Alterations in τ Immunostaining in the Rat Hippocampus following Transient Cerebral Ischemia

Geddes, James W.; Schwab, Claudia; Craddock, Susan D.; Wilson, Janice L.; Pettigrew, L. Creed

doi:10.1038/jcbfm.1994.69

Cited by 85 publications

(45 citation statements)

References 54 publications

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“…In both instances, the level of phosphorylation was decreased and neurones were stained more intensively by antibodies specific to nonphosphorylated T Davis et al, 1995;Fleming and Johnson, 1995). r has also been reported to be dephosphorylated in vivo in response to ischaemia (Geddes et a!., 1994;Shackelford and Nelson, 1996), consistent with our findings on cultured neurones treated with glutamate or subjected to oxidative stress.…”

Section: Discussionsupporting

confidence: 82%

Oxidative Stress Induces Dephosphorylation of τ in Rat Brain Primary Neuronal Cultures

Davis

Anderton

Brion

et al. 1997

Journal of Neurochemistry

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Abstract:Oxidative stress and free radical damage have been implicated in the neurodegenerative changes characteristic of several neurodegenerative diseases, including Alzheimer's disease. There is experimental evidence that the neurotoxicity of~3-amyIoid is mediated via free radicals, and as the deposition of~3-amyloid apparently precedes the formation of paired helical filaments (PHF) in Alzheimer's disease, we have investigated whether subjecting primary neuronal cultures to oxidative stress induces changes in the phosphorylation state of the principal PHF protein 7~that resemble those found in PHF-r. Contrary to causing an increase in~-phosphorylation, treatment of neurones with hydrogen peroxide caused a dephosphorylation of~-and so we conclude that oxidative stress is not the direct cause of r hyperphosphorylation and hence of PHF formation. Keywords: Free radicalsReactive oxygen species-Alzheimer's disease-Excitotoxicity-Neurodegeneration. J. Neurochem. 68, 1590-1597 (1997).There is a substantial body of evidence that free radical damage occurs in the brain in several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and motor neurone disease, and this has been taken to implicate oxidative stress in the pathogeneses of these conditions (Beal, 1995; Wi!-hams, 1995). However, from the presence of stigmata of free radical damage in postmortem tissues, it is impossible to know if free radicals play an active role in the neurodegenerative process or simply are generated as cells die and, hence, secondarily to other primary events. As each of the above three neurodegenerative conditions has a characteristic histopathology that involves changes in cytoskeletal proteins, we have adopted an experimental approach to investigate if free radical damage to healthy neurories results in cytoskeletal changes that mirror those that are associated with neurodegenerative disease.In the case of Alzheimer's disease, the microtubuleassociated protein r is the principal constituent of paired helical filaments (PHF) that comprise neurofibrillary tangles and neuropil threads and are also found in the dystrophic neurites of senile plaques (Smith and Anderton, 1994;Lee, 1995). PHF-y is in a stable state of hyperphosphorylation compared with normal r, which in both foetal and adult brain has been demonstrated recently to be in a more elevated state of phosphorylation than was believed previously (Bramblett et al., 1993; Brion et al., 1993a,b;Kenessey and Yen, 1993; Watanabe et al., 1993; Garver et al., 1994; Matsuo et al., 1994; Mawal-Dewan et al., 1994;Morishima-Kawashima et al., 1995). A number of phosphorylation sites that are phosphorylated extensively in PHF-r and to a lesser degree in foetal and normal adult 'i-are serines or threonines followed by a proline and hence are candidates for phosphorylation by proline-directed protein kinases.The biochemical stimulus for a change in T phosphorylation in Alzheimer's disease is unknown, but as deposition of /3-amyloid is an early event, much attention ha...

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Section: Discussionsupporting

confidence: 82%

Oxidative Stress Induces Dephosphorylation of τ in Rat Brain Primary Neuronal Cultures

Davis

Anderton

Brion

et al. 1997

Journal of Neurochemistry

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“…At 2 mg/kg, protein S reduced the amount of fibrin deposited in the ischemic hemisphere by 40% (PϽ0.05; Figure 4B), the number of CD11b-positive leukocytes by 53% (PϽ0.01; Figure 4C), and the number of TUNELpositive neurons in the ischemic cortex by 67% (Figure 4, D-E). The ischemia-induced changes in tau accumulation in neuronal soma 35 were prevented by protein S.…”

Section: Resultsmentioning

confidence: 94%

“…33,34 Double-labeling for in situ DNA fragmentation in neurons was performed on paraffin sections stained with terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) (Intergen Co) and tau. 35 Tau was detected with a rabbit polyclonal anti-tau antibody (Chemicon, 1:100) and a secondary rhodamine conjugated goat anti-rabbit IgG (Molecular Probes, 1:150).…”

Section: Histopathology and Fibrin Detectionmentioning

confidence: 99%

Protein S Confers Neuronal Protection During Ischemic/Hypoxic Injury in Mice

et al. 2003

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Background-Protein S is an antithrombotic factor that also exhibits mitogenic activity. Thus, we hypothesized that protein S may control cerebrovascular thrombosis in stroke and protect brain tissue from ischemic injury. Methods and Results-We studied protein S in a murine in vivo model of stroke and an in vitro model of neuronal hypoxia/reoxygenation injury. Animals received purified human plasma-derived protein S or vehicle intravenously 10 minutes after initiation of middle cerebral artery occlusion followed by reperfusion. Protein S at 0.2 to 2 mg/kg significantly improved the motor neurological deficit by 3.8-to 3.2-fold and reduced infarction and edema volumes by 45% to 54% and 45% to 62%, respectively. Protein S at 2 mg/kg improved postischemic cerebral blood flow by 21% to 26% and reduced brain fibrin deposition and infiltration with neutrophils by 40% and 53%, respectively. Intracerebral bleeding was not observed with protein S. Protein S protected ischemic neurons in vivo and cultured neurons from hypoxia/reoxygenation-induced apoptosis in a time-and dose-dependent manner. Recombinant human protein S exerted protective effects from hypoxia-induced damage similar to the plasma-derived protein S both in vivo and in vitro. Conclusions-Protein S is a significant neuroprotectant during ischemic brain injury with direct effects on neurons and antithrombotic effects. Thus, protein S could be a prototype of a new class of agents for clinical stroke with combined direct neuronal protective effects and systemic antithrombotic and antiinflammatory activities.

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“…The possibility that different results might be seen at different time points after the lesion cannot be completely ruled out. However, it should be noted that the molecular mechanisms promoting neuronal cell death (i.e., apoptosis) in the permanent focal ischemia and KA experimental models are not superimposable (30,31). It is also well known that different mechanisms contribute to the neurodegeneration associated with animal models of permanent and transient cerebral ischemia.…”

Section: Discussionmentioning

confidence: 99%

Presenilin-1 regulates the neuronal threshold to excitotoxicity both physiologically and pathologically

Grilli

Diodato

Lozza

et al. 2000

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

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A direct pathophysiological role of Familial Alzheimer's Disease (FAD)-associated Presenilin 1 (PS1) mutations in neuronal vulnerability remains a controversial matter. We evaluated the relationship between PS1 and excitotoxicity in four different experimental models of neurotoxicity by using primary neurons from (i) transgenic (tg) mice overexpressing a human FAD-linked PS1 variant (L286V mutation), (ii) tg mice overexpressing human wild-type (wt) PS1, (iii) PS1 knockout mice, and (iv) wt mice in which PS1 gene expression was knocked down by antisense treatment. We found that primary neurons overexpressing mutated PS1 showed an increased vulnerability to both excitotoxic and hypoxic-hypoglycemic damage when compared with neurons obtained from either mice overexpressing human wt PS1 or in wt mice. In addition, reduced excitotoxic damage was obtained in neurons in which PS1 expression was absent or diminished. Data obtained in in vivo experimental models of excitotoxicity partially supported the in vitro observations. Accelerated neuronal death was demonstrated in the hippocampus of mice overexpressing mutated PS1 after peripheral administration of kainic acid in comparison with wt animals. However, measurement of the infarct volume after middle cerebral artery occlusion did not show significant difference between the two animal groups. The results altogether suggest that expression of FAD-linked PS1 variants increases the vulnerability of neurons to a specific type of damage in which excitotoxicity plays a relevant role. In addition, they support the view that reduction of endogenous PS1 expression results in neuroprotection.

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Alterations in τ Immunostaining in the Rat Hippocampus following Transient Cerebral Ischemia

Cited by 85 publications

References 54 publications

Oxidative Stress Induces Dephosphorylation of τ in Rat Brain Primary Neuronal Cultures

Oxidative Stress Induces Dephosphorylation of τ in Rat Brain Primary Neuronal Cultures

Protein S Confers Neuronal Protection During Ischemic/Hypoxic Injury in Mice

Presenilin-1 regulates the neuronal threshold to excitotoxicity both physiologically and pathologically

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