The activation of microglia in cerebral white matter is a hallmark of normal aging, yet the basis for this activation remains a contentious issue, due to the lack of a clear association with any underlying brain pathology. A potential stimulator of microglial activation is the degeneration of myelinated nerve fibers that takes place with age. In this study, a rhesus monkey ( Maccaca mulatta) model of normal aging was used to test the hypothesis that microglial activation occurs in response to a deterioration of myelinated nerve fibers.; Tissue blocks through the cingulum bundle and genu of the corpus callosum were removed from 21 monkeys between 4 and 32 years of age and processed for the ultrastructural analysis of myelinated nerve fibers. Aging was associated with a progressive loss of nerve fibers, degeneration of myelin sheaths, and remyelination of some axons. Degenerative changes to myelin sheaths occurred on axons of all calibers, while remyelination was limited to smaller axons, suggesting a selective vulnerability of large axons to age-related degeneration.; To determine if microglial cells are activated by this breakdown in myelinated nerve fibers, adjacent vibratome-cut sections were immunohistochemically stained for Major Histocompatability Complex Class II expressing microglia. During aging there was an eight-fold increase in the density of labeled microglia in the cingulum bundle (p0.05) and a four-fold increase in the genu (p=0.06). Despite this difference in the extent of microglial activation, the density of cells in each structure was significantly correlated with the extent of degenerative changes in myelinated nerve fibers.; The age-related increase in the activation of microglia was further examined in a separate cohort of 19 rhesus monkeys between 6 and 31 years of age using more extensive design-based stereological techniques. Significant increases in the number of activated microlgia were observed in the cingulum bundle (p0.001) and splenium of the corpus callosum (p0.05), but not in the genu of callosum or fornix in which increases only approached significance.; Together, these findings support the hypothesis that the age-related breakdown in myelinated nerve fibers is accompanied by a glial cell response aimed at the removal of cellular debris and the repair of axons with damaged myelin. The quality of this response may depend on the fiber size and/or ontogeny of individual pathways.
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