Acta Neuropathol (2010) 119:7–35 25 Fig. 7 Reactive astrogliosis in two degenerative diseases. a High magniﬁcation image of autopsy specimen from a person with longstanding Alzheimer’s disease immunohistochemically stained for GFAP. Section of cerebral cortex shows an amyloid senile plaque with a pale unstained center (Ab) ringed by dense layers of reactive astrocytic processes (arrows) that circumferentially surround the plaque as if forming a scar-like barrier around it. b High magniﬁ- cation image of autopsy specimen from a person with Creutzfeldt– Jakob disease (CJD) transmissible spongiform encephalopathy. Section of cerebral cortex shows pronounced neuron loss and severe diffuse reactive astrogliosis. Most of the cortex is packed with gemistocytic astrocytes, while spongiform change is relatively minimal in this area. Scale bars a, b 10 lm astrogliosis exhibits some characteristics of severe diffuse reactive astrogliosis (Figs. 3c, 4c), it is not clear whether astrocytes play an active role in prion replication and dis- ease pathogenesis or whether astrogliosis is largely reactive to the disease process in other cell types [115]. It is interesting that the hippocampal neuronal degeneration associated with experimental ablation of reactive astrocytes has a vacuolar appearance with similarities to spongiform changes [33]. Parkinson’s disease The role of astrocytes in Parkinson’s disease and related syndromes is sparsely investigated and poorly understood [140]. Reactive astrogliosis is generally mild or moderate and rarely severe in autopsy specimens of substantia nigra from Parkinson’s disease patients [72, 149]. Astrocytes have been implicated as potentially exerting both neuro- toxic and neuroprotective activities in Parkinson’s disease. Experimental studies show that astrocytes take up the Parkinson’s syndrome causing molecule, MPTP, from the blood stream and convert it to neurotoxic MPP? and may similarly convert other environmental molecules that have been implicated in dopaminergic toxicity [54, 187]. On the other hand, activation of the transcription factor Nrf2 selectively in astrocytes protects mice from MPTP-induced Parkinsonism by activating anti-oxidative response path- ways [40]. Rare mutations in Nurr1 lead to familial Parkinson’s disease, and expression of Nurr1 in astrocytes suppresses production of potentially toxic molecules and protects against loss of dopaminergic neurons [203]. Recent ﬁndings also show that subpopulations of astrocytes express disease-related proteins such as a-synuclein, parkin and phosho-tau to different levels and in different combinations in Parkinson’s disease, multiple-system atrophy, and progressive supranuclear palsy [227], but the roles of astrocytes in these conditions are not yet deﬁned. Amyotrophic lateral sclerosis (ALS) Evidence is available suggesting two quite different potential roles for astrocytes in amyotrophic lateral sclerosis (ALS) or motor neuron disease, through either the loss of a neuroprotective function or the gain of a neurotoxic effect. Sporadic ALS is characterized by selective loss or dysfunction of astrocyte glutamate transporters in spinal cord and cerebral cortical areas that exhibit loss of lower and upper motor neurons [73, 136, 194, 197], suggesting that increased glutamate excito- toxicity may contribute to motor neuron death and raising the possibility of different types of potential interventions. A high-throughput screen of small mole- cules has identiﬁed that certain b-lactam antibiotics can stimulate the expression of glutamate transporters by astrocyte and thereby enhance glutamate uptake sufﬁciently to reduce excitotoxicity, and provide neuroprotection in animal models of stroke and ALS [199]. The b-lactam antibiotic, Ceftriaxone, began stage 3 clinical trials in May 2009 to determine efﬁcacy in reducing excitotoxicity and neurodegeneration in ALS. Focal grafts of healthy astro- cytes are reported to be neuroprotective in an animal model of ALS, suggesting that transplantation of astrocytes may be a potential therapeutic strategy [120]. From a different perspective, astrocytes may also exhibit neurotoxic dys- function in ALS. Approximately 20% of familial ALS cases, and about 5% of apparently sporadic cases, exhibit missense mutations of the gene encoding superoxide 123