Enhanced hippocampal neurodegeneration after traumatic or kainate excitotoxicity in GFAP-null mice

Otani, Naoki; Nawashiro, Hiroshi; Fukui, Shinji; Ooigawa, Hidetoshi; Ohsumi, Atsushi; Toyo’oka, Toshimasa; Shima, Katsuji; Gomi, Hiroshi; Brenner, Michael

doi:10.1016/j.jocn.2005.10.018

Cited by 61 publications

(48 citation statements)

References 24 publications

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“…41 Transgenic and knockout mouse models for certain astrocyte-specific proteins demon- strated neuropathologies. 42,43 Astrocyte abnormalities and their influence on Purkinje cells have also been reported in Atm Ϫ/Ϫ cells. 41,44,45 Electron microscopy observations have detected structural activation of glial cells in Atm knockout mice.…”

Section: Discussionmentioning

confidence: 95%

A Role for Vascular Deficiency in Retinal Pathology in a Mouse Model of Ataxia-Telangiectasia

Raz-Prag

Galron

Segev-Amzaleg

et al. 2011

The American Journal of Pathology

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Ataxia-telangiectasia is a multifaceted syndrome caused by null mutations in the ATM gene, which encodes the protein kinase ATM, a key participant in the DNA damage response. Retinal neurons are highly susceptible to DNA damage because they are terminally differentiated and have the highest metabolic activity in the central nervous system. In this study, we characterized the retina in young and aged Atmdeficient mice (Atm ؊/؊ ). At 2 months of age, angiography revealed faint retinal vasculature in Atm ؊/؊ animals relative to wild-type controls. This finding was accompanied by increased expression of vascular endothelial growth factor protein and mRNA. Fibrinogen, generally absent from wild-type retinal tissue, was evident in Atm ؊/؊ retinas, whereas mRNA of the tight junction protein occludin was significantly decreased. Immunohistochemistry labeling for occludin in 6-month-old mice showed that this decrease persists in advanced stages of the disease. Some brain disorders may have a vascular origin, 1,2 and vascular diseases can be directly linked to neuronal and synaptic dysfunction through changes in the blood flow, increase in blood-brain barrier permeability, and in nutrient supply. 3 A healthy brain relies on the proper function and communication of all cells comprising the neurovascular unit: neurons, astrocytes, brain endothelium, and vascular smooth muscle cells. 4 Impaired genomic stability interferes with cellular homeostasis and poses a constant threat to cellular viability. 5 The cell combats this threat by activating the DNA damage response (DDR), a complex signaling network that detects the DNA lesions, promotes their repair, and temporarily modulates cellular metabolism while the damage is being repaired. 6 The DDR is vigorously activated by DNA double-strand breaks (DSBs), a particularly cytotoxic DNA lesion induced by ionizing radiation, radiomimetic chemicals, and oxygen radicals. 7,8 The DNA damage response is a hierarchical process executed by sensor/mediator proteins that accumulate at DSB sites and by protein kinases that serve as transducers of the DNA damage alarm to numerous downstream effectors. 6 The primary transducer of the cellular response to DSBs is the protein kinase ATM, which phosphorylates many key players in the various branches of the DDR. 9 Ataxia-telangiectasia (A-T) is an autosomal recessive disorder caused by mutations in the ATM gene that encodes the ATM protein. 10 A-T is characterized by progressive neurodegeneration affecting mainly the cerebellum, which develops into severe neuromotor dysfunction;

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Section: Discussionmentioning

confidence: 95%

A Role for Vascular Deficiency in Retinal Pathology in a Mouse Model of Ataxia-Telangiectasia

Raz-Prag

Galron

Segev-Amzaleg

et al. 2011

The American Journal of Pathology

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“…However, accumulating evidence now suggests that astrocytes are key elements serving pivotal functions in the central nervous system, including structural and redox support for neuron, neurotransmitter synthesis, and transport of nutrients and metabolic precursors to neurons (17, 19, 38 -40). Previous studies have reported that transgenic and knock-out mouse models for certain astrocyte-specific proteins result in neurodegenerative disorders (41,42). This implies that abnormalities in astrocytes might also cause neuropathophysiology of A-T.…”

Section: Discussionmentioning

confidence: 99%

Oxidative Stress Is Linked to ERK1/2-p16 Signaling-mediated Growth Defect in ATM-deficient Astrocytes

Kim

Wong

2009

Journal of Biological Chemistry

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The gene that encodes the ATM protein kinase is mutated in ataxia-telangiectasia (A-T). One of the prominent features of A-T is progressive neurodegeneration. We have previously reported that primary astrocytes isolated from Atm ؊/؊ mice grow slowly and die earlier than control cells in culture. However, the mechanisms for this remain unclear. We show here that intrinsic elevated intracellular levels of reactive oxygen species (ROS) are associated with the senescence-like growth defect of Atm ؊/؊ astrocytes. This condition is accompanied by constitutively higher levels of ERK1/2 phosphorylation and p16Ink4a in Atm ؊/؊ astrocytes. We also observe that ROS-induced up-regulation of p16Ink4a occurs correlatively with ERK1/2-dependent down-regulation and subsequent dissociation from chromatin of Bmi-1. Furthermore, both mitogen-activated protein kinase (MAPK)/ERK inhibitor PD98059 and antioxidant N-acetyl-Lcysteine restored normal proliferation of Atm ؊/؊ astrocytes. These results suggest that ATM is required for normal astrocyte growth through its ability to stabilize intracellular redox status and that the inability to control ROS is the molecular basis of limited cell growth of Atm ؊/؊ astrocytes. This defect may be mediated by a mechanism involving ERK1/2 activation and Bmi-1 derepression of p16 Ink4a. These data identify new potential targets for therapeutic intervention in A-T neurodegeneration.

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“…Quantitative data pointed out that GFAP-and Vim-positive astrocytes display a similar behavior in regard to apoptosis and cell density in younger cases compared to older cases ( table 5 ). A high susceptibility to cerebral ischemia was demonstrated in GFAP-null mice, suggesting an important role for astrocytes in the progress of ischemic brain damage [56,57] , and/or a crucial role for GFAP in survival [58] . Interestingly, neonatal corticoid administration in the rat has a neuroprotective effect against ischemia [57,59,60] and corticoids upregulate GFAP expression in neonatal rat brains [61,62] .…”

Section: Discussionmentioning

confidence: 99%

Astrocytic Demise in the Developing Rat and Human Brain after Hypoxic-Ischemic Damage

et al. 2009

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In order to approach the physiopathological mechanism underlying the selective susceptibility of the immature brain to hypoxia-ischemia (HI), we have compared the lesions experimentally induced in postnatal day 7 rats using a model of neonatal stroke with those occurring in human fetal and neonatal brains. We first observed that gray and white matter lesions demonstrated a similar organization (core with cell loss and/or cavity and penumbra) and evolutionary pattern between experimental and human HI lesions. We then observed that, in the intermediate white matter, GFAP- and vimentin-positive astrocytes exhibited clasmatodendrosis and represent a major cell population involved in cell death in human brains (56.3 and 67.9%, respectively). In rat brains, GFAP- and TUNEL-positive astrocytes were also highly vulnerable, increasing between 6 (31%) and 72 (58%) hours after ischemia. Together, these results indicate that astroglial dysfunction may play a critical role in determining the progress and outcome of acute hypoxic-ischemic injury particularly in the developing brain.

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Enhanced hippocampal neurodegeneration after traumatic or kainate excitotoxicity in GFAP-null mice

Cited by 61 publications

References 24 publications

A Role for Vascular Deficiency in Retinal Pathology in a Mouse Model of Ataxia-Telangiectasia

A Role for Vascular Deficiency in Retinal Pathology in a Mouse Model of Ataxia-Telangiectasia

Oxidative Stress Is Linked to ERK1/2-p16 Signaling-mediated Growth Defect in ATM-deficient Astrocytes

Astrocytic Demise in the Developing Rat and Human Brain after Hypoxic-Ischemic Damage

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