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Figure 9.4 At the top of the figure is an Alzheimer type II astrocyte (long arrow) displaying an enlarged pale nucleus that contains a prominent nucleolus attached to the nuclear membrane (top of the nucleus). No well-defined cytoplasm is evident, except for the presence of lipofuscin pigment granules (crossed arrow). Relatively normal astrocytes are seen below (short arrows) for comparison.
are referred to as Alzheimer type II astrocytes. This astrocyte response has also been observed in the very early phase of ischemia, trauma and other acute injuries. The precise significance of this change is not known. By electron microscopy, the cytoplasm is slightly swollen and alterations in organelles have been described.91 It is likely that these swollen cells are dysfunctional and that such dysfunction represents a major mechanism by which metabolic conditions bring about a disorder of the CNS.92 As signaling systems involved in Alzheimer type II astrocytosis are unknown, this change will not be further considered in this chapter. For additional information on the Alzheimer type II astrocyte response, see references 93–94.
9.2Intracellular Signaling System in Reactive Astrocytes
As noted above, cytokines, ATP, thrombin and various trophic factors are considered to be potent triggering agents for reactive astrocytosis. These factors stimulate various signaling systems that have been implicated in the development of reactive astrocytosis. This section will discuss the role of oxidative/nitrosative stress, mitogen-activated protein kinases, protein kinase C, phosphatidylinositol 3-kinase, STAT3 and NF-kB in the evolution of reactive astrocytosis.
9.2.1Oxidative/Nitrosative Stress (ONS)
ONS is perhaps the earliest and most important factor that triggers various downstream signaling systems leading to reactive astrocytosis. ONS has been
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considered as a major pathogenic factor in ischemic stroke, traumatic brain injury and acute hepatic encephalopathy (acute HE), as well as in most neurodegenerative disorders. Astrocytes are known to have potent antioxidant defense systems as they possess high concentrations of antioxidant enzymes
such as superoxide dismutase and glutathione peroxidase. Nevertheless, astrocytes are also vulnerable to ONS.95–96
Free radicals have been shown to induce reactive astrocytosis as demonstrated by increased levels of GFAP as well as by morphological characterization (stellate appearance).97–99 Similarly, oxidative stress following ischemic
insult was reported to result in reactive astrocytosis in cultured astrocytes100 and inhibition of ONS was shown to reduce astrogliosis in culture.101,102 On
the other hand, several reports indicate that reactive astrocytes can also produce free radicals, possibly by enhancing the production of proinflammatory cytokines and reactive oxygen/nitrogen species.103
9.2.2Protein Kinase C (PKC)
PKC is involved in controlling the function of various proteins through the
phosphorylation of serine and threonine amino acid residues on these proteins.104,105 Upon phosphorylation (activation) by Ca21- and ONS-mediated
pathways,106 PKC is translocated to the plasma membrane where it is involved in proliferation, di erentiation, apoptosis, receptor desensitization, plasma membrane modulation and cell growth.107 Transforming growth factor-beta 1-induced activation of PKC in cultured astrocytes has been implicated in reactive astrocytosis.108,109 Additionally, increased GFAP mRNA levels and PKC activation was observed in astrocytes over-expressing the HIV-1 envelope protein gp120 in mice.110 Further, exposure of astrocyte cultures to soluble gp120 led to the activation of PKC and an increase in GFAP mRNA levels, while inhibition of PKC prevented the rise in GFAP mRNA levels, as well as the development of reactive astrocytosis.110
9.2.3Phosphatidylinositol 3-Kinases (PI3K)
PI3K is an intracellular signaling kinase involved in cell growth and proliferation, di erentiation, motility, survival and intracellular tra cking.111,112 Astrocytes express PI3K, and its activation was implicated in the formation of reactive astrocytes after transient forebrain ischemia.113 Further, purinergic receptor-mediated reactive astrogliosis was shown to occur through stimulation of PI3K signaling in cultured astrocytes.114
9.2.4Mitogen-activated Protein Kinases (MAPKs)
One important consequence of oxidative stress is the activation of mitogenactivated protein kinases (MAPKs), including p38MAPK, c-Jun N-terminal kinase (JNK) and the extracellular signal-regulated kinase (ERK).115 MAPKs
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are serine/threonine-specific protein kinases that regulate gene expression, di erentiation and proliferation as well as cell survival.
Activation of MAPK represents a major signal transduction pathway in reactive astrocytes. Activation of ERK/MAPK was observed in reactive astrocytes associated with various human conditions (trauma, chronic epilepsy, progressive multi-focal leukoencephalopathy).116 Sustained ERK/MAPK activation was observed in reactive astrocytes following a forebrain stab lesion in mice.117 Activation of ERK was also found in reactive astrocytes induced by a mechanical injury in cultured astrocytes.118
Increased activation of MAPK was detected in penumbral reactive astrocytes after middle cerebral artery occlusion in rats,119,120 and in cultured astrocytes
after an ischemic insult.121 Activation of MAPKs was also implicated in reactive astrocytosis after focal mechanical injury in cultured astrocytes.118
Increased levels of ERK immunoreactivity were observed in reactive astrocytes in brain areas prone to neurofibrillary tangle formation (CAl/subiculum) in patients with Alzheimer’s disease.122 Likewise, activation of MAPKs was observed in cultured astrocytes after exposure to amyloid precursor protein (a key protein in the pathogenesis of Alzheimer’s disease), and such activationmediated reactive astrocytosis as demonstrated by increased GFAP expression and a stellate morphology.101
Activated ERK1/2 was identified in reactive astrocytes following injection
of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice (model of Parkinson’s disease),123,124 after kainic acid-induced seizures in mice,125,126 and in scrapie agent infected sheep and hamsters.127–129
Reactive astrocytosis, as demonstrated by increased GFAP levels, was also shown in astrocyte cultures exposed to stromal-derived cell factor-1 alpha
(SDF-1 alpha; CXCL12) and cysteinyl-leukotriene receptor 1 (cys-LT1), agents known to activate ERK1/2.130,131 Additionally, purines were shown to cause
reactive astrocytosis in cultured astrocytes by their activation of ERK/ MAPK.132 Activation of JNK signaling was also reported to be involved in the astrogliosis associated with amyotrophic lateral sclerosis.133
9.2.5Signal Transducer and Activator of Transcription 3 (STAT3)
One key signaling molecule that regulates GFAP expression is the transcription
factor STAT3. Ciliary neurotrophic factor or cytokine induced STAT3 activation was shown to induce reactive astrocytosis.134–136 Additionally, LPS and
other inflammatory mediators such as meteorin, oncostatin M (a member of the IL-6 subfamily of cytokines, likely derived from activated microglia) and neuropoietin (a recently discovered cytokine of the gp130 family that shares functional and structural features with CNTF), were all shown to induce STAT3 activation in vivo or in vitro, and such activation led to reactive astrocytosis.137–139 Conversely, use of a conditional gene deletion strategy that targets STAT3 in astrocytes in mice, or pharmacological inhibition of STAT3