30 results on '"Giunta, B."'
Search Results
2. p75NTR ectodomain is a physiological neuroprotective molecule against amyloid-beta toxicity in the brain of Alzheimerʼs disease
- Author
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Yao, X-Q, Jiao, S-S, Saadipour, K, Zeng, F, Wang, Q-H, Zhu, C, Shen, L-L, Zeng, G-H, Liang, C-R, Wang, J, Liu, Y-H, Hou, H-Y, Xu, X, Su, Y-P, Fan, X-T, Xiao, H-L, Lue, L-F, Zeng, Y-Q, Giunta, B, Zhong, J-H, Walker, D G, Zhou, H-D, Tan, J, Zhou, X-F, and Wang, Y-J
- Published
- 2015
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3. Blood-derived amyloid-β protein induces Alzheimer’s disease pathologies
- Author
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Bu, X-L, primary, Xiang, Y, additional, Jin, W-S, additional, Wang, J, additional, Shen, L-L, additional, Huang, Z-L, additional, Zhang, K, additional, Liu, Y-H, additional, Zeng, F, additional, Liu, J-H, additional, Sun, H-L, additional, Zhuang, Z-Q, additional, Chen, S-H, additional, Yao, X-Q, additional, Giunta, B, additional, Shan, Y-C, additional, Tan, J, additional, Chen, X-W, additional, Dong, Z-F, additional, Zhou, H-D, additional, Zhou, X-F, additional, Song, W, additional, and Wang, Y-J, additional
- Published
- 2017
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4. The role of glycogen synthase kinase-3 signaling in neurodevelopment and fragile X syndrome
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Samantha Portis, Giunta, B., Obregon, D., and Tan, J.
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Review Article - Abstract
Fragile X syndrome (FXS), one of the most common genetic causes of autism, results from a loss of fragile X mental retardation protein (FMRP) expression. At the molecular level, abnormal neurodevelopment is thought to result from dysregulated protein synthesis of key neural synaptic proteins, however recent evidence suggests broader roles for this protein including glutamate signaling, memory, and regulation of the critical serine/threonine regulatory kinase, glycogen synthase kinase-3 (GSK-3). In this review, genetic and molecular features of FXS are detailed in the context of FXS neuropathology. Additionally, potential mechanisms by which FMRP silencing impacts GSK-3 and GSK-3-associated signaling pathways are discussed. As GSK-3 signaling represents a central regulatory node for critical neurodevelopmental pathways, understanding how FXS results from FMRP-mediated GSK-3 dysregulation may provide novel therapeutic targets for disease-modifying interventions for FXS and related ASDs.
- Published
- 2012
5. Specific antibody binding to the APP672–699 region shifts APP processing from α- to β-cleavage
- Author
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Li, S, primary, Deng, J, additional, Hou, H, additional, Tian, J, additional, Giunta, B, additional, Wang, Y, additional, Sawmiller, D, additional, Smith, A, additional, Sanberg, P R, additional, Obregon, D, additional, Mori, T, additional, and Tan, J, additional
- Published
- 2014
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6. Immunotherapy for Alzheimer disease: the challenge of adverse effects.
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Liu YH, Giunta B, Zhou HD, Tan J, Wang YJ, Liu, Yu-Hui, Giunta, Brian, Zhou, Hua-Dong, Tan, Jun, and Wang, Yan-Jiang
- Abstract
Amyloid-β (Aβ) plays a crucial part in the pathogenesis of Alzheimer disease (AD), making this peptide an attractive therapeutic target. However, clearance of brain Aβ in clinical trials of Aβ-specific antibodies did not improve cognition in patients with AD, leading to reassessment of the current therapeutic strategies. Moreover, current immunotherapies are associated with autoimmunity-related adverse effects, and mobilization of neurotoxic insoluble Aβ-oligomers. Despite the fact that antibodies to the N-terminal domain of Aβ can promote Aβ production, immunotherapies in ongoing clinical trials predominantly target this peptide region. Here, we address the challenges of adverse effects of immunotherapy for AD. We discuss available evidence regarding the mechanisms of both endogenous and exogenous Aβ-specific antibodies, with a view to developing optimal immunotherapy based on peripheral Aβ clearance, targeting of the toxic domain of Aβ, and improvement of antibody specificity. Such strategies should help to make immunotherapy a safe and efficacious disease-modifying treatment option for AD. [ABSTRACT FROM AUTHOR]
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- 2012
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7. Mycoplasma hyorhinis markedly degrades β-amyloid peptides in vitro and ex vivo: A novel biological approach for treating Alzheimer's disease?
- Author
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Habib, A., Deng, J., Hou, H., Zou, Q., Giunta, B., Wang, Y. -J, Obregon, D., Darrell Sawmiller, Li, S., Mori, T., and Tan, J.
- Subjects
Original Article - Abstract
Accumulation of amyloid-β (Aβ) peptides (predominantly Aβ40, 42) and their aggregation into plaques in the brain are thought to be the one of the major causes of Alzheimer's disease (AD). Originally discovered in our Chinese hamster ovary (CHO) cell line stably expressing human wild-type amyloid precursor protein (APP) (CHO/APPwt) cultures devoid of Aβ production, we found that Mycoplasma selectively degrades soluble Aβ in a time and dose (colony forming unit) dependent manner. Moreover, we fully characterized the Mycoplasma species as Mycoplasma hyorhinis (M. hyorhinis) by genetic and colony morphological analyses by light microscopy. Most interestingly, we attenuated the pathogenicity of M. hyorhinis by γ irradiation (3.5 Gy), and found that its ability to degrade Aβ was retained. On the other hand, heated and sonicated M. hyorhinis failed to retain this ability to degrade Aβ, suggesting that this degradation requires viable cells and likely a biologically active signaling pathway. In addition, we found that M. hyorhinis can degrade Aβ produced in AD model mice (PSAPP mice) ex vivo. Finally, we found that irradiated (non-pathogenic) M. hyorhinis also can degrade Aβ produced in PSAPP mice in vivo. These studies suggest that irradiated (non-pathogenic) M. hyorhinis can be a novel and alternative biological strategy for AD treatment.
8. Chromatographic Recognition of Some Palatable and Unpalatable Subspecies of Rubber Rabbitbrush in and around Utah
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Hanks, D. L., primary, McArthur, E. D., additional, Plummer, A. P., additional, Giunta, B. C., additional, and Blauer, A. C., additional
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- 1975
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9. Chromatographic Recognition of Some Palatable and Unpalatable Subspecies of Rubber Rabbitbrush in and around Utah
- Author
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McArthur, E. D., Blauer, A. C., Plummer, A.P., Hanks, D. L., and Giunta, B. C.
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- 1975
10. Retraction Note to: LISPRO mitigates β-amyloid and associated pathologies in Alzheimer's mice.
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Habib A, Sawmiller D, Li S, Xiang Y, Rongo D, Tian J, Hou H, Zeng J, Smith A, Fan S, Giunta B, Mori T, Currier G, Shytle DR, and Tan J
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- 2021
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11. Human Umbilical Cord Blood Serum-derived α-Secretase: Functional Testing in Alzheimer's Disease Mouse Models.
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Habib A, Hou H, Mori T, Tian J, Zeng J, Fan S, Giunta B, Sanberg PR, Sawmiller D, and Tan J
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- Alzheimer Disease metabolism, Amyloid beta-Peptides metabolism, Amyloid beta-Protein Precursor metabolism, Animals, CHO Cells, Cricetulus, Enzyme-Linked Immunosorbent Assay, Humans, Immunohistochemistry, Mice, Phosphorylation, tau Proteins metabolism, Alzheimer Disease enzymology
- Abstract
Alzheimer's disease (AD) is an age-related disorder that affects cognition. Our previous studies showed that the neuroprotective fragment of amyloid procurer protein (APP) metabolite, soluble APPα (sAPPα), interferes with β-site APP-cleaving enzyme 1 (BACE1, β-secretase) cleavage and reduces amyloid-β (Aβ) generation. In an attempt to identify approaches to restore sAPPα levels, we found that human cord blood serum (CBS) significantly promotes sAPPα production compared with adult blood serum (ABS) and aged blood serum (AgBS) in Chinese hamster ovary cells stably expressing wild-type human APP. Interestingly, CBS selectively mediated the α-secretase cleavage of human neuron-specific recombinant APP
695 in a cell-free system independent of tumor necrosis factor-α converting enzyme (TACE; a disintegrin and metalloproteinase domain-containing protein 17 [ADAM17]) and ADAM. Subsequently, using 3-step chromatographic separation techniques (i.e., diethylaminoethanol, size-exclusion, and ion-exchange chromatography), we purified and ultimately identified a CBS-specific fraction with enhanced α-secretase catalytic activity (termed αCBSF) and found that αCBSF has more than 3,000-fold increased α-secretase catalytic activity compared with the original pooled CBS. Furthermore, intracerebroventricular injection of αCBSF markedly increased cerebral sAPPα levels together with significant decreases in cerebral Aβ production and abnormal tau (Thr231 ) phosphorylation compared with the AgBS fraction with enhanced α-secretase activity (AgBSF) treatment in triple transgenic Alzheimer's disease (3xTg-AD) mice. Moreover, AgBSF administered intraperitoneally to transgenic mice with five familial Alzheimer's disease mutations (5XFAD) via an osmotic mini pump for 6 weeks (wk) ameliorated β-amyloid plaques and reversed cognitive impairment measures. Together, our results propose the necessity for further study aimed at identification and characterization of α-secretase in CBS for novel and effective AD therapy.- Published
- 2018
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12. LISPRO mitigates β-amyloid and associated pathologies in Alzheimer's mice.
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Habib A, Sawmiller D, Li S, Xiang Y, Rongo D, Tian J, Hou H, Zeng J, Smith A, Fan S, Giunta B, Mori T, Currier G, Shytle DR, and Tan J
- Subjects
- Administration, Oral, Alzheimer Disease drug therapy, Animals, Autophagy, Glycogen Synthase Kinase 3 beta metabolism, HeLa Cells, Humans, Inflammation, Lithium Carbonate administration & dosage, Lithium Carbonate blood, Lithium Compounds blood, Lithium Compounds chemistry, Male, Mice, Mice, Transgenic, Microglia metabolism, Phagocytosis, Phosphorylation, Proline blood, Proline chemistry, Treatment Outcome, Alzheimer Disease metabolism, Amyloid beta-Peptides metabolism, Lithium Compounds administration & dosage, Proline administration & dosage
- Abstract
Lithium has been marketed in the United States of America since the 1970s as a treatment for bipolar disorder. More recently, studies have shown that lithium can improve cognitive decline associated with Alzheimer's disease (AD). However, the current United States Food and Drug Administration-approved lithium pharmaceutics (carbonate and citrate chemical forms) have a narrow therapeutic window and unstable pharmacokinetics that, without careful monitoring, can cause serious adverse effects. Here, we investigated the safety profile, pharmacokinetics, and therapeutic efficacy of LISPRO (ionic co-crystal of lithium salicylate and l-proline), lithium salicylate, and lithium carbonate (Li
2 CO3 ). We found that LISPRO (8-week oral treatment) reduces β-amyloid plaques and phosphorylation of tau by reducing neuroinflammation and inactivating glycogen synthase kinase 3β in transgenic Tg2576 mice. Specifically, cytokine profiles from the brain, plasma, and splenocytes suggested that 8-week oral treatment with LISPRO downregulates pro-inflammatory cytokines, upregulates anti-inflammatory cytokines, and suppresses renal cyclooxygenase 2 expression in transgenic Tg2576 mice. Pharmacokinetic studies indicated that LISPRO provides significantly higher brain lithium levels and more steady plasma lithium levels in both B6129SF2/J (2-week oral treatment) and transgenic Tg2576 (8-week oral treatment) mice compared with Li2 CO3 . Oral administration of LISPRO for 28 weeks significantly reduced β-amyloid plaques and tau-phosphorylation. In addition, LISPRO significantly elevated pre-synaptic (synaptophysin) and post-synaptic protein (post synaptic density protein 95) expression in brains from transgenic 3XTg-AD mice. Taken together, our data suggest that LISPRO may be a superior form of lithium with improved safety and efficacy as a potential new disease modifying drug for AD.- Published
- 2017
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13. Swedish mutant APP-based BACE1 binding site peptide reduces APP β-cleavage and cerebral Aβ levels in Alzheimer's mice.
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Li S, Hou H, Mori T, Sawmiller D, Smith A, Tian J, Wang Y, Giunta B, Sanberg PR, Zhang S, and Tan J
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- Alzheimer Disease pathology, Alzheimer Disease physiopathology, Amino Acid Sequence, Amyloid Precursor Protein Secretases antagonists & inhibitors, Amyloid beta-Protein Precursor chemistry, Animals, Aspartic Acid Endopeptidases antagonists & inhibitors, Behavior, Animal, Blood-Brain Barrier metabolism, CHO Cells, Cerebral Cortex metabolism, Cerebral Cortex pathology, Cricetulus, Disease Models, Animal, Gene Expression, Hippocampus metabolism, Memory, Mice, Models, Molecular, Molecular Sequence Data, Peptides chemistry, Protein Binding, Protein Conformation, Proteolysis, Recombinant Fusion Proteins chemistry, Recombinant Fusion Proteins metabolism, Alzheimer Disease genetics, Alzheimer Disease metabolism, Amyloid Precursor Protein Secretases metabolism, Amyloid beta-Peptides metabolism, Amyloid beta-Protein Precursor genetics, Amyloid beta-Protein Precursor metabolism, Aspartic Acid Endopeptidases metabolism, Binding Sites genetics, Mutation, Peptides metabolism
- Abstract
BACE1 initiates amyloid-β (Aβ) generation and the resultant cerebral amyloidosis, as a characteristic of Alzheimer's disease (AD). Thus, inhibition of BACE1 has been the focus of a large body of research. The most recent clinical trials highlight the difficulty involved in this type of anti-AD therapy as evidenced by side effects likely due to the ubiquitous nature of BACE1, which cleaves multiple substrates. The human Swedish mutant form of amyloid protein precursor (APPswe) has been shown to possess a higher affinity for BACE1 compared to wild-type APP (APPwt). We pursued a new approach wherein harnessing this greater affinity to modulate BACE1 APP processing activity. We found that one peptide derived from APPswe, containing the β-cleavage site, strongly inhibits BACE1 activity and thereby reduces Aβ production. This peptide, termed APPswe BACE1 binding site peptide (APPsweBBP), was further conjugated to the fusion domain of the HIV-1 Tat protein (TAT) at the C-terminus to facilitate its biomembrane-penetrating activity. APPwt and APPswe over-expressing CHO cells treated with this TAT-conjugated peptide resulted in a marked reduction of Aβ and a significant increase of soluble APPα. Intraperitoneal administration of this peptide to 5XFAD mice markedly reduced β-amyloid deposits as well as improved hippocampal-dependent learning and memory.
- Published
- 2015
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14. The impact of HIV-1 on neurogenesis: implications for HAND.
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Ferrell D and Giunta B
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- Amyloid beta-Peptides metabolism, HIV Envelope Protein gp120 metabolism, Humans, Neurodegenerative Diseases etiology, tat Gene Products, Human Immunodeficiency Virus metabolism, HIV Infections complications, HIV Infections physiopathology, HIV-1 metabolism, Neurodegenerative Diseases metabolism, Neurogenesis
- Abstract
HIV-1 infection, in addition to its destructive effects on the immune system, plays a role in the development of neurocognitive deficits. Indeed up to 50% of long-term HIV infected patients suffer from HIV-associated neurocognitive disorders (HAND). These deficits have been well characterized and defined clinically according to a number of cognitive parameters. HAND is often accompanied by atrophy of the brain including inhibition of neurogenesis, especially in the hippocampus. Many mechanisms have been proposed as contributing factors to HAND including induction of oxidative stress in the central nervous system (CNS), chronic microglial-mediated neuroinflammation, amyloid-beta (Aβ) deposition, hyperphosphorylated tau protein, and toxic effects of combination antiretroviral therapy (cART). In these review we focus solely on recent experimental evidence suggesting that disturbance by HIV-1 results in impairment of neurogenesis as one contributing factor to HAND. Impaired neurogenesis has been linked to cognitive deficits and other neurodegenerative disorders. This article will highlight recently identified pathological mechanisms which potentially contribute to the development of impaired neurogenesis by HIV-1 or HIV-1-associated proteins from both animal and human studies.
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- 2014
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15. The role of tau protein in HIV-associated neurocognitive disorders.
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Brown LA, Scarola J, Smith AJ, Sanberg PR, Tan J, and Giunta B
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- Brain metabolism, Humans, Brain pathology, HIV Infections complications, HIV Infections metabolism, HIV Infections pathology, tau Proteins metabolism
- Abstract
Given the increased life expectancy of human immunodeficiency virus (HIV) infected individuals treated with combination antiretroviral therapy (cART) and the ongoing inflammation observed in the brains of these patients, it is likely that premature neurodegeneration as measured by phospho-tau (p-tau) or increased total tau (t-tau) protein may become an increasing problem. This review examines the seven human studies that have occurred over the past 14 years measuring p-tau and/or t-tau in cerebrospinal fluid (CSF) or via post-mortem brain immunohistochemistry. Although not all studies are in agreement as to the changes in p-and t-tau in HIV infected patients, HIV persists in the brain despite cART. Thus is it is suggested that those maintained on long-term cART may develop tau pathology beyond the extent seen in the studies reviewed herein and overtime may then reach the threshold for clinical manifestation.
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- 2014
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16. Efavirenz promotes β-secretase expression and increased Aβ1-40,42 via oxidative stress and reduced microglial phagocytosis: implications for HIV associated neurocognitive disorders (HAND).
- Author
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Brown LA, Jin J, Ferrell D, Sadic E, Obregon D, Smith AJ, Tan J, and Giunta B
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- Alkynes, Animals, Benzoxazines administration & dosage, Cell Line, Cognition Disorders drug therapy, Cognition Disorders etiology, Cyclopropanes, Female, HIV Infections complications, HIV Infections drug therapy, Humans, Lamivudine administration & dosage, Lamivudine therapeutic use, Mice, Oxidative Stress drug effects, Phagocytosis drug effects, Reverse Transcriptase Inhibitors administration & dosage, Reverse Transcriptase Inhibitors therapeutic use, Zidovudine administration & dosage, Zidovudine therapeutic use, Amyloid Precursor Protein Secretases metabolism, Amyloid beta-Peptides metabolism, Benzoxazines therapeutic use
- Abstract
Efavirenz (EFV) is among the most commonly used antiretroviral drugs globally, causes neurological symptoms that interfere with adherence and reduce tolerability, and may have central nervous system (CNS) effects that contribute in part to HIV associated neurocognitive disorders (HAND) in patients on combination antiretroviral therapy (cART). Thus we evaluated a commonly used EFV containing regimen: EFV/zidovudine (AZT)/lamivudine (3TC) in murine N2a cells transfected with the human "Swedish" mutant form of amyloid precursor protein (SweAPP N2a cells) to assess for promotion of amyloid-beta (Aβ) production. Treatment with EFV or the EFV containing regimen generated significantly increased soluble amyloid beta (Aβ), and promoted increased β-secretase-1 (BACE-1) expression while 3TC, AZT, or, vehicle control did not significantly alter these endpoints. Further, EFV or the EFV containing regimen promoted significantly more mitochondrial stress in SweAPP N2a cells as compared to 3TC, AZT, or vehicle control. We next tested the EFV containing regimen in Aβ - producing Tg2576 mice combined or singly using clinically relevant doses. EFV or the EFV containing regimen promoted significantly more BACE-1 expression and soluble Aβ generation while 3TC, AZT, or vehicle control did not. Finally, microglial Aβ phagocytosis was significantly reduced by EFV or the EFV containing regimen but not by AZT, 3TC, or vehicle control alone. These data suggest the majority of Aβ promoting effects of this cART regimen are dependent upon EFV as it promotes both increased production, and decreased clearance of Aβ peptide.
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- 2014
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17. Luteolin reduces Alzheimer's disease pathologies induced by traumatic brain injury.
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Sawmiller D, Li S, Shahaduzzaman M, Smith AJ, Obregon D, Giunta B, Borlongan CV, Sanberg PR, and Tan J
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- Alzheimer Disease etiology, Amyloid beta-Peptides metabolism, Animals, Brain metabolism, Brain Injuries drug therapy, Cytokines genetics, Cytokines metabolism, Glycogen Synthase Kinase 3 metabolism, Luteolin pharmacokinetics, Luteolin pharmacology, Mice, Tissue Distribution, tau Proteins metabolism, Alzheimer Disease drug therapy, Brain drug effects, Brain Injuries complications, Luteolin therapeutic use
- Abstract
Traumatic brain injury (TBI) occurs in response to an acute insult to the head and is recognized as a major risk factor for Alzheimer's disease (AD). Indeed, recent studies have suggested a pathological overlap between TBI and AD, with both conditions exhibiting amyloid-beta (Aβ) deposits, tauopathy, and neuroinflammation. Additional studies involving animal models of AD indicate that some AD-related genotypic determinants may be critical factors enhancing temporal and phenotypic symptoms of TBI. Thus in the present study, we examined sub-acute effects of moderate TBI delivered by a gas-driven shock tube device in Aβ depositing Tg2576 mice. Three days later, significant increases in b-amyloid deposition, glycogen synthase-3 (GSK-3) activation, phospho-tau, and pro-inflammatory cytokines were observed. Importantly, peripheral treatment with the naturally occurring flavonoid, luteolin, significantly abolished these accelerated pathologies. This study lays the groundwork for a safe and natural compound that could prevent or treat TBI with minimal or no deleterious side effects in combat personnel and others at risk or who have experienced TBI.
- Published
- 2014
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18. Octyl gallate markedly promotes anti-amyloidogenic processing of APP through estrogen receptor-mediated ADAM10 activation.
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Zhang SQ, Sawmiller D, Li S, Rezai-Zadeh K, Hou H, Zhou S, Shytle D, Giunta B, Fernandez F, Mori T, and Tan J
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- ADAM10 Protein, Alzheimer Disease metabolism, Animals, Cell Line, Tumor, Drug Evaluation, Preclinical, Enzyme Activation drug effects, Estrogen Receptor alpha antagonists & inhibitors, Female, Gallic Acid pharmacology, Humans, Male, Mice, Mice, Transgenic, Phosphatidylinositol 3-Kinases metabolism, Proteolysis, Proto-Oncogene Proteins c-akt metabolism, Signal Transduction, ADAM Proteins metabolism, Alzheimer Disease drug therapy, Amyloid Precursor Protein Secretases metabolism, Amyloid beta-Protein Precursor metabolism, Estrogen Receptor alpha metabolism, Gallic Acid analogs & derivatives, Membrane Proteins metabolism
- Abstract
Our previous studies showed that the green tea-derived polyphenolic compound (-)-epigallocatechin-3 gallate (EGCG) reduces amyloid-β (Aβ) production in both neuronal and mouse Alzheimer's disease (AD) models in concert with activation of estrogen receptor-α/phosphatidylinositide 3-kinase/protein kinase B (ERα/PI3K/Akt) signaling and anti-amyloidogenic amyloid precursor protein (APP) α-secretase (a disintegrin and metallopeptidase domain-10, ADAM10) processing. Since the gallate moiety in EGCG may correspond to the 7α position of estrogen, thereby facilitating ER binding, we extensively screened the effect of other gallate containing phenolic compounds on APP anti-amyloidogenic processing. Octyl gallate (OG; 10 µM), drastically decreased Aβ generation, in concert with increased APP α-proteolysis, in murine neuron-like cells transfected with human wild-type APP or "Swedish" mutant APP. OG markedly increased production of the neuroprotective amino-terminal APP cleavage product, soluble APP-α (sAPPα). In accord with our previous study, these cleavage events were associated with increased ADAM10 maturation and reduced by blockade of ERα/PI3k/Akt signaling. To validate these findings in vivo, we treated Aβ-overproducing Tg2576 mice with OG daily for one week by intracerebroventricular injection and found decreased Aβ levels associated with increased sAPPα. These data indicate that OG increases anti-amyloidogenic APP α-secretase processing by activation of ERα/PI3k/Akt signaling and ADAM10, suggesting that this compound may be an effective treatment for AD.
- Published
- 2013
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19. Microglia activation as a biomarker for traumatic brain injury.
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Hernandez-Ontiveros DG, Tajiri N, Acosta S, Giunta B, Tan J, and Borlongan CV
- Abstract
Traumatic brain injury (TBI) has become the signature wound of wars in Afghanistan and Iraq. Injury may result from a mechanical force, a rapid acceleration-deceleration movement, or a blast wave. A cascade of secondary cell death events ensues after the initial injury. In particular, multiple inflammatory responses accompany TBI. A series of inflammatory cytokines and chemokines spreads to normal brain areas juxtaposed to the core impacted tissue. Among the repertoire of immune cells involved, microglia is a key player in propagating inflammation to tissues neighboring the core site of injury. Neuroprotective drug trials in TBI have failed, likely due to their sole focus on abrogating neuronal cell death and ignoring the microglia response despite these inflammatory cells' detrimental effects on the brain. Another relevant point to consider is the veracity of results of animal experiments due to deficiencies in experimental design, such as incomplete or inadequate method description, data misinterpretation, and reporting may introduce bias and give false-positive results. Thus, scientific publications should follow strict guidelines that include randomization, blinding, sample-size estimation, and accurate handling of all data (Landis et al., 2012). A prolonged state of inflammation after brain injury may linger for years and predispose patients to develop other neurological disorders, such as Alzheimer's disease. TBI patients display progressive and long-lasting impairments in their physical, cognitive, behavioral, and social performance. Here, we discuss inflammatory mechanisms that accompany TBI in an effort to increase our understanding of the dynamic pathological condition as the disease evolves over time and begin to translate these findings for defining new and existing inflammation-based biomarkers and treatments for TBI.
- Published
- 2013
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20. The immunology of traumatic brain injury: a prime target for Alzheimer's disease prevention.
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Giunta B, Obregon D, Velisetty R, Sanberg PR, Borlongan CV, and Tan J
- Subjects
- Alzheimer Disease epidemiology, Animals, Brain drug effects, Brain Injuries epidemiology, Humans, Inflammation Mediators antagonists & inhibitors, Inflammation Mediators physiology, Alzheimer Disease immunology, Alzheimer Disease prevention & control, Brain immunology, Brain Injuries immunology, Brain Injuries prevention & control, Disease Progression
- Abstract
A global health problem, traumatic brain injury (TBI) is especially prevalent in the current era of ongoing world military conflicts. Its pathological hallmark is one or more primary injury foci, followed by a spread to initially normal brain areas via cascades of inflammatory cytokines and chemokines resulting in an amplification of the original tissue injury by microglia and other central nervous system immune cells. In some cases this may predispose individuals to later development of Alzheimer's disease (AD). The inflammatory-based progression of TBI has been shown to be active in humans for up to 17 years post TBI. Unfortunately, all neuroprotective drug trials have failed, and specific treatments remain less than efficacious. These poor results might be explained by too much of a scientific focus on neurons without addressing the functions of microglia in the brain, which are at the center of proinflammatory cytokine generation. To address this issue, we provide a survey of the TBI-related brain immunological mechanisms that may promote progression to AD. We discuss these immune and microglia-based inflammatory mechanisms involved in the progression of post-trauma brain damage to AD. Flavonoid-based strategies to oppose the antigen-presenting cell-like inflammatory phenotype of microglia will also be reviewed. The goal is to provide a rationale for investigations of inflammatory response following TBI which may represent a pathological link to AD. In the end, a better understanding of neuroinflammation could open therapeutic avenues for abrogation of secondary cell death and behavioral symptoms that may mediate the progression of TBI to later AD.
- Published
- 2012
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21. Is vitamin D beneficial to Alzheimer disease? A surprising dilemma.
- Author
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Qiao DL, Zhang SQ, and Giunta B
- Subjects
- Alzheimer Disease pathology, Amyloid beta-Peptides antagonists & inhibitors, Amyloid beta-Peptides metabolism, Cell Line, Humans, Microglia drug effects, Microglia metabolism, Microglia pathology, Tumor Necrosis Factor-alpha antagonists & inhibitors, Tumor Necrosis Factor-alpha metabolism, Vitamin D pharmacology, Alzheimer Disease drug therapy, Alzheimer Disease metabolism, Vitamin D therapeutic use
- Published
- 2012
- Full Text
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22. Soluble amyloid precursor protein-α modulates β-secretase activity and amyloid-β generation.
- Author
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Obregon D, Hou H, Deng J, Giunta B, Tian J, Darlington D, Shahaduzzaman M, Zhu Y, Mori T, Mattson MP, and Tan J
- Subjects
- Alzheimer Disease enzymology, Alzheimer Disease genetics, Amino Acid Motifs, Amyloid Precursor Protein Secretases genetics, Amyloid beta-Peptides chemistry, Amyloid beta-Peptides genetics, Amyloid beta-Protein Precursor chemistry, Amyloid beta-Protein Precursor genetics, Animals, Aspartic Acid Endopeptidases genetics, Cell Line, Humans, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Transgenic, Protein Processing, Post-Translational, Alzheimer Disease metabolism, Amyloid Precursor Protein Secretases metabolism, Amyloid beta-Peptides metabolism, Amyloid beta-Protein Precursor metabolism, Aspartic Acid Endopeptidases metabolism
- Abstract
In sporadic age-related forms of Alzheimer's disease (AD), it is unclear why amyloid-β (Aβ) peptides accumulate. Here we show that soluble amyloid precursor protein-α (sAPP-α) decreases Aβ generation by directly associating with β-site APP-converting enzyme (BACE)1, thereby modulating APP processing. Whereas specifically targeting sAPP-α using antibodies enhances Aβ production; in transgenic mice with AD-like pathology, sAPP-α overexpression decreases β-amyloid plaques and soluble Aβ. In support, immunoneutralization of sAPP-α increases APP amyloidogenic processing in these mice. Given our current findings, and because a number of risk factors for sporadic AD serve to lower levels of sAPP-α in brains of AD patients, inadequate sAPP-α levels may be sufficient to polarize APP processing towards the amyloidogenic, Aβ-producing route. Therefore, restoration of sAPP-α or enhancement of its association with BACE may be viable strategies to ameliorate imbalances in APP processing that can lead to AD pathogenesis.
- Published
- 2012
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23. Antiretroviral medications disrupt microglial phagocytosis of β-amyloid and increase its production by neurons: implications for HIV-associated neurocognitive disorders.
- Author
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Giunta B, Ehrhart J, Obregon DF, Lam L, Le L, Jin J, Fernandez F, Tan J, and Shytle RD
- Subjects
- AIDS Dementia Complex physiopathology, Anti-Retroviral Agents therapeutic use, Cell Line, Cognition Disorders pathology, Cognition Disorders physiopathology, HIV Infections drug therapy, HIV Infections pathology, Humans, AIDS Dementia Complex pathology, Amyloid beta-Peptides metabolism, Anti-Retroviral Agents pharmacology, HIV-1, Microglia drug effects, Microglia physiology, Neurons metabolism, Neurons pathology, Phagocytosis drug effects
- Abstract
Up to 50% of long-term HIV infected patients, including those with systemically well-controlled infection, commonly experience memory problems and slowness, difficulties in concentration, planning, and multitasking. Deposition of Aβ plaques is also a common pathological feature of HIV infection. However, it is not clear whether this accumulation is due to AD-like processes, HIV-associated immunosuppression, Tat protein-induced Aβ elevations, and/or the effects of single highly active antiretroviral therapy (ART). Here we evaluated the effects of several ART medications (Zidovudine, Lamivudine, Indinavir, and Abacavir) alone and in combination on: 1) Aβ1-40, 42 generation in murine N2a cells transfected with the human "Swedish" mutant form of APP; 2) microglial phagocytosis of FITC-Aβ1-42 peptides in cultured murine N9 microglia. We report for the first time that these antiretroviral compounds (10 μM) generally increase Aβ generation (~50-200%) in SweAPP N2a cells and markedly inhibit microglial phagocytosis of FITC-Aβ1-42 peptides in murine microglia. The most significant amyloidogenic effects were observed with combined ART (p < 0.05); suggesting certain ART medications may have additive amyloidogenic effects when combined. As these antiretroviral compounds are capable of penetrating the blood brain barrier and reaching the concentrations employed in the in vitro studies, these findings raise the possibility that ART may play a casual role in the elevated Aβ found in the brains of those infected with HIV. Therefore these compounds may consequently contribute to cognitive decline observed in HIV associated neurocognitive disorders (HAND).
- Published
- 2011
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24. Mutant presenilin-1 deregulated peripheral immunity exacerbates Alzheimer-like pathology.
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Zhu Y, Obregon D, Hou H, Giunta B, Ehrhart J, Fernandez F, Mori T, Nikolic W, Zhao Y, Morgan D, Town T, and Tan J
- Subjects
- Alzheimer Disease immunology, Amyloid beta-Protein Precursor genetics, Animals, Brain metabolism, Brain pathology, CD11b Antigen biosynthesis, Cytokines biosynthesis, Mice, Mice, Transgenic, Mutant Proteins metabolism, Mutation, Plaque, Amyloid, Alzheimer Disease pathology, Amyloid beta-Protein Precursor metabolism, Brain immunology, Presenilin-1 genetics, Presenilin-1 metabolism, Th1 Cells immunology, Th2 Cells immunology
- Abstract
Mutations in the presenilin-1 (PS1) gene are independent causes of familial Alzheimer's disease (AD). AD patients have dysregulated immunity, and PS1 mutant mice exhibit abnormal systemic immune responses. To test whether immune function abnormality caused by a mutant human PS1 gene (mhPS1) could modify AD-like pathology, we reconstituted immune systems of AD model mice carrying a mutant human amyloid precursor protein gene (mhAPP; Tg2576 mice) or both mhAPP and mhPS1 genes (PSAPP mice) with allogeneic bone marrow cells. Here, we report a marked reduction in amyloid-β (Aβ) levels, β-amyloid plaques and brain inflammatory responses in PSAPP mice following strain-matched wild-type PS1 bone marrow reconstitution. These effects occurred with immune switching from pro-inflammatory T helper (Th) 1 to anti-inflammatory Th2 immune responses in the periphery and in the brain, which likely instructed microglia to phagocytose and clear Aβ in an ex vivo assay. Conversely, Tg2576 mice displayed accelerated AD-like pathology when reconstituted with mhPS1 bone marrow. These data show that haematopoietic cells bearing the mhPS1 transgene exacerbate AD-like pathology, suggesting a novel therapeutic strategy for AD based on targeting PS1 in peripheral immune cells., (© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.)
- Published
- 2011
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25. CD45 deficiency drives amyloid-β peptide oligomers and neuronal loss in Alzheimer's disease mice.
- Author
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Zhu Y, Hou H, Rezai-Zadeh K, Giunta B, Ruscin A, Gemma C, Jin J, Dragicevic N, Bradshaw P, Rasool S, Glabe CG, Ehrhart J, Bickford P, Mori T, Obregon D, Town T, and Tan J
- Subjects
- Aging metabolism, Aging pathology, Alzheimer Disease pathology, Amyloid beta-Protein Precursor genetics, Amyloidosis metabolism, Amyloidosis pathology, Animals, Blood-Brain Barrier metabolism, Cells, Cultured, Cerebral Cortex cytology, Cerebral Cortex metabolism, Cerebral Cortex pathology, Humans, Inflammation pathology, Interleukin-1beta metabolism, Mice, Mice, Mutant Strains, Mice, Transgenic, Microglia immunology, Microglia pathology, Mitochondria metabolism, Neurons metabolism, Presenilin-1 genetics, Protein Multimerization, Transgenes, Tumor Necrosis Factor-alpha metabolism, Alzheimer Disease metabolism, Amyloid beta-Peptides metabolism, Leukocyte Common Antigens genetics, Neurons pathology, Peptide Fragments metabolism
- Abstract
Converging lines of evidence indicate dysregulation of the key immunoregulatory molecule CD45 (also known as leukocyte common antigen) in Alzheimer's disease (AD). We report that transgenic mice overproducing amyloid-β peptide (Aβ) but deficient in CD45 (PSAPP/CD45(-/-) mice) faithfully recapitulate AD neuropathology. Specifically, we find increased abundance of cerebral intracellular and extracellular soluble oligomeric and insoluble Aβ, decreased plasma soluble Aβ, increased abundance of microglial neurotoxic cytokines tumor necrosis factor-α and interleukin-1β, and neuronal loss in PSAPP/CD45(-/-) mice compared with CD45-sufficient PSAPP littermates (bearing mutant human amyloid precursor protein and mutant human presenilin-1 transgenes). After CD45 ablation, in vitro and in vivo studies demonstrate an anti-Aβ phagocytic but proinflammatory microglial phenotype. This form of microglial activation occurs with elevated Aβ oligomers and neural injury and loss as determined by decreased ratio of anti-apoptotic Bcl-xL to proapoptotic Bax, increased activated caspase-3, mitochondrial dysfunction, and loss of cortical neurons in PSAPP/CD45(-/-) mice. These data show that deficiency in CD45 activity leads to brain accumulation of neurotoxic Aβ oligomers and validate CD45-mediated microglial clearance of oligomeric Aβ as a novel AD therapeutic target.
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- 2011
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26. Flipping the switches: CD40 and CD45 modulation of microglial activation states in HIV associated dementia (HAD).
- Author
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Salemi J, Obregon DF, Cobb A, Reed S, Sadic E, Jin J, Fernandez F, Tan J, and Giunta B
- Abstract
Microglial dysfunction is associated with the pathogenesis and progression of a number of neurodegenerative disorders including HIV associated dementia (HAD). HIV promotion of an M1 antigen presenting cell (APC) - like microglial phenotype, through the promotion of CD40 activity, may impair endogenous mechanisms important for amyloid- beta (Aβ) protein clearance. Further, a chronic pro-inflammatory cycle is established in this manner. CD45 is a protein tyrosine phosphatase receptor which negatively regulates CD40L-CD40-induced microglial M1 activation; an effect leading to the promotion of an M2 phenotype better suited to phagocytose and clear Aβ. Moreover, this CD45 mediated activation state appears to dampen harmful cytokine production. As such, this property of microglial CD45 as a regulatory "off switch" for a CD40-promoted M1, APC-type microglia activation phenotype may represent a critical therapeutic target for the prevention and treatment of neurodegeneration, as well as microglial dysfunction, found in patients with HAD.
- Published
- 2011
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27. Inflammaging as a prodrome to Alzheimer's disease.
- Author
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Giunta B, Fernandez F, Nikolic WV, Obregon D, Rrapo E, Town T, and Tan J
- Subjects
- Alzheimer Disease drug therapy, Alzheimer Disease prevention & control, Amyloid beta-Peptides administration & dosage, Amyloid beta-Peptides immunology, Animals, Anti-Inflammatory Agents, Non-Steroidal therapeutic use, Disease Models, Animal, Fetal Blood, Flavonoids therapeutic use, Humans, Vaccination, Aging immunology, Aging physiology, Alzheimer Disease immunology, Alzheimer Disease physiopathology, Immune System physiology, Inflammation immunology, Inflammation physiopathology
- Abstract
Recently, the term "inflammaging" was coined by Franceshci and colleagues to characterize a widely accepted paradigm that ageing is accompanied by a low-grade chronic up-regulation of certain pro-inflammatory responses. Inflammaging differs significantly from the traditional five cardinal features of acute inflammation in that it is characterized by a relative decline in adaptive immunity and T-helper 2 responses and is associated with increased innate immunity by cells of the mononuclear phagocyte lineage. While the over-active innate immunity characteristic of inflammaging may remain subclinical in many elderly individuals, a portion of individuals (postulated to have a "high responder inflammatory genotype") may shift from a state of "normal" or "subclinical" inflammaging to one or more of a number of age-associated diseases. We and others have found that IFN-gamma and other pro-inflammatory cytokines interact with processing and production of Abeta peptide, the pathological hallmark feature of Alzheimer's disease (AD), suggesting that inflammaging may be a "prodrome" to AD. Although conditions of enhanced innate immune response with overproduction of pro-inflammatory proteins are associated with both healthy aging and AD, it is suggested that those who age "well" demonstrate anti-inflammaging mechanisms and biomarkers that likely counteract the adverse immune response of inflammaging. Thus, opposing the features of inflammaging may prevent or treat the symptoms of AD. In this review, we fully characterize the aging immune system. In addition, we explain how three novel treatments, (1) human umbilical cord blood cells (HUCBC), (2) flavanoids, and (3) Abeta vaccination oppose the forces of inflammaging and AD-like pathology in various mouse models.
- Published
- 2008
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28. CD45RB is a novel molecular therapeutic target to inhibit Abeta peptide-induced microglial MAPK activation.
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Zhu Y, Hou H, Nikolic WV, Ehrhart J, Rrapo E, Bickford P, Giunta B, and Tan J
- Subjects
- Amyloid beta-Peptides physiology, Animals, Blotting, Western, Culture Media, Enzyme Activation, Enzyme-Linked Immunosorbent Assay, Interleukin-6 metabolism, Mice, Mice, Inbred BALB C, Microscopy, Fluorescence, Phagocytosis, Tumor Necrosis Factor-alpha metabolism, Amyloid beta-Peptides antagonists & inhibitors, Leukocyte Common Antigens drug effects, Microglia enzymology, Mitogen-Activated Protein Kinases metabolism
- Abstract
Background: Microglial activation, characterized by p38 MAPK or p44/42 MAPK pathway signal transduction, occurs in Alzheimer's disease (AD). Our previous studies demonstrated CD45, a membrane-bound protein tyrosine phosphatase (PTP), opposed beta-amyloid (Abeta) peptide-induced microglial activation via inhibition of p44/42 MAPK. Additionally we have shown agonism of the RB isoform of CD45 (CD45RB) abrogates lipopolysaccharide (LPS)-induced microglial activation., Methodology and Results: In this study, CD45RB modulation of Abeta peptide or LPS-activated primary cultured microglial cells was further investigated. Microglial cells were co-treated with "aged" FITC-Abeta(1-42) and multiple CD45 isoform agonist antibodies. Data revealed cross-linking of CD45, particularly the CD45RB isoform, enhances microglial phagocytosis of Abeta(1-42) peptide and inhibits LPS-induced activation of p44/42 and p38 pathways. Co-treatment of microglial cells with agonist CD45 antibodies results in significant inhibition of LPS-induced microglial TNF-alpha and IL-6 release through p44/42 and/or p38 pathways. Moreover, inhibition of either of these pathways augmented CD45RB cross-linking induced microglial phagocytosis of Abeta(1-42) peptide. To investigate the mechanism(s) involved, microglial cells were co-treated with a PTP inhibitor (potassium bisperoxo [1,10-phenanthroline oxovanadate; Phen]) and Abeta(1-42) peptides. Data showed synergistic induction of microglial activation as evidenced by TNF-alpha and IL-6 release; both of which are demonstrated to be dependent on increased p44/42 and/or p38 activation. Finally, it was observed that cross-linking of CD45RB in the presence of Abeta(1-42) peptide, inhibits co-localization of microglial MHC class II and Abeta peptide; suggesting CD45 activation inhibits the antigen presenting phenotype of microglial cells., Conclusion: In summary, p38 MAPK is another novel signaling pathway, besides p44/42, in which CD45RB cross-linking negatively regulates microglial Abeta phagocytosis while increasing potentially neurotoxic inflammation. Therefore, agonism of CD45RB PTP activity may be an effective therapeutic target for novel agents to treat AD due to its Abeta lowering, and inflammation reducing, properties that are particularly targeted at microglial cells. Such treatments may be more effective with less potential to produce systemic side-effects than therapeutics which induce non-specific, systemic down-regulation of inflammation.
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- 2008
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29. Transcutaneous beta-amyloid immunization reduces cerebral beta-amyloid deposits without T cell infiltration and microhemorrhage.
- Author
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Nikolic WV, Bai Y, Obregon D, Hou H, Mori T, Zeng J, Ehrhart J, Shytle RD, Giunta B, Morgan D, Town T, and Tan J
- Subjects
- Alzheimer Disease pathology, Amyloid beta-Peptides immunology, Amyloid beta-Peptides therapeutic use, Amyloidosis, Animals, Antibodies blood, Antibody Formation drug effects, Cerebral Hemorrhage etiology, Chemotaxis, Leukocyte, Langerhans Cells immunology, Meningoencephalitis etiology, Mice, Peptide Fragments immunology, Peptide Fragments therapeutic use, T-Lymphocytes, Treatment Outcome, Vaccination adverse effects, Alzheimer Disease therapy, Amyloid beta-Peptides analysis, Brain pathology, Vaccination methods
- Abstract
Alzheimer's disease (AD) immunotherapy accomplished by vaccination with beta-amyloid (Abeta) peptide has proved efficacious in AD mouse models. However, "active" Abeta vaccination strategies for the treatment of cerebral amyloidosis without concurrent induction of detrimental side effects are lacking. We have developed a transcutaneous (t.c.) Abeta vaccination approach and evaluated efficacy and monitored for deleterious side effects, including meningoencephalitis and microhemorrhage, in WT mice and a transgenic mouse model of AD. We demonstrate that t.c. immunization of WT mice with aggregated Abeta(1-42) plus the adjuvant cholera toxin (CT) results in high-titer Abeta antibodies (mainly of the Ig G1 class) and Abeta(1-42)-specific splenocyte immune responses. Confocal microscopy of the t.c. immunization site revealed Langerhans cells in areas of the skin containing the Abeta(1-42) immunogen, suggesting that these unique innate immune cells participate in Abeta(1-42) antigen processing. To evaluate the efficacy of t.c. immunization in reducing cerebral amyloidosis, transgenic PSAPP (APPsw, PSEN1dE9) mice were immunized with aggregated Abeta(1-42) peptide plus CT. Similar to WT mice, PSAPP mice showed high Abeta antibody titers. Most importantly, t.c. immunization with Abeta(1-42) plus CT resulted in significant decreases in cerebral Abeta(1-40,42) levels coincident with increased circulating levels of Abeta(1-40,42), suggesting brain-to-blood efflux of Abeta. Reduction in cerebral amyloidosis was not associated with deleterious side effects, including brain T cell infiltration or cerebral microhemorrhage. Together, these data suggest that t.c. immunization constitutes an effective and potentially safe treatment strategy for AD.
- Published
- 2007
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30. Microinfusion of pituitary adenylate cyclase-activating polypeptide into the central nucleus of amygdala of the rat produces a shift from an active to passive mode of coping in the shock-probe fear/defensive burying test.
- Author
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Legradi G, Das M, Giunta B, Hirani K, Mitchell EA, and Diamond DM
- Subjects
- Adaptation, Psychological physiology, Amygdala physiology, Animals, Electroshock methods, Fear physiology, Male, Motor Activity drug effects, Motor Activity physiology, Rats, Rats, Sprague-Dawley, Adaptation, Psychological drug effects, Amygdala drug effects, Fear drug effects, Microinjections methods, Pituitary Adenylate Cyclase-Activating Polypeptide administration & dosage
- Abstract
High concentrations of pituitary adenylate cyclase-activating polypeptide (PACAP) nerve fibers are present in the central nucleus of amygdala (CeA), a brain region implicated in the control of fear-related behavior. This study evaluated PACAPergic modulation of fear responses at the CeA in male Sprague-Dawley rats. PACAP (50-100 pmol) microinfusion via intra-CeA cannulae produced increases in immobility and time the rats spent withdrawn into a corner opposite to the electrified probe compared to controls in the shock-probe fear/defensive burying test. Shock-probe burying and exploration, numbers of shocks received, locomotion distance, and velocity were all reduced by intra-CeA PACAP injection. Further, intra-CeA PACAP effects were manifested only when the animals were challenged by shock, as intra-CeA PACAP injections did not cause significant changes in the behaviors of unshocked rats. Thus, intra-CeA administration of PACAP produces a distinct reorganization of stress-coping behaviors from active (burying) to passive modes, such as withdrawal and immobility. These findings are potentially significant toward enhancing our understanding of the involvement of PACAP and the CeA in the neural basis of fear and anxiety.
- Published
- 2007
- Full Text
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