Effects of estrogen treatment on glutamate uptake in cultured human astrocytes derived from cortex of Alzheimer's disease patients

Liang, Zhe; Valla, Jon; Sefidvash-Hockley, Sepideh; Rogers, Joseph; Li, Rena

doi:10.1046/j.0022-3042.2002.00779.x

Cited by 130 publications

(75 citation statements)

References 44 publications

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“…In agreement with the hypothesis that Akt pathway is induced by PDTC treatment, we observed decreased immunoreactivity for phosphorylated tau in the CA3 pyramidal neurons and overall increase in GLT-1, a major astrocytic glutamate transporter that has previously been reported to be reduced in AD models (Harris et al, 1996;Masliah et al, 2000;Liang et al, 2002). Although GSK-3␤ is responsible for phosphorylating Ser202 (Mandelkow et al, 1992;Ishiguro et al, 1993), the major site for abnormal phosphorylation of tau resulting in formation of paired helical filaments (PHFs) in AD (Ikura et al, 1998), it is uncertain whether the PDTC-induced reduction we observed in Ser202 phosphorylation (AT8 immunoreactivity) contributes to the improved cognitive functions, because PHFs cannot be found in transgenic APP or APP/PS1 mice and we could not detect reduction in AT8-immunoreactive dystrophic neurites around A␤ deposits.…”

Section: Discussionsupporting

confidence: 78%

“…PDTC treatment upregulates the reduced GLT-1 levels in APP/PS1 mouse brain Because defects in uptake of glutamate through glial glutamate transporter GLT-1 have been reported in AD and in A␤-treated cultured astrocytes (Harris et al, 1996;Masliah et al, 2000;Liang et al, 2002) and the expression of GLT-1 is regulated by Akt pathway (Li et al, 2006), we determined the changes in GLT-1 in our experimental settings by Western blotting. The cortical GLT-1 levels were 18% lower in untreated APP/PS1 mice compared with untreated wt mice (Fig.…”

Section: Pdtc Treatment Reduces Phosphorylated Tau In the Hippocampusmentioning

confidence: 99%

“…In addition to its direct harmful effect on neurons, aggregated A␤ activates microglia and astrocytes (Akiyama et al, 2000) to secrete proinflammatory molecules, reactive oxygen species, and other neurotoxins, causing indirect neurotoxicity. Moreover, expression of glutamate transporter 1 (GLT-1), an astrocytic glutamate transporter maintaining glutamate at nontoxic concentrations, is decreased in the AD brain and in A␤-treated astrocytes (Harris et al, 1996;Masliah et al, 1996Masliah et al, , 2000Liang et al, 2002). There are several hypotheses for the molecular mechanisms for these pathogenic cascades triggered by A␤ in neurons and glia, including the pathway mediated by glycogen synthase kinase 3␤ (GSK-3␤) (Grimes and Jope, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Pyrrolidine Dithiocarbamate Activates Akt and Improves Spatial Learning in APP/PS1 Mice without Affecting β-Amyloid Burden

Malm¹,

Iivonen²,

Goldsteins³

et al. 2007

J. Neurosci.

146

108

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Pyrrolidine dithiocarbamate (PDTC) is a clinically tolerated inhibitor of nuclear factor-B (NF-B), antioxidant and antiinflammatory agent, which provides protection in brain ischemia models. In neonatal hypoxia-ischemia model, PDTC activates Akt and reduces activation of glycogen synthase kinase 3␤ (GSK-3␤). Because chronic inflammation, oxidative stress, and increased GSK-3␤ activity are features of Alzheimer's disease (AD) pathology, we tested whether PDTC reduces brain pathology and improves cognitive function in a transgenic animal model of AD. A 7 month oral treatment with PDTC prevented the decline in cognition in AD mice without altering ␤-amyloid burden or gliosis. Moreover, marked oxidative stress and activation of NF-B were not part of the brain pathology. Instead, the phosphorylated form of GSK-3␤ was decreased in the AD mouse brain, and PDTC treatment increased the phosphorylation of Akt and GSK-3␤. Also, PDTC treatment increased the copper concentration in the brain. In addition, PDTC rescued cultured hippocampal neurons from the toxicity of oligomeric A␤ and reduced tau phosphorylation in the hippocampus of AD mice. Finally, astrocytic glutamate transporter GLT-1, known to be regulated by Akt pathway, was decreased in the transgenic AD mice but upregulated back to the wild-type levels by PDTC treatment. Thus, PDTC may improve spatial learning in AD by interfering with Akt-GSK pathway both in neurons and astrocytes. Because PDTC is capable of transferring external Cu 2ϩ into a cell, and, in turn, Cu 2ϩ is able to activate Akt, we hypothesize that PDTC provides the beneficial effect in transgenic AD mice through Cu 2ϩ -activated Akt pathway.

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Section: Discussionsupporting

confidence: 78%

Section: Pdtc Treatment Reduces Phosphorylated Tau In the Hippocampusmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Pyrrolidine Dithiocarbamate Activates Akt and Improves Spatial Learning in APP/PS1 Mice without Affecting β-Amyloid Burden

Malm¹,

Iivonen²,

Goldsteins³

et al. 2007

J. Neurosci.

146

108

View full text Add to dashboard Cite

show abstract

“…Of note, a study by Liang et al implicates the female steroid hormone estrogen to elevate GLT-1 and GLAST expression levels in astrocytes derived from Alzheimer disease patients (60), indicating that steroid hormones in general exert promoting effects on glutamate transporters. Interestingly, Rothstein et al (61) recently published the first evidence of pharmaceutical modulation of GLT-1 expression by ␤-lactam antibiotics.…”

Section: Discussionmentioning

confidence: 99%

Differential Promotion of Glutamate Transporter Expression and Function by Glucocorticoids in Astrocytes from Various Brain Regions

Zschocke

Bayatti

Clement

et al. 2005

Journal of Biological Chemistry

124

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Steroids that activate glucocorticoid receptors (GRs) and mineralocorticoid receptors have important regulatory effects on neural development, plasticity, and the body's stress response. Here, we investigated the role of corticosteroids in regulating the expression of the glial glutamate transporters glial glutamate transporter-1 (GLT-1) and glutamate-aspartate transporter (GLAST) in rat primary astrocytes. The synthetic glucocorticoid dexamethasone provoked a marked increase of GLT-1 transcription and protein levels in cortical astrocytes, whereas GLAST expression remained unaffected. Up-regulation of GLT-1 expression was accompanied by an enhanced glutamate uptake, which could be blocked by the specific GLT-1 inhibitor dihydrokainate. The promoting effect of dexamethasone on GLT-1 gene expression and function was abolished by the GR antagonist mifepristone. A predominant role of the GR was further supported by the observation that corticosterone could elevate GLT-1 expression in a dose-dependent manner, whereas aldosterone, the physiological ligand of the mineralocorticoid receptor, exerted only weak effects even when applied at high concentrations. Moreover, we monitored brain region-specific differences, since all corticosteroids used in this study failed to alter the expression of GLT-1 in midbrain and cerebellar glia, although expression levels of both corticosteroid receptor subtypes were similar in all brain regions analyzed. Dexamethasone, however, modestly enhanced GLT-1 expression in cerebellar glia in combination with the DNA methyltransferase inhibitor 5-aza-2-deoxycytidine, suggesting that suppression of GLT-1 expression in cerebellar cultures may at least in part be epigenetically mediated by a DNA methylation-dependent process. Taken together, our data highlight a potential role for glucocorticoids in regulating GLT-1 gene expression during central nervous system development or pathophysiogical processes including stress. Steroid hormones possessing glucocorticoid (GC)2 or mineralocorticoid (MC) activity exert profound regulatory effects in the central nervous system (1). Being synthesized in the adrenal gland and ultimately secreted into circulation, they penetrate the blood brain barrier and influence neuronal development and plasticity. Moreover, GCs are the main effectors of the hypothalamic-pituitary-adrenal axis and regulate the body's stress response by inducing a variety of physiological changes including mobilization of energy from storage sites and the suppression of parts of the immune system (2). Due to their anti-inflammatory properties, they are administered in the treatment of central nervous system diseases such as edema arising from brain tumors, viral encephalitis, bacterial meningitis, and multiple sclerosis (3).The effects of adrenal steroid hormones (GCs and MCs) are classically mediated through the activation of mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) (4, 5), which display a wide distribution in the brain. Corticosterone, cortisol, and aldosteron...

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“…Estrogen is suggested to play a protective role against AD pathogenesis through a variety of mechanisms including upregulation of glutamate transporter 26 , activation of protein kinase C…”

mentioning

confidence: 99%

Dietary Cholesterol and Estrogen Administration Elevate Brain Apolipoprotein E in Mice by Different Mechanisms

Srivastava¹,

Averna²,

Srivastava

2008

ANS

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Apolipoprotein (apo) E plays an important role in the whole body cholesterol homeostasis. Recent studies suggest that it may also be involved in the local cholesterol transport in the brain, and influence the pathogenesis of Alzheimer's disease (AD) by interacting with the β-amyloid protein and brain lipoprotein receptors. Since apoE expression is highest in the brain, next only to the liver and associated with the pathogenesis of AD, we hypothesized that dietary and hormonal intervention, known to regulate hepatic apoE expression may also regulate brain apoE and thereby influence local cholesterol transport. To test this hypothesis, groups of male C57BL mice were fed either regular rodent chow or high fat (HF) and high cholesterol enriched diet for 3 weeks. In a separate study, groups of male mice were administered pharmacological doses of 17-β estradiol for 5 consecutive days and sacrificed on the 6 th day. As expected, HF diet elevated liver apoE mRNA and apoE synthesis. Similar to liver, brain apoE mRNA and synthesis also increased, following HF feeding. Estradiol administration increased liver apoE synthesis without affecting apoE mRNA. Interestingly, estradiol administration also increased the brain apoE synthesis, but without altering the brain apoE mRNA. These studies suggested that dietary cholesterol and estrogen administration elevated the brain apoE by different mechanisms.

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Effects of estrogen treatment on glutamate uptake in cultured human astrocytes derived from cortex of Alzheimer's disease patients

Cited by 130 publications

References 44 publications

Pyrrolidine Dithiocarbamate Activates Akt and Improves Spatial Learning in APP/PS1 Mice without Affecting β-Amyloid Burden

Pyrrolidine Dithiocarbamate Activates Akt and Improves Spatial Learning in APP/PS1 Mice without Affecting β-Amyloid Burden

Differential Promotion of Glutamate Transporter Expression and Function by Glucocorticoids in Astrocytes from Various Brain Regions

Dietary Cholesterol and Estrogen Administration Elevate Brain Apolipoprotein E in Mice by Different Mechanisms

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