General Differences between Astrocytes and NG2-

One important difference between astrocytes and NG2+ glia may be that the developmental neuroepithelial cells first transform into radial glia, which then directly transform into astrocytes. Besides that these neuronal progenitors transform into adult neural stem cells as well as ependymal cells35,40,68,547,556-

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tical progenitors as well as NG2+ cells during development70,129,561,562. Con- versely, an early neuroepithelial origin for NG2+ glia is not observed so far. There is evidence obtained from fatemapping of ventral radial glial cells indi- cating some direct transformation of these cells into into NG2+ cells29. In the dorsal telencephalon, however, NG2 glia are mostly generated from commit- ted intermediate progenitors29,40,100,547,563. This indicates that NG2+ glia may divert from the astroglial cells, since the latter are directly derived from neural stem cells. However, as NG2+ cells also give rise to certain astrocyte sub- types may indicate some overlap between these two cell population.

The close relationship of adult parenchymal astrocytes with neural stem cells is further underlined by the shared expression of specific markers. Amongst them are e.g. the beta subunit of the calcium binding protein S100 (S100b), the excitatory amino acid transporter 2 (also known as GLT1) or the gluta- mine synthetase (GS)74. Furthermore, parenchymal astrocytes retain the ex- pression of stem cell-related markers such as Sox2, Sox9 and Musashi, which are not expressed by NG2+ glia399,547,564-568. Other molecular features reminiscent of the stem cell niches are downregulated in parenchymal astro- cytes (e.g. Tenascin C, nestin, DSD-1) but can be re-expressed after le- sion48,95,216.

In addition, the neurogenic potential of adult astroglia-like stem cells is well established569,570, while the neurogenic potential of NG2+ glia remains de- bated. Some studies claim the generation of interneurons in the olfactory bulb from NG2+ cells located in the subventricular zone, which are fate mapped utilizing the 2’,3’-cyclic nucleotide 3’-phosphodiesterase (CNPase) promoter571,572, while fate mapping studies of NG2+ or Olig2+ glia do not re- veal such neurogenic potential69,70,105,121,129.

In the adult, a subset of NG2-glia expresses astrocytic proteins121, while some astroglia-like stem cells in the adult subependymal zone were shown to express the Plateled Derived Growth Factor receptor alpha (PDGFRα)573, which is most commonly expressed by NG2+ glia125. Yet another study does not confirm the co-expression of PDGFRα in GFAP+ neural stem cells574. Apart from the discrepancies concerning the PDGFRα expression, still some overlap in the expression of certain markers between these two cell types exists. Yet, despite this small overlap in expression of markers, in APPPS1

mice fate mapping of Olig2+ cells of the oligodendrocyte lineage shows that they do not overt the potential to transdifferentiate into astrocytes, as ob- served after cortical cryolesion229,230. These cells rather stay within their line- age upon chronic plaque deposition, which is in line with observations ob- tained from stab wounded animals105,231 Therefore, the ability of NG2-glia to generate astrocytes seems to depend on the specific lesion paradigm or may be due to the transgenic mouse lines utilized.

One striking difference of these two cell populations in the adult healthy corti- cal GM is that astrocytes are quiescent103,217 and may only resume prolifera- tion after large invasive injury, while NG2+ glia continuously divide in the healthy brain and further increase in proliferation after e.g. acute stab wound injury and in APPPS1 mice but not in CK/p25 mice (Fig. 3- 5; 3- 11)103,105. This indicates that after lesion these cell types may be more similar, as they both respond with an increase in proliferation after injury. Interestingly, after acute stab wound lesion only astrocytes have the ability to give rise to multi- potent neurospheres217. However, the generated neurospheres from APPPS1 mice may be derived from both astrocytes or NG2+ glia, which both hold a certain potential (see above).

This study provides evidence that astrocytes exert different potentials be- tween acute invasive and AD-related pathologies. Furthermore, also different aspects of AD pathology influence the extent of astroglial cell reactivity. Fur- ther investigation of signalling cascades involved in the brain’s reaction to- ward injury may give new ideas how to promote astrocyte proliferation also in APPPS1 and CK/p25 mice. In addition to that, another glial cell type, the NG2+ glia react only in the APPPS1 mice, while in CK/p25 mice this reaction does not take place. Upon AD pathology NG2+ glia seem to exert their func- tions while remaining in their lineage. However, signalling molecules that in- duce that response in APPPS1 mice may be important to be investigated with the aim to increase myelin repair mechanisms that seem to be ongoing upon extracellular plaque deposition. This is of special importance in light of the finding that in human AD oligodendrocytes are lost.

In summary, all data indicate dramatic differences between the glial cell reac- tivity toward different pathologies. In addition to that, the different glial cell types exert very distinct functions. The glial cell reactivity in such a complex pathological disease as AD is determined by different aspects of the pathol- ogy, which may induce different beneficial as well as detrimental glial cell responses.

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