The Integrated Stress Response in Hypoxia-Induced Diffuse White Matter Injury.

Currently no treatments exist for preterm infants with diffuse white matter injury (DWMI) caused by hypoxia. Due to the improved care of preterm neonates and increased recognition by advanced imaging techniques, the prevalence of DWMI is increasing. A better understanding of the pathophysiology of DWMI is therefore of critical importance.

Neonatal Hypoxia Results in Peripheral Nerve Abnormalities.

Although the adverse effects of neonatal hypoxia associated with premature birth on the central nervous system are well known, the contribution of hypoxic damage to the peripheral nervous system (PNS) has not been addressed. We demonstrate that neonatal hypoxia results in hypomyelination and delayed axonal sorting in mice leading to electrophysiological and motor deficits that persist into adulthood. These findings support a potential role for PNS hypoxic damage in the motor impairment that results from premature birth and suggest that therapies designed to protect the PNS may provide clinical benefit.

Predominant expression of Alzheimer's disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts.

Background: Genome-wide association studies have identified BIN1 within the second most significant susceptibility locus in late-onset Alzheimer's disease (AD). BIN1 undergoes complex alternative splicing to generate multiple isoforms with diverse functions in multiple cellular processes including endocytosis and membrane remodeling. An increase in BIN1 expression in AD and an interaction between BIN1 and Tau have been reported.

Pharmaceutical integrated stress response enhancement protects oligodendrocytes and provides a potential multiple sclerosis therapeutic.

Oligodendrocyte death contributes to the pathogenesis of the inflammatory demyelinating disease multiple sclerosis (MS). Nevertheless, current MS therapies are mainly immunomodulatory and have demonstrated limited ability to inhibit MS progression. Protection of oligodendrocytes is therefore a desirable strategy for alleviating disease.

IFNγ-stimulated dendritic cell exosomes as a potential therapeutic for remyelination.

Dendritic cells (DCs) release exosomes with different characteristics based on stimulus. Here, we showed that DC cultures stimulated with low-level IFNγ released exosomes (IFNγ-DC-Exos) that contained microRNA species that can increase baseline myelination, reduce oxidative stress, and improve remyelination following acute lysolecithin-induced demyelination. Furthermore, nasally administered IFNγ-DC-Exos increased CNS myelination in vivo.