Kovalenko, Tetiana

Abstract Mitochondrial dysfunction and lipid dysregulation are among the earliest abnormalities in Alzheimer’s disease (AD), yet their mechanistic interplay and therapeutic potential remain poorly understood. Here, we investigated whether restoration of mitochondrial function can reverse metabolic dysfunction and promote resilience in advanced-stage AD. Female APP/PS1 mice were treated with the brain-penetrant mitochondrial complex I (mtCI) modulator CP2 beginning at 19 months of age, when pathology and cognitive deficits were well established. To define the metabolic mechanisms underlying therapeutic response, we developed iMiceBrain , the first brain-specific genome-scale metabolic model of the mouse brain, and integrated transcriptomics, targeted metabolomics, lipidomics, and metabolic network analyses. CP2 treatment broadly reprogrammed AD-associated molecular signatures and restored pathways involved in mitochondrial function, glucose utilization, lipid metabolism, synaptic activity, and cellular stress responses. Metabolic modeling identified enhanced mitochondrial substrate flexibility, activation of fatty acid utilization, restoration of pyruvate dehydrogenase flux, and normalization of cholesterol metabolism as key features of the therapeutic response. Lipidomic analyses further demonstrated correction of disease-associated alterations in cholesteryl esters, phospholipids, and sphingolipids. Together, these findings demonstrate that mild mtCI modulation restores metabolic resilience by coordinating mitochondrial and lipid metabolism, establishing it as a disease-modifying therapeutic strategy for AD.

The exact physiological role of BACE2 in endothelial function of systemic arteries is unknown. Our study shows that thromboxane A2 and prostaglandin F2α are responsible for impairment of endothelium-dependent relaxations in endothelium-specific BACE2-deficient mice. The data support an important role of BACE2 in the control of endothelial arachidonic acid metabolism and vasomotor function.

AbstractA series of reactive copolymers with peroxide functionality (RCPFs) were synthesized via radical copolymerization of monomer mixtures in an organic solvent comprised of a peroxide monomer 5‐(tert‐butyl peroxy)‐5‐methylhex‐1‐en‐3‐yne, acrylamide, maleic anhydride, and butyl methacrylate. Peroxide functionality allows the RCPFs to initiate a variety of radical processes, including cross‐linking of organic polymers. Hydrophilic monomer subunits (acrylamide and maleic anhydride) within the RCPF macromolecules promote cross‐linking of water‐soluble polymers. We aimed to investigate RCPF comonomer ratio and its effects on copolymerization kinetics and composition, as well as physico‐chemical and colloidal properties. We also evaluated and characterized the kinetic parameters of the thermal decomposition of peroxide moieties in the synthesized RCPF. Findings revealed that RCPF possessed surface‐active properties and reduced surface tension at its aqueous solution–air interface. The data indicated that the decomposition process complied with the first‐order kinetics, and complex thermal analysis confirmed the presence of peroxide moieties. RCPFs' ability to cross‐link water‐soluble polymers was demonstrated on poly(acrylamide) and poly(vinyl alcohol).

AbstractMagnetite nanoparticles (Fe3O4 NPs) with peroxide‐containing polymer shell have been synthesized using the method of coprecipitation from the mixture solutions of Fe (II) and Fe (III) salts in the presence of peroxide‐containing copolymer (PCC). Polymer shell presence has been proved by elemental and complex thermal analysis. Synthesized Fe3O4 NPs possess superparamagnetic properties. Their specific saturation magnetization decreases gradually from 65 to 54 A·m2·kg−1 with increasing PCC concentration owing to the surface spin pinning effect caused by a polymer shell. The average sizes of Fe3O4 NPs estimated from the data of XRD analysis and magnetic measurements are in the range of 9–12 nm. The NP sizes determined by the DLS method lie in the range of 150–270 nm; this result is significantly larger than the sizes estimated by the two aforementioned methods evidencing a tendency for Fe3O4 NPs toward self‐association. Cross‐linked composite films based on polyvinyl alcohol have been obtained via radical curing initiated by the PCC shell of nanoparticles. The resulting composite films are magnetically sensitive films with rather high physico‐mechanical properties (tensile strength reaches 48–67 MPa and relative elongation – 4%–21% depending on cross‐linking degree), a priori non‐toxic and biocompatible, which makes them promising materials for various applications.