier concentration distribution, and superposition of volume and surface components. Generally numerical simulation is required for the correct determination of g-r parameters in thin-film SOI devices

Structural basis of laminin binding to the LARGE glycans on dystroglycan

Dystroglycan is a highly glycosylated extracellular matrix receptor with essential functions in skeletal muscle and the nervous system. Reduced matrix binding by α-dystroglycan (α-DG) due to perturbed glycosylation is a pathological feature of several forms of muscular dystrophy. Like-acetylglucosaminyltransferase (LARGE) synthesizes the matrix-binding heteropolysaccharide [-glucuronic acid-β1,3-xylose- α1,3-]n. Using a dual exoglycosidase digestion, we confirm that this polysaccharide is present on native α-DG from skeletal muscle. The atomic details of matrix binding were revealed by a high-resolution crystal structure of laminin G-like (LG) domains 4-5 of laminin α2 bound to a LARGE-synthesized oligosaccharide. A single glucuronic acid- β1,3-xylose disaccharide repeat straddles a Ca2+ ion in the LG4 domain, with oxygen atoms from both sugars replacing Ca2+-bound water molecules. The chelating binding mode accounts for the high affinity of this protein-carbohydrate interaction. These results reveal a novel mechanism of carbohydrate recognition and provide a structural framework for elucidating the mechanisms underlying muscular dystrophy