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Overcoming the lesion microenvironment to promote regeneration in the ageing central nervous system

Khalil Rawji

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 sub-
jects 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 contrib-
utor 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 clear-
ance 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.