Variable Dependiente

Given the potential of astroglial cells to act as stem cells in two neurogenic niches such as the SEZ and the sugranular layer of the dentate gyrus of the hippocampus, it is of special interest to determine their reaction towards in- jury also in non-neurogenic zones such as the cortical grey matter.

Reactive astrogliosis is a well known feature upon brain injury where astro- cytes become reactive. Depending on the duration, severity and type of in- jury, the features of this phenomenon vary. The most striking event where astroglia take part is glial scar formation, which seems to be restricted to large invasive injuries. The glial scar is not only comprised of astrocytes but may also include e.g. fibromeningeal cells188, other glia (e.g. NG2+ glia) and dense collagen extracellular matrix. The astrocytes present in the glial scar include astrocytes, which were present before injury as well as the astrocytes

generated by proliferation after the lesion. Interestingly, protoplasmic astro- cytes present in the glial scar now display overlapping regions contrary to their physiological non-overlapping distribution199,200. It has to be considered that the astrocyte’s reaction toward injury exerts both detrimental and benefi- cial effects. Along this line, glial scar formation inhibits axonal regeneration, due to the enrichment in chondroitin sulphate proteoglycans (CSPGs) in the ECM, which are also released by astrocytes186. Other detrimental effects in- clude e.g. the possible release of neurotoxic levels of glutamate201, reactive oxygen species202 or cytokines from astrocytes upon injury. The latter may worsen the inflammatory response, since in vivo antagonization of a cytokine signalling pathway (the NFkB pathway) in astrocytes promotes neuronal re- sistance to injury203,204. Pro-apoptotic molecules may diffuse via gap junc- tions into surrounding brain areas, thereby triggering further brain damage201. Strikingly, deletion of reactive astrocytes (GFAP/vimentin double knockout or GFAP ablationed mice) results in improved synaptic and post-traumatic re- generation205,206.

This view has been challenged by the fact that reactive astrocytes also pro- tect the brain tissue in many ways. Ablation of reactive astrocytes simultane- ously increases the infarct volume as seen e.g. upon MCAO207. This indi- cates that astrocyte reactivity may exert different effects switching from ini- tially positive to negative ones95. The glial scar additionally prevents inflam- matory cells and other cells from entering the intact parts of the brain199,205,208. Consequently, ablation of proliferating astrocytes after injury results in an increase in inflammation and lesion volume as well as insuffi- cient BBB repair205,208. Astrocytes additionally protect e.g. against oxidative stress209,210 and take-up potentially excitotoxic glutamate211. Furthermore, they metabolically support neurons upon brain lesion212. Beyond that, astro- cytes are capable of releasing pro- and anti-inflammatory molecules, thereby contributing to the brain’s immune response213,214.

Other prominent characteristics of astrocyte reactivity after injury include as- trocytic hyperthrophy, up-regulation of intermediary filaments (Figure 2- 6) and eventual proliferation187. Moreover, extracellular matrix molecules such as the glycoprotein tenascin C (TNC) and the DSD-1 chondroitin sulfate epi-

tope (detected by the 473HD antibody) are released by reactive astrocytes upon acute brain lesion48,95,215,216.

Most interestingly, upon acute brain injury a subset of reactive astrocytes re- gains the ability to proliferate, the most striking feature of embryonic and adult neural stem cells103,216,217. On the contrary, in the healthy cortical grey matter astrocytes rarely divide217. In terms of a time course of the reaction it is known that e.g. after acute stab wound injury, protoplasmic astrocytes first become hyperthrophic and up-regulate GFAP and/or nestin expression. At this early time point, astrocytes also up-regulate and secrete extracellular matrix proteins such as TNC and DSD-1. At later time points (7 days after injury) about 55 % of the total astrocyte cell pool resumes proliferation95,103. Could all astrocytes proliferate in a sufficiently large injury condition or is it a specific subset of astrocytes exhibiting a greater potential? So far these questions still need to be elucidated.

Figure 2- 6. Reactive Astrocyte.

Representative picture of an astrocyte in the healthy brain in (A) and a hyperthrophic, reac- tive astrocyte, that up-regulated expression of the intermediate filament GFAP in (B). GFP is a staining performed in the GLAST::CreERT2 x CAGGFP, which is almost exclusively ex- pressed by astrocytes. Notably, GFAP expression only co-localizes to the main fibers of the whole astrocyte. Scale bar: 10µm.

Another striking feature of protoplasmic reactive astrocytes after acute injury is that they exhibit the potential to generate multipotent neurospheres in vitro, a hallmark of neural stem cells216-218. Furthermore, upon injury distinct sub- sets of reactive astrocytes in the cortical grey matter re-express markers reminiscent of stem cells (see table 2- 1). A further prove for their potential after acute injury is the astrocyte’s ability to adopt a neuronal fate e.g. upon forced expression of a neurogenic transcription factor116.

In summary, the astrocyte’s reaction can exert beneficial as well as detrimen- tal effects. Furthemore, protoplasmic astrocytes de-differentiate upon acute brain injuries, acquiring features of neural stem cells. However, if astrocytes would have an equivalent stem cells potential also upon AD pathology has not been investigated so far.