All types of brain insults, regardless of aetiology, trigger a complex astroglial response, which is manifested by astrocyte hypertrophy and proliferation. This glial response is defined as reactive astrogliosis (Figure 9.1). Reactive astrogliosis is a defensive brain reaction which is aimed at (a) isolation of the damaged area from the rest of the CNS tissue, (b) reconstruction of the blood-brain barrier, and (c) facilitation of the remodelling of brain circuits in areas surrounding the lesioned region. These main tasks are solved in two distinct ways: the reaction of astrocytes close to the insult is very different from that in astroglial cells positioned
Formation of protective glial scar
Angiogenesls and re-formation of BBB
Preserve neurones away from site of damage
Destroy neurones at the site of damage Limit extent of damage Promote rewiring in neuronal circuits
Figure 9.1 Stages of reactive astrogliosis. Insults to the CNS trigger release of numerous factors that interact with astroglial cells and trigger reactive astrogliosis, which is generally represented by hypertrophy and proliferation of astrocytes. Astrogliosis ultimately ends up in complete substitution of previously existing tissue architecture with a permanent glial scar (see the text for detailed explanation)
at a distance from the primary lesion. Astrocytes located immediately around the damaged zone undergo a robust hypertrophy and proliferation, which ultimately ends up in complete substitution of previously existing tissue architecture with a permanent glial scar, this process is called anisomorphic (i.e. changing the morphology) astrogliosis. Reactive astrocytes in these areas produce chondroitin and keratin, which inhibit axonal regeneration, and thus prevent nerve processes from entering the damaged zone. Reactive astroglia also release quantities of mucopolysaccharides, which eventually cement the areas of damage, and produce the astrocytic scar.
In astrocytes more distal to the lesion site, the reactive changes are much milder and, although astroglial cells modify their appearance and undergo multiple biochemical and immunological changes, they do not distort the normal architecture of CNS tissue, but rather permit growth of neurites and synaptogenesis, thus facilitating the remodelling of neuronal networks. This type of astrocyte reaction is defined as isomorphic (i.e. preserving morphology) astrogliosis.
Reactive astrocytes in the areas of isomorphic astrogliosis produce and release several types of growth factors, such as NGF and FGF, and cytokines, such as interleukins. These factors may be important for preservation of neurones from delayed death. Simultaneously, reactive astrocytes synthesize numerous recognition molecules (such as extracellular matrix molecules, cell adhesion molecules,
etc.) which promote neuronal-astrocyte interaction and help axonal growth. Therefore, reactive astroglia may either inhibit axonal entry, by forming a nonpermissive scar around the necrotic areas, or assist axonal growth and neuronal remodelling in areas distant to the site of initial insult.
The primary signals, which trigger both forms of astrogliosis, derive from damaged cells in the core of the insult, and are represented by neurotransmitters (most importantly glutamate and ATP), cytokines, adhesion molecules, growth factors, and blood factors (serum, thrombin etc.). The actual combination of these 'damage signals' and their relative concentrations most likely determine the type of astrogliosis experienced by astrocytes in different regions surrounding the initial insult zone.
On a cellular level, insults to the brain, be they ischaemia, trauma or inflammation, result in hypertrophy of astroglial processes and a significant increase in the astrocyte cytoskeleton. The biochemical hallmark of astrogliosis is the up-regulation of synthesis of intermediate filament proteins, especially GFAP and vimentin, which together with actin and microtubules form the cytoskeleton. Brain damage very rapidly turns most of the astroglial cells into GFAP-expressing 'reactive' astrocytes. Both GFAP and vimentin are critically important for development of reactive astrogliosis. In animals with genetically deleted GFAP and/or vimentin the astroglial scar is formed slower, it is much less organized and the healing of brain traumas is generally prolonged.
It is still unclear how the normal mature astrocytes are turned into the reactive ones. First, the mature astrocytes can, under the influence of damage-associated signals, dedifferentiate and enter a proliferative state. Alternatively, the reactive astrocytes may arise from astroglial precursors, diffusely dispersed throughout the brain parenchyma, or even from multipotent NG2-expressing precursors and radial glial stem cells. The considerable heterogeneity displayed by reactive astroglial cells most likely indicates that all these routes may be involved in astrogliosis.
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