Editors' ChoiceNeurodegenerative Disease

Out with the old (myelin), in with the new

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Science Translational Medicine  28 Oct 2015:
Vol. 7, Issue 311, pp. 311ec186
DOI: 10.1126/scitranslmed.aad5502

Old macrophages do not clear myelin debris as efficiently as young cells. In chronic demyelinating diseases like multiple sclerosis, the rate of remeylination decreases with age. Myelin debris inhibits the differentiation of oligodendrocyte progenitor cells. Thus, clearance of myelin debris by phagocytic macrophages is crucial for creating an environment where oligodendrocytes can differentiate into cells that will remyelinate nerve lesions. In a new study, Natrajan and colleagues investigate the differences in clearance of myelin debris between old and young macrophages and identify down-regulation of the retinoid X receptor (RYR) pathway as a key event in the age-related decrease in myelin debris clearance.

These authors used a variety of in vitro and in vivo techniques to achieve their aims. These included isolation of peritoneal and bone-derived macrophages from young (2-month-old) and old (15- to 20-month-old) mice, and isolation of human blood-derived monocytes from young (≤35 years old) and old (≥55 years old) healthy volunteers and patients with multiple sclerosis. The authors also commandeered microarray and quantitative PCR gene profiling, as well as two mouse models: an RYRα knockout mouse and a macrophage-specific RYR conditional knockout mouse. They found decreased myelin debris clearance by macrophages from old mice, which was confirmed in blood-derived monocytes from healthy volunteers of different ages. Gene profiling of monocytes from healthy volunteers suggested a key role for downregulation of the RYR pathway in these age-related changes. The investigators then confirmed these observations in vivo in their mouse models. They observed an overall decrease in myelin debris clearance in their RYRα knockout mice, and delays in remyelination at 14 days post-lesion in their conditional macrophage-specific RYR knockout mice. Most intriguing, they were able to demonstrate a partial correction of the decreased clearance of myelin debris using an RYR agonist, bexarotene, in blood-derived monocytes from patients with multiple sclerosis.

This study suggests a key role for the RYR pathway in the age-related decrease in myelin debris clearance with RYRα involved as both a receptor and a transcriptional regulator. The authors have identified a new pathway that may have important therapeutic implications for patients with chronic demyelinating diseases.

M. S. Natrajan et al., Retinoid X receptor activation reverses age-related deficiencies in myelin debris phagocytosis and remyelination. Brain 10.1093/brain/awv289 (2015). [Abstract]

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