DNA End Labeling (TUNEL) in Huntington's Disease and Other Neuropathological Conditions

Thomas, L. Brannon; Gates, Diane; Richfield, Eric K.; O’Brien, Thomas F.; Schweitzer, John B.; Steindler, Dennis A.

doi:10.1006/exnr.1995.1029

Cited by 209 publications

(84 citation statements)

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“…Astrocytes can, however, be selectively damaged by injection of "glial-toxic" drugs, including 3-chloropropanediol (Willis et al, 2004), the aconitase inhibitor fluorocitrate (Paulsen et al, 1987), or 6-aminonicotinamide (see Krum, 1994 and references therein). Moreover, apoptotic astrocytes have been found in the early stages of Huntington's disease (Thomas et al, 1995). During development and throughout adult life, neural stem cells in the subgranular zone (SGZ) proliferate and generate neurons (reviewed in Gage et al, 1998;Parent, 2003;Kempermann et al, 2004;Lie et al, 2004) and to a lesser extent astrocytes (Palmer et al, 2000;Kempermann and Gage, 2002;Steiner et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Degeneration and proliferation of astrocytes in the mouse dentate gyrus after pilocarpine-induced status epilepticus

Borges

McDermott

Irier

et al. 2006

Experimental Neurology

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Astrocytes are relatively resistant to injury compared to neurons and oligodendrocytes. Here, we report transient region-specific loss of astrocytes in mice early after pilocarpine-induced status epilepticus (SE). In the dentate hilus, immunoreactivity for glial acidic fibrillary protein (GFAP) was decreased, and the number of healthy appearing GFAP-or S100β-positive cells was significantly reduced (≥ 65%) 1 and 3 days after pilocarpine-induced SE. Many remaining GFAPpositive cells were shrunken, and 1 day after SE electron microscopy revealed numerous electrondense degenerating astrocyte processes and degenerating glial somata in the hilus. Degeneration of GFAP-expressing cells may be linked to hilar neuronal death, because we did not observe loss of astrocytes after kainate-induced SE, after which hilar neurons remained intact. Ten days after SE, hilar GFAP immunoreactivity had returned, partially from GFAP-positive cells in the hilus. Unlike control mice, many GFAP-positive hilar processes originated from cell bodies located in the subgranular zone (SGZ). To investigate whether proliferation contributes to hilar repopulation, we injected 5-bromo-2′-deoxyuridine (BrdU) 3 days after SE. Five hours later and up to 31 days after SE, many BrdU/GFAP colabeled cells were found in the hilus and the SGZ, some with hilar processes, indicating that proliferation in both areas contributes to generation of hilar astrocytes and astrocyte processes. In contrast to pilocarpine-induced SE in mice, astrocyte degeneration was not found after pilocarpine-induced SE in rats. These findings demonstrate astrocyte degeneration in the mouse dentate hilus specifically in the mouse pilocarpine epilepsy model, followed by astrogenesis leading to hilar repopulation.

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Section: Introductionmentioning

confidence: 99%

Degeneration and proliferation of astrocytes in the mouse dentate gyrus after pilocarpine-induced status epilepticus

Borges

McDermott

Irier

et al. 2006

Experimental Neurology

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“…Patients suffering from Alexander disease bear GFAP mutations, which directly affect astrocytes, and result in profound fatal cerebral alterations (Rodriguez et al, 2001). In addition, astrocytes death participates in several neuropathological diseases ranging from HIVassociated dementia to ischemic and traumatic brain injury (Thomas et al, 1995;Thompson et al, 2001;Takuma et al, 2004;Giffard and Swanson, 2005). The identification of molecules capable of promoting the survival of astrocytes is therefore essential.…”

Section: Introductionmentioning

confidence: 99%

Transforming growth factor alpha acts as a gliatrophin for mouse and human astrocytes

et al. 2006

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Astrocyte death has been implicated in several neuropathological diseases, but the identification of molecules susceptible of promoting astrocyte survival has been elusive. We investigated whether transforming growth factor alpha (TGFa), an erbB1/EGFR ligand, which promotes glioma progression and affects astrocyte metabolism at embryonic and adult stages, regulates astrocyte survival. Primary serum-free astrocyte cultures from postnatal mouse and fetal human cortices were used. Transforming growth factor alpha protected both species of astrocytes from staurosporine-induced apoptosis. In serum-free medium, mouse astrocytes did not survive beyond 2 months while TGFa-treated astrocytes survived up to 12 months. Transforming growth factor alpha also promoted long-term survival of human astrocytes. We additionally extended TGFa proliferative effects to human astrocytes. After 3 days of permanent application, TGFa induced a major downregulation of both erbB1 and erbB2. This downregulation did not impair the functional activation of the receptors, as ascertained by their tyrosine phosphorylation and the continuous stimulation of both ERK/MAPK and PI3K/Akt pathways up to 7 days, the longest time examined. The full cellular effects of TGFa required activation of both transduction pathways. Enhanced proliferation and survival thus define TGFa as a gliatrophin for mammalian astrocytes. These results demonstrate that in normal, non-transformed astrocytes, sustained and functional erbBs activation is achieved without bypassing ligand-induced receptors downregulation.

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“…In fact, it has been demonstrated that lymphoblasts isolated from HD patients are more susceptible to apoptotic signals that are mediated through mitochondrial pathways (9). Apoptotic cells are elevated in HD neostriatum (18)(19)(20), and their frequency is positively correlated with the length of CAG repeats (10). Caspases, which are crucial for the initiation and execution of apoptosis, are elevated and activated in HD brain (21,22).…”

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confidence: 99%

Tauroursodeoxycholic acid, a bile acid, is neuroprotective in a transgenic animal model of Huntington's disease

Keene

Rodrigues

Eich

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

276

181

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Huntington's disease (HD) is an untreatable neurological disorder caused by selective and progressive degeneration of the caudate nucleus and putamen of the basal ganglia. Although the etiology of HD pathology is not fully understood, the observed loss of neuronal cells is thought to occur primarily through apoptosis. Furthermore, there is evidence in HD that cell death is mediated through mitochondrial pathways, and mitochondrial deficits are commonly associated with HD. We have previously reported that treatment with tauroursodeoxycholic acid (TUDCA), a hydrophilic bile acid, prevented neuropathology and associated behavioral deficits in the 3-nitropropionic acid rat model of HD. We therefore examined whether TUDCA would also be neuroprotective in a genetic mouse model of HD. Our results showed that systemically administered TUDCA led to a significant reduction in striatal neuropathology of the R6͞2 transgenic HD mouse. Specifically, R6͞2 mice began receiving TUDCA at 6 weeks of age and exhibited reduced striatal atrophy, decreased striatal apoptosis, as well as fewer and smaller size ubiquitinated neuronal intranuclear huntingtin inclusions. Moreover, locomotor and sensorimotor deficits were significantly improved in the TUDCA-treated mice. In conclusion, TUDCA is a nontoxic, endogenously produced hydrophilic bile acid that is neuroprotective in a transgenic mouse model of HD and, therefore, may provide a novel and effective treatment in patients with HD.

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DNA End Labeling (TUNEL) in Huntington's Disease and Other Neuropathological Conditions

Cited by 209 publications

References 0 publications

Degeneration and proliferation of astrocytes in the mouse dentate gyrus after pilocarpine-induced status epilepticus

Degeneration and proliferation of astrocytes in the mouse dentate gyrus after pilocarpine-induced status epilepticus

Transforming growth factor alpha acts as a gliatrophin for mouse and human astrocytes

Tauroursodeoxycholic acid, a bile acid, is neuroprotective in a transgenic animal model of Huntington's disease

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