GFAP-positive and myelin marker-positive glia in normal and pathologic environments

Abstract

The data herein demonstrate that in addition to the well-characterized myelin marker-positive, glial fibrillary acidic protein (GFAP)-negative, membrane sheet-bearing oligodendrocytes, another type of myelin marker-positive, process-bearing glia exists in normal and pathologic conditions. This second type of myelin marker-positive glia expresses GFAP, and therefore these cells have been referred to as mixed phenotype glia. Although mixed phenotype glia have been documented previously, their identity and function have remained a mystery. The goal of this immunocytochemical study was to further characterize these cells. Using the MBPlacZ transgenic mouse in which beta-galactosidase is under the control of the myelin basic protein (MBP) gene promoter, GFAP-positive/beta-galactosidase-positive and myelin/oligodendrocyte-specific protein (MOSP)-positive/beta-galactosidase-positive cells were detected in subcortical white matter and in perivascular locations within cerebral white and gray matter. In cultures prepared from highly enriched myelin marker-positive immature glia, mixed phenotype glia were detected that were GFAP-positive and either MOSP-, MBP-, O1-, and O4-positive. The expression of multiple myelin markers by mixed phenotype glia may suggest that these cells are of oligodendrocyte origin. Increased numbers of MOSP-positive/GFAP-positive mixed phenotype glia were detected in sections from adult hypomyelinated brain from shiverer, quaking, and PKU mice compared to myelinated control adult mouse brain. Similarly, cultures from control brain exposed to elevated pH for 2-3 weeks showed dramatically increased numbers of mixed phenotype glia (80%) compared to control (<10%). Increased numbers of mixed phenotype glia also were detected in shiverer cultures (40%). Since increases in the number of mixed phenotype glia occur in shiverer, quaking, and PKU mouse brain, these data suggest that mixed phenotype glia contribute to gliosis in pathologic white matter.

Relationship between myelin production and dopamine synthesis in the PKU mouse brain

“…1996). Thus, based upon these and additional studies (Dyer et al . 2000), it was postulated that the mixed phenotype glia detected in the hypomyelinated brain structures in the PKU brain are oligodendrocytes that have switched to a non‐myelinating phenotype.…”

“…The reason for the biphasic recovery in frontal cortex is unknown and may be due to different maturation times of (i) oligodendrocytes subpopulations, and/or (ii) subpopulations of non‐myelinating oligodendrocytes (mixed phenotype glia) switching to myelinating oligodendrocytes (Dyer and Philibotte 1995). Evidence for adult progenitor oligodendrocytes playing a role in myelination of the PKU brain was not previously found (Dyer et al . 2000).…”

“…1996). Since mixed phenotype glia are located within white matter tracts and along the blood vessels (Dyer et al. 2000), it is possible that they influence not only the gene expression of amino acid transporters in the blood–brain barrier, but the activity of these transporter proteins as well.…”

“…2000), it was postulated that the mixed phenotype glia detected in the hypomyelinated brain structures in the PKU brain are oligodendrocytes that have switched to a non‐myelinating phenotype. Indeed, mixed phenotype glia are process‐bearing, do not produce membrane sheaths, and express both myelin proteins (including MBP) and glial fibrillary acid protein (Dyer et al . 2000).…”

The absence of myelin basic protein promotes neuroinflammation and reduces amyloid β-protein accumulation in Tg-5xFAD mice

“…Although it is not well understood, the increase in neuroinflammatory cells observed in the MBP -/- mice appears to be a pleiotropic effect due to the loss of MBP and abnormal myelination, thereby disrupting normal interaction between glial cells. Indeed, it has been suggested that a proliferation of mixed-phenotype glial cells, which were found to be increased in the pathogenic white matter, contribute to this gliosis in MBP -/- mice [69]. …”