Editors' ChoiceNeuroscience

Myelin and microglia in the aging brain

Sci. Signal.  09 Aug 2016:
Vol. 9, Issue 440, pp. ec181
DOI: 10.1126/scisignal.aai7393

Myelin is a membrane sheath formed around axons, and its loss with disease, injury, or normal aging causes neurological dysfunction. Microglia, the resident macrophages and housekeeping cells of the central nervous system, scavenge molecular plaques, microorganisms, and damaged cells to maintain a healthy nervous system. The number of microglia increases with age in mice. Safaiyan et al. found that myelin turnover may overwhelm microglia in the aging brain. Electron microscopy and immunohistochemistry detected myelin fragments in the extracellular space and within microglia in the brains of older mice. The abundance of galectin-3, a signal that activates microglia, increased with age in the white matter of mice. The lysates of microglia isolated from 1-year-old mice contained large amounts of high molecular weight—indicating aggregated—myelin basic protein (MBP), a constituent of the myelin sheath. Applying purified myelin to organotypic mouse hippocampal slice cultures increased the accumulation of insoluble lysosomal lipofuscin granules that partially colocalized with myelin in the microglia, indicating an accumulation of aggregates within microglia that could not be degraded. Microglia in mice with genetic impairment of lysosomal function (Rab7ΔMG mice) were more likely to accumulate MBP and lipofuscin and at a younger age. In addition, these mice were more likely to show functional and morphological markers associated with microglial senescence. RNA-sequencing and pathway analysis revealed that genes with increased expression in Rab7ΔMG mice were associated with immune function and overlapped with those that were increased in aged mice (compared with wild-type or young mice, respectively), indicating that lysosomal dysfunction and aging have common microglial phenotypes. Mice that are a model for the demyelinating Pelizaeus-Merzbacher disease had increased MBP and lipofuscin accumulation in microglia coincident with decreased microglial function. Furthermore, in mice that at a young age underwent an acute demyelinating event induced by cuprizone ingestion, microglia accumulated MBP and lipofuscin shortly after cuprizone exposure, and this accumulation increased with age. Although a marker of microglial activation disappeared at an intermediate time point after cuprizone exposure, the marker returned with age, indicating that a single demyelinating event can have lasting effects in microglia. The findings suggest that through its effects on microglia function, the normal maintenance of myelin may contribute to age-associated neurological dysfunction.

S. Safaiyan, N. Kannaiyan, N. Snaidero, S. Brioschi, K. Biber, S. Yona, A. L. Edinger, S. Jung, M. J. Rossner, M. Simons, Age-related myelin degradation burdens the clearance function of microglia during aging. Nat. Neurosci. 19, 995–998 (2016). [PubMed]

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