Receptor for advanced glycation end products mediates sepsis-triggered amyloid-ß accumulation, Tau phosphorylation, and cognitive impairment.

Patients recovering from sepsis have higher rates of CNS morbidities associated with long-lasting impairment of cognitive functions, including neurodegenerative diseases. However, the molecular etiology of these sepsis-induced impairments is unclear. Here, we investigated the role of the receptor for advanced glycation end products (RAGE) in neuroinflammation, neurodegeneration-associated changes, and cognitive dysfunction arising after sepsis recovery. Adult Wistar rats underwent cecal ligation and perforation (CLP), and serum and brain (hippocampus and prefrontal cortex) samples were obtained at days 1, 15, and 30 after the CLP. We examined these samples for systemic and brain inflammation; amyloid-ß peptide (Aß) and Ser-202-phosphorylated Tau (p-TauSer-202) levels; and RAGE, RAGE ligands, and RAGE intracellular signaling. Serum markers associated with the acute proinflammatory phase of sepsis (TNFα, IL-1ß, and IL-6) rapidly increased and then progressively decreased during the 30-day period post-CLP, concomitant with a progressive increase in RAGE ligands (S100B, Nϵ-[carboxymethyl]lysine, HSP70, and HMGB1). In the brain, levels of RAGE and Toll-like receptor 4, glial fibrillary acidic protein and neuronal nitric-oxide synthase, and Aß and p-TauSer-202 also increased during that time. Of note, intracerebral injection of RAGE antibody into the hippocampus at days 15, 17, and 19 post-CLP reduced Aß and p-TauSer-202 accumulation, Akt/mechanistic target of rapamycin signaling, levels of ionized calcium-binding adapter molecule 1 and glial fibrillary acidic protein, and behavioral deficits associated with cognitive decline. These results indicate that brain RAGE is an essential factor in the pathogenesis of neurological disorders following acute systemic inflammation.

Influence of random and oriented electrospun fibrous poly(lactic-co-glycolic acid) scaffolds on neural differentiation of mouse embryonic stem cells.

Engineering neural tissue by combining biodegradable materials, cells and growth factors is a promising strategy for the treatment of central and peripheral nervous system injuries. In this study, neural differentiation of mouse embryonic stem cells (mESCs) was investigated in combination with three dimensional (3D) electrospun nanofibers as a substitute for the extracellular matrix (ECM). Nano/microfibrous poly(lactic-co-glycolic acid) (PLGA) 3D scaffolds were fabricated through electrospinning and characterized. The scaffolds consisted of either a randomly oriented or an aligned structure of PLGA fibers. The mESCs were induced to differentiate into neuronal lineage and the effect of the polymer and fiber orientation on cell survival, morphology and differentiation efficiency was studied. The neural progenitors derived from the mESCs could survive and migrate onto the fibrous scaffolds. Aligned fibers provided more contact guidance with the neurites preferentially extending along the long axis of fiber. The mESCs differentiated into neural lineages expressing neural markers as seen by the immunocytochemistry. The nestin and beta3-tubulin expression was enhanced on the PLGA aligned fibers in comparison with the other groups, as seen by the quantitative analysis. Taken together, a combination of electrospun fiber scaffolds and mESC derived neural progenitor cells could provide valuable information about the effects of topology on neural differentiation and axonal regeneration. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1333-1345, 2017.