Astrocytes have a capacity to react mainly in relation to an injury to the CNS and constitute reactive gliosis. Although there may also be associated proliferation and reactivity of microglial cells, the term gliosis is classically related to astrogliosis. This reaction is characterized by hypertrophy of astrocytes, both cytoplasmic and with enlarged nuclei, associated with a profusion of long, thick cytoplasmic processes. There is also an increase in gliofilament number and their constituent, GFAP. The gliotic reaction may also consist ofhyperplasia, with the proliferation occurring close to an acute lesion; in other cases, the proliferation of astrocytes may be discrete, even absent, and its degree seems to depend on the kind of lesion, the region, and the state of development of the brain. The proliferation of astrocytes, when it occurs, could originate from multipotential stem cells or glial precursors still widely present in adult CNS. There could also be dedifferentiation of mature astrocytes, which could explain the expression or overexpression of molecules during the first stages of astrogenesis by recapitulation of ontogenic stages.

There are two types of reactive astrocytes. One is isomorphous gliosis, in which there is a regular pattern of astrocytes that are parallel to degenerating axons— for instance, in Wallerian degeneration, in which glial fiber organization preserves a normal structure. This is observed in slowly degenerative lesions or at distance from a lesion. There is also an anisomorphic gliosis in which proximal reactive astrocytes, close to a lesion, form a dense mesh with no discernable pattern. Astrocyte reactivity is more intense in gray matter than in white matter, in which there is already a higher level of GFAP expression. Other markers of astrocytes are also expressed by reactive astrocytes, such as GS and S100 beta. Activated S100 beta+ astrocytes are dramatically increased in the brains of patients with Alzheimer's disease and in the Alzheimer-like neuro-pathological changes observed in Down's syndrome. This could favor calcium-mediated events in Alzheimer's disease, such as excessive phosphorylation of the tau protein present in neurofibrillary tangles, that could ultimately result in the neuronal cell death characteristic of this disease. The concomitant considerable increase in GFAP, even in regions that do not present the Alzheimer pathology, may reflect the prominent role played by astrocytes during this pathology. Interestingly, in Alzheimer's disease the production of b-amyloid precursor protein (APP) is increased in reactive astrocytes, as is the ApoE isoform, which is associated with the pathophysiology of APP metabolism. In this way, reactive astrocytes may be involved in the processing of APP, perhaps contributing to b-amyloid deposition in Alzheimer's disease.

Gliosis is also a secondary process observed during aging as well as in many pathological conditions affecting neural cells, such as brain trauma, ischemia, experimental autoimmune encephalomyelitis (EAE), and demyelinated areas of multiple sclerosis. The correlation of AIDS dementia with a high level of astrocytic expression of adhesion proteins such as VCAM-1 and ICAM-1 may be involved in cellular dysfunction. In myelin mutants, such as the jimpy mouse and the md and the taiep rat, gliosis is severe; nevertheless, axonal growth is not impaired.

The physiological role of astrogliosis remains controversial with respect to the beneficial or detrimental influence of reactive astrocytes on CNS recovery. On the one hand, the very dense network of processes built up in the scar by reactive astrocytes suggests that the scar tissue may fulfill important functions as a barrier isolating and protecting the intact tissue from the lesions, from which toxic molecules could be released. On the other hand, molecules expressed in lesion scars on the astroglial cell surface or secreted molecules render the reactive astrocyte a less favorable substrate, which could be inhibitory to neuritic outgrowth. Proteoglycans such as chondroitin sulfate proteogly-cans may act as inhibitors of neurite outgrowth by attenuating the potential for axon elongation that could occur due to a concomitant expression of growth-promoting molecules such as laminin in regions of reactive gliosis. There also seems to be regional differences in the capacity for the gliotic astrocytes to secrete inhibitory molecules.

In the injured brain, the release of immunoregula-tory cytokines by cells around lesion sites may be a mechanism contributing to the induction of gliosis. Molecular signaling may occur between lesioned neurons, glia, inflammatory cells, fibroblasts, and meningeal cells. Among these gliosis signaling molecules are macrophage inflammatory protein (MIP)-1a and MIP-1b, tumor necrosis factor-a, transforming growth factor-b, bFGF, interleukin-1, LIF, and CNTF.

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