Correction to: Niacin-mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system.

The article Niacin‑mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system, written by Khalil S. Rawji, Adam M.H. Young, Tanay Ghosh, Nathan J. Michaels, Reza Mirzaei, Janson Kappen, Kathleen L. Kolehmainen, Nima Alaeiilkhchi, Brian Lozinski, Manoj K. Mishra, Annie Pu, Weiwen Tang, Salma Zein, Deepak K. Kaushik, Michael B. Keough, Jason R. Plemel, Fiona Calvert, Andrew J. Knights, Daniel J. Gaffney, Wolfram Tetzlaff, Robin J. M. Franklin and V. Wee Yong, was originally published electronically on the publisher's internet

Niacin-mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system

Abstract: Remyelination following CNS demyelination restores rapid signal propagation and protects axons; however, its efficiency declines with increasing age. Both intrinsic changes in the oligodendrocyte progenitor cell population and extrinsic factors in the lesion microenvironment of older subjects contribute to this decline. Microglia and monocyte-derived macrophages are critical for successful remyelination, releasing growth factors and clearing inhibitory myelin debris. Several studies have implicated delayed recruitment of macrophages/microglia into lesions as a key contributor to the decline in remyelination observed in older subjects. Here we show that the decreased expression of the scavenger receptor CD36 of aging mouse microglia and human microglia in culture underlies their reduced phagocytic activity. Overexpression of CD36 in cultured microglia rescues the deficit in phagocytosis of myelin debris. By screening for clinically approved agents that stimulate macrophages/microglia, we have found that niacin (vitamin B3) upregulates CD36 expression and enhances myelin phagocytosis by microglia in culture. This increase in myelin phagocytosis is mediated through the niacin receptor (hydroxycarboxylic acid receptor 2). Genetic fate mapping and multiphoton live imaging show that systemic treatment of 9–12-month-old demyelinated mice with therapeutically relevant doses of niacin promotes myelin debris clearance in lesions by both peripherally derived macrophages and microglia. This is accompanied by enhancement of oligodendrocyte progenitor cell numbers and by improved remyelination in the treated mice. Niacin represents a safe and translationally amenable regenerative therapy for chronic demyelinating diseases such as multiple sclerosis

Ketogenic diet and ketone ester supplementation as an acute therapeutic for spinal cord injury

Spinal cord injury (SCI) is a debilitating condition with no curative treatment. In recent years metabolism has been suggested as a factor that could be altered to enhance recovery after SCI, and research from the Tetzlaff lab showed that a ketogenic diet (KD) can improve recovery after a cervical SCI in rodents. KDs are high fat, low carbohydrate diets that have been successfully used as a treatment for drug-resistant epilepsy in children. KDs produce high levels of the ketone body, beta-hydroxybutyrate (BHB), which can act as an energy source or bind and activate the cell surface receptor, hydroxycarboxylic acid receptor 2 (HCAR2). BHB levels can also be increased by oral ketone ester (KE) supplementation making KE a potential alternative to KD. In Chapter 2, the use of KD on recovery after a cervical forceps crush SCI in mice was assessed. In this injury model KD did not improve recovery of the mice. In Chapter 3, the effect of KD following a more clinically relevant T9 midline contusive SCI was investigated. We observed that KD could reduce pro-inflammatory cytokines CCL3 and CCL4 at 7 days post-injury and a scRNA-sequencing analysis of CD45+ cells at the injury site at 7 days after injury confirmed KD-mediated downregulation of many immune pathways. We also used the T9 contusion injury model with wild type and HCAR2₋/₋ mice to investigate the role of HCAR2 activation on KD-mediated effects. We found that KD could reduce the influx of CD45+CD11b+ myeloid cells into the injury site at 7 days post-injury, which required the HCAR2 receptor. Chapter 4 investigated the use of KE supplementation as a treatment following a C5 hemi-contusive injury in rats. Proteomic analysis at 2 weeks after injury showed that KE and KD appear to impact different cellular pathways. In this model, KE showed only minor improvements in behavioural recovery. Together these results suggest that KD can reduce inflammation at 7 days after injury in mice and that different paradigms of KE supplementation may be needed to see behavioral improvement following SCI in rats.Medicine, Faculty ofBiochemistry and Molecular Biology, Department ofGraduat

Niacin-mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system

Abstract: Remyelination following CNS demyelination restores rapid signal propagation and protects axons; however, its efficiency declines with increasing age. Both intrinsic changes in the oligodendrocyte progenitor cell population and extrinsic factors in the lesion microenvironment of older subjects contribute to this decline. Microglia and monocyte-derived macrophages are critical for successful remyelination, releasing growth factors and clearing inhibitory myelin debris. Several studies have implicated delayed recruitment of macrophages/microglia into lesions as a key contributor to the decline in remyelination observed in older subjects. Here we show that the decreased expression of the scavenger receptor CD36 of aging mouse microglia and human microglia in culture underlies their reduced phagocytic activity. Overexpression of CD36 in cultured microglia rescues the deficit in phagocytosis of myelin debris. By screening for clinically approved agents that stimulate macrophages/microglia, we have found that niacin (vitamin B3) upregulates CD36 expression and enhances myelin phagocytosis by microglia in culture. This increase in myelin phagocytosis is mediated through the niacin receptor (hydroxycarboxylic acid receptor 2). Genetic fate mapping and multiphoton live imaging show that systemic treatment of 9–12-month-old demyelinated mice with therapeutically relevant doses of niacin promotes myelin debris clearance in lesions by both peripherally derived macrophages and microglia. This is accompanied by enhancement of oligodendrocyte progenitor cell numbers and by improved remyelination in the treated mice. Niacin represents a safe and translationally amenable regenerative therapy for chronic demyelinating diseases such as multiple sclerosis