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Dive into the research topics where Debbie Callaghan is active.

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Featured researches published by Debbie Callaghan.


The Journal of Neuroscience | 2009

ABCG2 Is Upregulated in Alzheimer's Brain with Cerebral Amyloid Angiopathy and May Act as a Gatekeeper at the Blood–Brain Barrier for Aβ1–40 Peptides

Huaqi Xiong; Debbie Callaghan; Aimee Jones; Jianying Bai; Ingrid Rasquinha; Catherine Smith; Ke Pei; Douglas G. Walker; Lih-Fen Lue; Danica Stanimirovic; Wandong Zhang

Alzheimers disease (AD) is characterized by accumulation and deposition of Aβ peptides in the brain. Aβ deposition in cerebrovessels occurs in many AD patients and results in cerebral amyloid angiopathy (AD/CAA). Since Aβ can be transported across blood–brain barrier (BBB), aberrant Aβ trafficking across BBB may contribute to Aβ accumulation in the brain and CAA development. Expression analyses of 273 BBB-related genes performed in this study showed that the drug transporter, ABCG2, was significantly upregulated in the brains of AD/CAA compared with age-matched controls. Increased ABCG2 expression was confirmed by Q-PCR, Western blot, and immunohistochemistry. Abcg2 was also increased in mouse AD models, Tg-SwDI and 3XTg. Aβ alone or in combination with hypoxia/ischemia failed to stimulate ABCG2 expression in BBB endothelial cells; however, conditioned media from Aβ-activated microglia strongly induced ABCG2 expression. ABCG2 protein in AD/CAA brains interacted and coimmunoprecipitated with Aβ. Overexpression of hABCG2 reduced drug uptake in cells; however, interaction of Aβ1–40 with ABCG2 impaired ABCG2-mediated drug efflux. The role of Abcg2 in Aβ transport at the BBB was investigated in Abcg2-null and wild-type mice after intravenous injection of Cy5.5-labeled Aβ1–40 or scrambled Aβ40–1. Optical imaging analyses of live animals and their brains showed that Abcg2-null mice accumulated significantly more Aβ in their brains than wild-type mice. The finding was confirmed by immunohistochemistry. These results suggest that ABCG2 may act as a gatekeeper at the BBB to prevent blood Aβ from entering into brain. ABCG2 upregulation may serve as a biomarker of CAA vascular pathology in AD patients.


Neurobiology of Disease | 2009

Expression of inflammatory genes induced by beta-amyloid peptides in human brain endothelial cells and in Alzheimer's brain is mediated by the JNK-AP1 signaling pathway

Vanja Vukic; Debbie Callaghan; Douglas G. Walker; Lih-Fen Lue; Qing Yan Liu; Pierre-Oliver Couraud; Ignacio A. Romero; Babette B. Weksler; Danica Stanimirovic; Wandong Zhang

Alzheimers disease (AD) is characterized by accumulation and deposition of Abeta peptides in the brain. Abeta deposition in cerebral vessels occurs in many AD patients and results in cerebral amyloid angiopathy (AD/CAA). Abeta deposits evoke neuro- and neurovascular inflammation contributing to neurodegeneration. In this study, we found that exposure of cultured human brain endothelial cells (HBEC) to Abeta(1-40) elicited expression of inflammatory genes MCP-1, GRO, IL-1beta and IL-6. Up-regulation of these genes was confirmed in AD and AD/CAA brains by qRT-PCR. Profiling of 54 transcription factors indicated that AP-1 was strongly activated not only in Abeta-treated HBEC but also in AD and AD/CAA brains. AP-1 complex in nuclear extracts from Abeta-treated HBEC bound to AP-1 DNA-binding sequence and activated the reporter gene of a luciferase vector carrying AP-1-binding site from human MCP-1 gene. AP-1 is a dimeric protein complex and supershift assay identified c-Jun as a component of the activated AP-1 complex. Western blot analyses showed that c-Jun was activated via JNK-mediated phosphorylation, suggesting that as a result of c-Jun phosphorylation, AP-1 was activated and thus up-regulated MCP-1 expression. A JNK inhibitor SP600125 strongly inhibited Abeta-induced c-Jun phosphorylation, AP-1 activation, AP-1 reporter gene activity and MCP-1 expression in cells stimulated with Abeta peptides. The results suggested that JNK-AP1 signaling pathway is responsible for Abeta-induced neuroinflammation in HBEC and Alzheimers brain and that this signaling pathway may serve as a therapeutic target for relieving Abeta-induced inflammation.


Journal of Neurochemistry | 2001

The Transcription Factor E2F1 Modulates Apoptosis of Neurons

Sheng T. Hou; Debbie Callaghan; Marie-Christine Fournier; Irene E. Hill; Liping Kang; Bernard Massie; Paul Morley; Christine L. Murray; Ingrid Rasquinha; Ruth S. Slack; John P. MacManus

Abstract : The transcription factor E2F1 is known to mediate apoptosis in isolated quiescent and postmitotic cardiac myocytes, and its absence decreases the size of brain infarction following cerebral ischemia. To demonstrate directly that E2F1 modulates neuronal apoptosis, we used cultured cortical neurons to show a temporal association of the transcription and expression of E2F1 in neurons with increased neuronal apoptosis. Cortical neurons lacking E2F1 expression (derived from E2F1 ‐/‐ mice) were resistant to staurosporine‐induced apoptosis as evidenced by the significantly lower caspase 3‐like activity and a lesser number of cells with apoptotic morphology in comparison with cortical cultures derived from wild‐type mice. Furthermore, overexpressing E2F1 alone using replication‐deficient recombinant adenovirus was sufficient to cause neuronal cell death by apoptosis, as evidenced by the appearance of hallmarks of apoptosis, such as the threefold increase in caspase 3‐like activity and increased laddered DNA fragmentation, in situ endlabeled DNA fragmentation, and numbers of neuronal cells with punctate nuclei. Taken together, we conclude that E2F1 plays a key role in modulating neuronal apoptosis.


Journal of Neuroinflammation | 2007

Hypoxia-inducible factor-1 (HIF-1) is involved in the regulation of hypoxia-stimulated expression of monocyte chemoattractant protein-1 (MCP-1/CCL2) and MCP-5 (Ccl12) in astrocytes

Jelena Mojsilovic-Petrovic; Debbie Callaghan; Hong Cui; Clare Dean; Danica Stanimirovic; Wandong Zhang

BackgroundNeuroinflammation has been implicated in various brain pathologies characterized by hypoxia and ischemia. Astroglia play an important role in the initiation and propagation of hypoxia/ischemia-induced inflammation by secreting inflammatory chemokines that attract neutrophils and monocytes into the brain. However, triggers of chemokine up-regulation by hypoxia/ischemia in these cells are poorly understood. Hypoxia-inducible factor-1 (HIF-1) is a dimeric transcriptional factor consisting of HIF-1α and HIF-1β subunits. HIF-1 binds to HIF-1-binding sites in the target genes and activates their transcription. We have recently shown that hypoxia-induced expression of IL-1β in astrocytes is mediated by HIF-1α. In this study, we demonstrate the role of HIF-1α in hypoxia-induced up-regulation of inflammatory chemokines, human monocyte chemoattractant protein-1 (MCP-1/CCL2) and mouse MCP-5 (Ccl12), in human and mouse astrocytes, respectively.MethodsPrimary fetal human astrocytes or mouse astrocytes generated from HIF-1α+/+ and HIF-1α+/- mice were subjected to hypoxia (<2% oxygen) or 125 μM CoCl2 for 4 h and 6 h, respectively. The expression of HIF-1α, MCP-1 and MCP-5 was determined by semi-quantitative RT-PCR, western blot or ELISA. The interaction of HIF-1α with a HIF-1-binding DNA sequence was examined by EMSA and supershift assay. HIF-1-binding sequence in the promoter of MCP-1 gene was cloned and transcriptional activation of MCP-1 by HIF-1α was analyzed by reporter gene assay.ResultsSequence analyses identified HIF-1-binding sites in the promoters of MCP-1 and MCP-5 genes. Both hypoxia and HIF-1α inducer, CoCl2, strongly up-regulated HIF-1α expression in astrocytes. Mouse HIF-1α+/- astrocytes had lower basal levels of HIF-1α and MCP-5 expression. The up-regulation of MCP-5 by hypoxia or CoCl2 in HIF-1α+/+ and HIF-1α+/- astrocytes was correlated with the levels of HIF-1α in cells. Both hypoxia and CoCl2 also up-regulated HIF-1α and MCP-1 expression in human astrocytes. EMSA assay demonstrated that HIF-1 activated by either hypoxia or CoCl2 binds to wild-type HIF-1-binding DNA sequence, but not the mutant sequence. Furthermore, reporter gene assay demonstrated that hypoxia markedly activated MCP-1 transcription but not the mutated MCP-1 promoter in transfected astrocytes.ConclusionThese findings suggest that both MCP-1 and MCP-5 are HIF-1 target genes and that HIF-1α is involved in transcriptional induction of these two chemokines in astrocytes by hypoxia.


Neuroscience Bulletin | 2011

Biochemical and behavioral characterization of the double transgenic mouse model (APPswe/PS1dE9) of Alzheimer’s disease

Huaqi Xiong; Debbie Callaghan; Jolanta Wodzinska; Jiejing Xu; Maryna Premyslova; Qing-Yan Liu; John W. Connelly; Wandong Zhang

ObjectiveThe double transgenic mouse model (APPswe/PS1dE9) of Alzheimer’s disease (AD) has been widely used in experimental studies. β-Amyloid (Aβ) peptide is excessively produced in AD mouse brain, which affects synaptic function and the development of central nervous system. However, little has been reported on characterization of this model. The present study aimed to characterize this mouse AD model and its wild-type counterparts by biochemical and functional approaches.MethodsBlood samples were collected from the transgenic and the wild-type mice, and radial arm water maze behavioral test was conducted at the ages of 6 and 12 months. The mice were sacrificed at 12-month age. One hemisphere of the brain was frozen-sectioned for immunohistochemistry and the other hemisphere was dissected into 7 regions. The levels of Aβ1–40, Aβ1–42 and 8-hydroxydeoxyguanosine (8-OHdG) in blood or/and brain samples were analyzed by ELISA. Secretase activities in brain regions were analyzed by in vitro assays.ResultsThe pre-mature death rate of transgenic mice was approximately 35% before 6-month age, and high levels of Aβ1–40 and Aβ1–42 were detected in these dead mice brains with a ratio of 1:10. The level of blood-borne Aβ at 6-month age was similar with that at 12-month age. Besides, Aβ1–40 level in the blood was significantly higher than Aβ1–42 level at the ages of 6 and 12 months (ratio 2.37:1). In contrast, the level of Aβ1–42 in the brain (160.6 ng/mg protein) was higher than that of Aβ1–40 (74 ng/mg protein) (ratio 2.17:1). In addition, the levels of Aβ1–40 and Aβ1–42 varied markedly among different brain regions. Aβ1–42 level was significantly higher than Aβ1–40 level in cerebellum, frontal and posterior cortex, and hippocampus. Secretase activity assays did not reveal major differences among different brain regions or between wild-type and transgenic mice, suggesting that the transgene PS1 did not lead to higher γ-secretase activity but was more efficient in producing Aβ1–42 peptides. 8-OHdG, the biomarker of DNA oxidative damage, showed a trend of increase in the blood of transgenic mice, but with no significant difference, as compared with the wild-type mice. Behavioral tests showed that transgenic mice had significant memory deficits at 6-month age compared to wild-type controls, and the deficits were exacerbated at 12-month age with more errors.ConclusionThese results suggest that this mouse model mimics the early-onset human AD and may represent full-blown disease at as early as 6-month age for experimental studies.摘要目的阿尔茨海默病(Alzheimer’s disease, AD) APPswe/PS1dE9双转基因小鼠已被广泛运用于各种实验研究。 AD小鼠脑内产生过量的β淀粉样蛋白(Aβ), 后者会影响突触功能和中枢神经系统的发育。 然而, 该转基因小鼠模型的生化和行为学特征却未见报道。 本研究旨在对该小鼠模型的病理从生化和行为学角度进行检测。方法对6月和12月龄转基因和野生型小鼠取血约100 μL, 1 200 g离心后, 分离血清。 在小鼠6月和12月龄时, 进行为期15天的辐射状六臂水迷宫实验。 ELISA法检测血清和大脑中Aβ1–40和Aβ1–42的含量, 以及血清中8-羟基脱氧鸟苷的含量。 比较转基因和野生型小鼠大脑不同部位中α-, β- 和 γ-分泌酶活性的差异。结果在6月龄之前, APPswe/PS1dE9双转基因小鼠的死亡率约为35%, 这些死亡的小鼠脑内Aβ1–40和Aβ1–42水平较高, 两者比例约为1:10。 在6月和12月龄时, 转基因小鼠血清中Aβ1–40水平均显著高于Aβ1–42水平, Aβ1–40与Aβ1–42比例为 2.37:1。 在12月龄时, 转基因小鼠大脑中Aβ1–42水平显著高于Aβ1–40水平, 两者比例约为2.17: 1, 并且在不同脑区中, Aβ1–42和Aβ1–40含量变化较大。 在小脑、 前、 后部皮质层以及海马中, Aβ1–42水平显著高于Aβ1–40。 分泌酶活性在转基因和野生型小鼠之间以及在不同脑部位之间没有很大的差异, 这提示PS1转基因并没有导致高γ-分泌酶活性, 该基因可能使 γ-分泌酶更有效的切割和产生Aβ1–42。 此外, 转基因小鼠血清中8-羟基脱氧鸟苷含量较野生型小鼠升高, 但没有显著性差异。 行为学结果显示, 在6月龄时, 转基因小鼠与野生型相比呈现出显著的记忆障碍, 到12月龄时, 这种障碍变得更为严重, 表现为水迷宫实验中产生更多的错误。结论APPswe/PS1dE9双转基因小鼠最早在6月龄时就能很好地模拟早发性AD, 可用于实验研究。


Journal of Neurochemistry | 2010

ABCG2 reduces ROS-mediated toxicity and inflammation: a potential role in Alzheimer's disease.

Shanshan Shen; Debbie Callaghan; Camille Juzwik; Huaqi Xiong; Peilin Huang; Wandong Zhang

J. Neurochem. (2010) 114, 1590–1604.


Journal of Alzheimer's Disease | 2014

Stimulation of Insulin Signaling and Inhibition of JNK-AP1 Activation Protect Cells from Amyloid-β-Induced Signaling Dysregulation and Inflammatory Response

Michelle Bamji-Mirza; Debbie Callaghan; Dema Najem; Shanshan Shen; Mohamed S. Hasim; Ze Yang; Wandong Zhang

One of the hallmarks of Alzheimers disease (AD) is the accumulation and deposition of amyloid-β (Aβ) peptides in the brain and cerebral vasculature. Aβ evokes neuroinflammation and has been implicated in insulin signaling disruption and JNK-AP1 activation, contributing to AD neuropathologies including oxidative injury and vascular insufficiencies. In this study we aim to better understand the protective mechanisms of insulin signaling and JNK-AP1 inhibition on the adverse effects of Aβ. Four-hour treatment of hCMEC/D3, the immortalized human brain endothelial cells (iHBEC), with Aβ1-42 resulted in significant c-Jun phosphorylation, oxidative stress, and cell toxicity. Concurrent treatment with Aβ1-42 and insulin or Aβ1-42 and JNK inhibitor SP600125 significantly improved cell viability. Cytokine array on conditioned media showed that insulin and SP600125 strongly reduced all Aβ1-42-induced cytokines. ELISA confirmed the protective effect of insulin and SP600125 on Aβ-induced expression of interleukin (IL)-8 and Growth related oncogene-α (Gro-α). qRT-PCR revealed that insulin and SP600125 protected iHBEC from Aβ1-42-induced inflammatory gene expression. Transcription factor profiling showed that treatment of iHBEC with Aβ1-42, insulin, or SP600125 alone or in combination resulted in profound changes in modulating the activities of multiple transcription factors and relevant pathways, some of which were validated by western blot. Insulin treatment and JNK inhibition in vitro synergistically reduced c-Jun phosphorylation and thus JNK-AP1 signaling activation. The study suggests that activation of insulin and blocking of JNK-AP1 signaling inhibits Aβ-induced dysregulation of insulin signaling and inflammatory response.


Journal of Neurochemistry | 2012

Abcg2 deficiency augments oxidative stress and cognitive deficits in Tg‐SwDI transgenic mice

Yu Zeng; Debbie Callaghan; Huaqi Xiong; Ze Yang; Peilin Huang; Wandong Zhang

J. Neurochem. (2012) 122, 456–469.


Journal of Alzheimer's Disease | 2017

Apolipoprotein E Isoforms Differentially Regulate Alzheimer’s Disease and Amyloid-β-Induced Inflammatory Response in vivo and in vitro

Evan Dorey; Michelle Bamji-Mirza; Dema Najem; Yan Li; Hong Liu; Debbie Callaghan; Douglas G. Walker; Lih-Fen Lue; Danica Stanimirovic; Wandong Zhang

Neuroinflammation plays a critical role in neuronal dysfunction and death of Alzheimers disease (AD). ApoE4 is a major risk factor of AD, while ApoE2 is neuroprotective. Little is known about the roles of ApoE isoforms in the neuroinflammation seen in AD. Their roles and mechanisms in Aβ-induced/neuroinflammation were investigated in this study using in vivo and in vitro models. Rat astrocytes were treated with lipid-poor recombinant hApoE and/or Aβ42. Mouse astrocyte lines-expressing lipidated hApoE were treated with Aβ42 and/or vitamin D receptor (VDR) agonist, 1α,25-dihydroxyvitamin D3. Cells and media were harvested for cytokine ELISA, RNA isolated for qRT-PCR, and nuclear protein for transcription factor (TF) arrays and EMSA. hApoE-transgenic and AD mice were mated to generate hApoE2/AD and hApoE4/AD mice. Mice were euthanized at 6 months of age. Brain tissues were collected for cytokine ELISA array, Aβ ELISA, immunoblotting, and immunohistochemistry. hApoE4/AD mice had significantly higher levels of inflammatory cytokines than hApoE2/AD mice. Lipidated hApoE4 significantly promoted inflammatory gene expression induced by Aβ42 but not recombinant hApoE4 in astrocytes as compared to controls. Lipidated hApoE3 provided a certain degree of protection against Aβ42-induced inflammatory response but not recombinant hApoE3 as compared to controls. Both lipidated and recombinant hApoE2 provided protection against Aβ42-induced inflammatory response compared to controls. TF array revealed that ApoE2 strongly activated VDR in Aβ42-treated astrocytes. Application of 1α,25-dihydroxyvitamin D3 completely inhibited Aβ-induced inflammatory gene expression in hApoE4-expressing astrocytes. The results suggest that ApoE4 promotes, but ApoE2 inhibits, AD/Aβ-induced neuroinflammation via VDR signaling. Targeting VDR signaling or active form of VD3 may relieve AD neuroinflammation or/and neurodegeneration.


Alzheimers & Dementia | 2010

Rapid transmission of exogenous beta-amyloid peptides from blood to the brain

Wandong Zhang; Huaqi Xiong; Shanshan Shen; Debbie Callaghan; Peilin Huang; Howard Njoo; Jun Wu

of inhibition is indicated by the lack of similar inhibition of OGG1. Furthermore, Fe(II) inhibits NEIL1’s interaction 4to 6-fold with the downstream repair enzymes DNA polymerase b (Polb) and flap endonuclease-1 (FEN1), a prerequisite for efficient repair of 5-hydroxy uracil (5-OHU), a common base lesion product of cytidine. As expected, Fe(II/III) and Cu(II) inhibited NEIL-initiated complete repair. Further, we also found inhibition of mitochondrial BER in SH-SY5Y cells treated with MPTP and/or Fe and correlated with accumulation of mitochondrial DNA damage in Parkinson’s cell culture model. Specific metal chelators and the natural chemopreventive compound curcumin reversed NEILs’ inhibition both in vitro and in cells. Conclusions: Excess accumulation of transition metals in PD brain can act as a ‘double edged sword’ by inducing DNA damage (by ROS formation) and also by blocking DNA repair. The study provides evidence to inhibiton of repair of oxidative DNA damage by etiological factors of PD and correlation to accumulation of oxidized DNA bases in human brain dopaminergic neurons, and importantly develop potential strategies to reverse this inhibition using natural compounds (e.g. curcumin) for improved therapeutic intervention of PD.

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Wandong Zhang

National Research Council

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Huaqi Xiong

National Research Council

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Aimee Jones

National Research Council

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Lih-Fen Lue

Arizona State University

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Lucia I. Sue

Arizona State University

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Hong Liu

National Research Council

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