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

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

Metabolic treatments in murine models of multiple sclerosis

Multiple sclerosis (MS) is a debilitating neurological disorder characterized by autoimmune-driven demyelination within the central nervous system (CNS). Impaired remyelination contributes to the progressive stage of MS, ultimately leading to axonal and neuronal degeneration, exacerbating disability. Currently, no remyelination treatments exist for MS, and therapeutic options for progressive MS are limited. Furthermore, the impact of metabolism and dietary interventions on MS prevention and treatment remains unclear. Recent evidence suggests that ketogenic diet (KD) may offer potential benefits for individuals with MS, though its restrictive nature poses compliance challenges. To facilitate the development of targeted pharmacological treatments, this dissertation investigates the mechanisms underpinning KD benefits in preclinical murine models of MS, hypothesizing that ketone body production mediates these effects. In Chapter 2, I administered KD and intraperitoneal ketone esters (iKE) in a murine cuprizone/rapamycin (Cup/R) demyelination model, and observed enhanced myelin debris clearance, oligodendrocyte lineage cell differentiation, and remyelination. In Chapter 3, I utilized the experimental autoimmune encephalomyelitis (EAE) preclinical model of MS and administered dietary ketone esters (KED) and found that KED conferred prophylactic and therapeutic benefits comparable to KD. Mechanisms behind KED's efficacy were explored, showing that KED can promote proliferation, recruitment, and differentiation of oligodendrocyte lineage cells by targeting the hydroxycarboxylic acid receptor 2 (HCAR2). In Chapter 4, I combined KED with metformin to synergistically augment KED's benefits, observing a significantly enhanced prophylactic effect in the KED + Metformin combination. Overall, this dissertation demonstrates that ketone esters can effectively substitute KD in providing benefits in murine models of MS. Moreover, combining ketone esters with metformin results in a synergistic accumulation of benefits, offering potential avenues for future MS treatment strategies.Medicine, Faculty 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