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Article: Examining the endogenous antioxidant response through immunofluorescent analysis of Nrf2 in tissue.

Lindl, Kathryn A / Jordan-Sciutto, Kelly L

Methods in molecular biology (Clifton, N.J.)

2008 Volume 477, Page(s) 229–243

Abstract: As organisms designed to depend upon oxygen to sustain life, humans are necessarily and continually exposed to damaging oxidizing agents. As a vital protective measure, oxygen-dependent organisms have developed a highly evolutionarily conserved mechanism ...

Abstract	As organisms designed to depend upon oxygen to sustain life, humans are necessarily and continually exposed to damaging oxidizing agents. As a vital protective measure, oxygen-dependent organisms have developed a highly evolutionarily conserved mechanism for preventing oxidative stress. NF-E2 (nuclear factor (erythroid-derived 2))-related factor-2 (Nrf2) is the primary regulator of this endogenous antioxidant response. Many diseases that plague human society, ranging from various cancers to neurodegenerative diseases, have oxidative stress as a component of their etiology, and thus, much disease research has focused on Nrf2, both as a potential point of biological failure and as a promising therapeutic target. As a transcription factor, Nrf2 is active only when it is nuclear, and is regulated largely by its subcellular distribution. Thus, Nrf2 protein levels and subcellular localization are both key pieces of information when studying the endogenous antioxidant response. Immunofluorescent analysis (IFA) of Nrf2 in human tissue is a particularly powerful tool in the study of Nrf2 in disease, because it allows examination of both of these regulatory mechanisms that modulate Nrf2 activity.
MeSH term(s)	Antibodies ; Antioxidants/metabolism ; Fluorescent Antibody Technique/methods ; Humans ; Microscopy, Confocal ; NF-E2-Related Factor 2/metabolism ; Paraffin Embedding
Chemical Substances	Antibodies ; Antioxidants ; NF-E2-Related Factor 2
Language	English
Publishing date	2008-12-13
Publishing country	United States
Document type	Journal Article
ISSN	1064-3745
ISSN	1064-3745
DOI	10.1007/978-1-60327-517-0_18
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Article ; Online: HIV-associated neurocognitive disorder: pathogenesis and therapeutic opportunities.

Lindl, Kathryn A / Marks, David R / Kolson, Dennis L / Jordan-Sciutto, Kelly L

Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology

2010 Volume 5, Issue 3, Page(s) 294–309

Abstract: Human immunodeficiency virus type 1 (HIV) infection presently affects more that 40 million people worldwide, and is associated with central nervous system (CNS) disruption in at least 30% of infected individuals. The use of highly active antiretroviral ... ...

Abstract	Human immunodeficiency virus type 1 (HIV) infection presently affects more that 40 million people worldwide, and is associated with central nervous system (CNS) disruption in at least 30% of infected individuals. The use of highly active antiretroviral therapy has lessened the incidence, but not the prevalence of mild impairment of higher cognitive and cortical functions (HIV-associated neurocognitive disorders) as well as substantially reduced a more severe form dementia (HIV-associated dementia). Furthermore, improving neurological outcomes will require novel, adjunctive therapies that are targeted towards mechanisms of HIV-induced neurodegeneration. Identifying such molecular and pharmacological targets requires an understanding of the events preceding irreversible neuronal damage in the CNS, such as actions of neurotoxins (HIV proteins and cellular factors), disruption of ion channel properties, synaptic damage, and loss of adult neurogenesis. By considering the specific mechanisms and consequences of HIV neuropathogenesis, unified approaches for neuroprotection will likely emerge using a tailored, combined, and non-invasive approach.
MeSH term(s)	AIDS Dementia Complex/drug therapy ; AIDS Dementia Complex/etiology ; AIDS Dementia Complex/immunology ; Animals ; Anti-HIV Agents/therapeutic use ; Brain/virology ; HIV-1/physiology ; Humans ; Memantine/therapeutic use ; Minocycline/therapeutic use ; Neuroimmunomodulation/immunology ; Neuroimmunomodulation/physiology ; Selegiline/therapeutic use
Chemical Substances	Anti-HIV Agents ; Selegiline (2K1V7GP655) ; Minocycline (FYY3R43WGO) ; Memantine (W8O17SJF3T)
Language	English
Publishing date	2010-04-16
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2227405-4
ISSN	1557-1904 ; 1557-1890
ISSN (online)	1557-1904
ISSN	1557-1890
DOI	10.1007/s11481-010-9205-z
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Article ; Online: Differential roles for caspase-mediated and calpain-mediated cell death in 1- and 3-week-old rat cortical cultures.

Wang, Ying / Zyskind, Jacob W / Colacurcio, Daniel J / Lindl, Kathryn A / Ting, Jenhao H / Grigoriev, Galina / Jordan-Sciutto, Kelly L

Neuroreport

2012 Volume 23, Issue 18, Page(s) 1052–1058

Abstract: Necrosis and apoptosis are well established as two primary cell death pathways. Mixed neuroglial cultures are commonly used to study cell death mechanisms in neural cells. However, the ages of these cultures vary across studies and little attention has ... ...

Abstract	Necrosis and apoptosis are well established as two primary cell death pathways. Mixed neuroglial cultures are commonly used to study cell death mechanisms in neural cells. However, the ages of these cultures vary across studies and little attention has been paid to how cell death processes may change as the cultures mature. To clarify whether neuroglial culture age affects cell death mechanisms, we treated 1- and 3-week-old neuroglial cultures with either the excitotoxic stimulus, N-methyl-D-aspartate (NMDA), or with the oxidative stressor, hydrogen peroxide (H2O2). Although NMDA is known to be toxic only in cultures that are at least 2 weeks old, H2O2 is toxic in cultures of all ages. Here, we confirm that, in 1-week-old neuroglial cultures, NMDA does not induce toxicity, whereas H2O2 induces both calpain-mediated and caspase-mediated neuronal death. In 3-week-old cultures, both NMDA and H2O2 trigger calpain-mediated, but not caspase-mediated, neuronal death. Further, we observed a decrease in caspase-3 levels and an increase in calpain levels in untreated neuroglial cultures as they aged. The findings presented here show that neuronal cell death mechanisms vary with culture age and highlight the necessity of considering culture age when interpreting neural cell culture data.
MeSH term(s)	Age Factors ; Animals ; Animals, Newborn ; Calpain/physiology ; Caspases/physiology ; Cell Death/drug effects ; Cell Death/physiology ; Cells, Cultured ; Cellular Senescence/drug effects ; Cerebral Cortex/cytology ; Cerebral Cortex/drug effects ; Cerebral Cortex/enzymology ; Dose-Response Relationship, Drug ; Hydrogen Peroxide/pharmacology ; N-Methylaspartate/pharmacology ; Rats ; Rats, Sprague-Dawley
Chemical Substances	N-Methylaspartate (6384-92-5) ; Hydrogen Peroxide (BBX060AN9V) ; Calpain (EC 3.4.22.-) ; Caspases (EC 3.4.22.-)
Language	English
Publishing date	2012-10-30
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1049746-8
ISSN	1473-558X ; 0959-4965
ISSN (online)	1473-558X
ISSN	0959-4965
DOI	10.1097/WNR.0b013e32835ad25d
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Zs.A 3118: Show issues

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Article ; Online: Parallel high throughput neuronal toxicity assays demonstrate uncoupling between loss of mitochondrial membrane potential and neuronal damage in a model of HIV-induced neurodegeneration.

White, Michael G / Wang, Ying / Akay, Cagla / Lindl, Kathryn A / Kolson, Dennis L / Jordan-Sciutto, Kelly L

Neuroscience research

2011 Volume 70, Issue 2, Page(s) 220–229

Abstract: Neurocognitive deficits seen in HIV-associated neurocognitive disorders (HANDs) are attributed to the release of soluble factors from CNS-resident, HIV-infected and/or activated macrophages and microglia. To study HIV-associated neurotoxicity, we used ... ...

Abstract	Neurocognitive deficits seen in HIV-associated neurocognitive disorders (HANDs) are attributed to the release of soluble factors from CNS-resident, HIV-infected and/or activated macrophages and microglia. To study HIV-associated neurotoxicity, we used our in vitro model in which primary rat neuronal/glial cultures are treated with supernatants from cultured human monocyte-derived macrophages, infected with a CNS-isolated HIV-1 strain (HIV-MDM). We found that neuronal damage, detected as a loss of microtubule-associated protein-2 (MAP2), begins as early as 2h and is preceded by a loss of mitochondrial membrane potential (Δψ(m)). Interestingly, inhibitors of calpains, but not inhibitors of caspases, blocked MAP2 loss, however neither type of inhibitor prevented the loss of Δψ(m). To facilitate throughput for these studies, we refined a MAP2 cell-based-ELISA whose data closely compare with our standardized method of hand counting neurons. In addition, we developed a tetramethyl rhodamine methyl ester (TMRM)-based multi-well fluorescent plate assay for the evaluation of whole culture Δψ(m). Together, these findings indicate that calpain activation and loss of Δψ(m) may be parallel pathways to death in HIV-MDM-treated neurons and also demonstrate the validity of plate assays for assessing multiple experimental parameters as is useful for screening neurotherapeutics for neuronal damage and death.
MeSH term(s)	AIDS Dementia Complex/metabolism ; AIDS Dementia Complex/pathology ; Animals ; Calpain/antagonists & inhibitors ; Calpain/physiology ; Cell Culture Techniques/methods ; Cell Death/physiology ; Cells, Cultured ; Macrophages/metabolism ; Macrophages/pathology ; Macrophages/virology ; Membrane Potential, Mitochondrial/physiology ; Microtubule-Associated Proteins/deficiency ; Mitochondrial Diseases/pathology ; Mitochondrial Diseases/virology ; Nerve Degeneration/metabolism ; Nerve Degeneration/pathology ; Nerve Degeneration/virology ; Neurons/metabolism ; Neurons/pathology ; Neurons/virology ; Rats ; Rats, Sprague-Dawley ; Rhodamines
Chemical Substances	Microtubule-Associated Proteins ; Rhodamines ; tetramethylrhodamine methyl ester ; Calpain (EC 3.4.22.-)
Language	English
Publishing date	2011-02-01
Publishing country	Ireland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	605842-5
ISSN	1872-8111 ; 0168-0102 ; 0921-8696
ISSN (online)	1872-8111
ISSN	0168-0102 ; 0921-8696
DOI	10.1016/j.neures.2011.01.013
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Zs.A 1993: Show issues

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Article ; Online: Targeted gene mutation of E2F1 evokes age-dependent synaptic disruption and behavioral deficits.

Ting, Jenhao H / Marks, David R / Schleidt, Stephanie S / Wu, Joanna N / Zyskind, Jacob W / Lindl, Kathryn A / Blendy, Julie A / Pierce, R Christopher / Jordan-Sciutto, Kelly L

Journal of neurochemistry

2014 Volume 129, Issue 5, Page(s) 850–863

Abstract: Aberrant expression and activation of the cell cycle protein E2F1 in neurons has been implicated in many neurodegenerative diseases. As a transcription factor regulating G1 to S phase progression in proliferative cells, E2F1 is often up-regulated and ... ...

Abstract	Aberrant expression and activation of the cell cycle protein E2F1 in neurons has been implicated in many neurodegenerative diseases. As a transcription factor regulating G1 to S phase progression in proliferative cells, E2F1 is often up-regulated and activated in models of neuronal death. However, despite its well-studied functions in neuronal death, little is known regarding the role of E2F1 in the mature brain. In this study, we used a combined approach to study the effect of E2F1 gene disruption on mouse behavior and brain biochemistry. We identified significant age-dependent olfactory and memory-related deficits in E2f1 mutant mice. In addition, we found that E2F1 exhibits punctated staining and localizes closely to the synapse. Furthermore, we found a mirroring age-dependent loss of post-synaptic protein-95 in the hippocampus and olfactory bulb as well as a global loss of several other synaptic proteins. Coincidently, E2F1 expression is significantly elevated at the ages, in which behavioral and synaptic perturbations were observed. Finally, we show that deficits in adult neurogenesis persist late in aged E2f1 mutant mice which may partially contribute to the behavior phenotypes. Taken together, our data suggest that the disruption of E2F1 function leads to specific age-dependent behavioral deficits and synaptic perturbations. E2F1 is a transcription factor regulating cell cycle progression and apoptosis. Although E2F1 dysregulation under toxic conditions can lead to neuronal death, little is known about its physiologic activity in the healthy brain. Here, we report significant age-dependent olfactory and memory deficits in mice with dysfunctional E2F1. Coincident with these behavioral changes, we also found age-matched synaptic disruption and persisting reduction in adult neurogenesis. Our study demonstrates that E2F1 contributes to physiologic brain structure and function.
MeSH term(s)	Aging/genetics ; Aging/psychology ; Animals ; Behavior, Animal/physiology ; Blotting, Western ; Cells, Cultured ; E2F1 Transcription Factor/genetics ; Gene Targeting ; Image Processing, Computer-Assisted ; Immunohistochemistry ; Memory/physiology ; Mice, Inbred C57BL ; Motor Activity/physiology ; Mutation/genetics ; Odorants ; Olfaction Disorders/genetics ; Olfaction Disorders/psychology ; Postural Balance/genetics ; Postural Balance/physiology ; Psychomotor Performance/physiology ; Rats ; Rats, Sprague-Dawley ; Recognition, Psychology ; Smell/genetics ; Smell/physiology ; Synapses/pathology ; Synaptosomes/physiology
Chemical Substances	E2F1 Transcription Factor ; E2f1 protein, mouse
Language	English
Publishing date	2014-02-12
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80158-6
ISSN	1471-4159 ; 0022-3042 ; 1474-1644
ISSN (online)	1471-4159
ISSN	0022-3042 ; 1474-1644
DOI	10.1111/jnc.12655
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Article ; Online: E2F1 localizes predominantly to neuronal cytoplasm and fails to induce expression of its transcriptional targets in human immunodeficiency virus-induced neuronal damage.

Wang, Ying / Shyam, Nikhil / Ting, Jenhao H / Akay, Cagla / Lindl, Kathryn A / Jordan-Sciutto, Kelly L

Neuroscience letters

2010 Volume 479, Issue 2, Page(s) 97–101

Abstract: As human immunodeficiency virus (HIV) does not induce neuronal damage by direct infection, the mechanisms of neuronal damage or loss in HIV-associated dementia (HAD) remain unclear. We have shown previously that immunoreactivity of transcription factor, ... ...

Abstract	As human immunodeficiency virus (HIV) does not induce neuronal damage by direct infection, the mechanisms of neuronal damage or loss in HIV-associated dementia (HAD) remain unclear. We have shown previously that immunoreactivity of transcription factor, E2F1, increases in neurons, localizing predominantly to the cytoplasm, in HIV-associated pathologies. Here we confirm that E2F1 localization is predominantly cytoplasmic in primary postmitotic neurons in vitro and cortical neurons in vivo. To determine whether E2F1 contributes to neuronal death in HAD via transactivation of target promoters, we assessed the mRNA and protein levels of several classical E2F1 transcriptional targets implicated in cell cycle progression and apoptosis in an in vitro model of HIV-induced neurotoxicity and in cortical autopsy tissue from patients infected with HIV. By Q-PCR, we show that mRNA levels of E2F1 transcriptional targets implicated in cell cycle progression (E2F1, Cyclin A, proliferating cell nuclear antigen (PCNA), and dyhydrofolate reductase (DHFR)) and apoptosis (caspases 3, 8, 9 and p19(ARF)) remain unchanged in an in vitro model of HIV-induced neurotoxicity. Further, we show that protein levels of p19(ARF), Cyclin A, and PCNA are not altered in vitro or in the cortex of patients with HAD. We propose that the predominantly cytoplasmic localization of E2F1 in neurons may account for the lack of E2F1 target transactivation in neurons responding to HIV-induced neurotoxicity.
MeSH term(s)	AIDS Dementia Complex/metabolism ; AIDS Dementia Complex/pathology ; Animals ; Apoptosis ; Caspases/biosynthesis ; Caspases/genetics ; Cell Proliferation ; Cells, Cultured ; Cerebral Cortex/metabolism ; Cyclin A/biosynthesis ; Cyclin A/genetics ; Cytoplasm/metabolism ; E2F1 Transcription Factor/genetics ; E2F1 Transcription Factor/metabolism ; HIV/physiology ; Humans ; Macrophages/virology ; Neurons/metabolism ; Neurons/pathology ; Neurons/virology ; Proliferating Cell Nuclear Antigen/biosynthesis ; Proliferating Cell Nuclear Antigen/genetics ; Rats ; Rats, Sprague-Dawley ; Tetrahydrofolate Dehydrogenase/biosynthesis ; Tetrahydrofolate Dehydrogenase/genetics ; Transcriptional Activation ; Tumor Suppressor Protein p14ARF/biosynthesis ; Tumor Suppressor Protein p14ARF/genetics
Chemical Substances	Cyclin A ; E2F1 Transcription Factor ; E2f1 protein, rat ; Proliferating Cell Nuclear Antigen ; Tumor Suppressor Protein p14ARF ; p19(ARF) protein, rat ; Tetrahydrofolate Dehydrogenase (EC 1.5.1.3) ; Caspases (EC 3.4.22.-)
Language	English
Publishing date	2010-05-16
Publishing country	Ireland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	194929-9
ISSN	1872-7972 ; 0304-3940
ISSN (online)	1872-7972
ISSN	0304-3940
DOI	10.1016/j.neulet.2010.05.032
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Article: Requirement of NMDA receptor reactivation for consolidation and storage of nondeclarative taste memory revealed by inducible NR1 knockout.

Cui, Zhenzhong / Lindl, Kathryn A / Mei, Bing / Zhang, Shuqing / Tsien, Joe Z

The European journal of neuroscience

2005 Volume 22, Issue 3, Page(s) 755–763

Abstract: We employed an inducible, reversible and region-specific gene knockout technique to investigate the requirements for cortical NMDA receptors (NMDAR) during the various stages (acquisition, consolidation and storage, and retrieval) of nondeclarative, ... ...

Abstract	We employed an inducible, reversible and region-specific gene knockout technique to investigate the requirements for cortical NMDA receptors (NMDAR) during the various stages (acquisition, consolidation and storage, and retrieval) of nondeclarative, hippocampal-independent memory in mice using a conditioned taste aversion memory paradigm. Here we show that temporary knockout of the cortical NMDAR during either the learning or postlearning consolidation stage, but not during the retrieval stage, causes severe performance deficits in the 1-month taste memory retention tests. More importantly, we found that the consolidation and storage of the long-term nondeclarative taste memories requires cortical NMDAR reactivation. Thus, the dynamic engagement of the NMDAR during the postlearning stage leads us to postulate that NMDAR reactivation-mediated synaptic re-entry reinforcement is crucial for overcoming the destabilizing effects intrinsic to synaptic protein turnover and for achieving consolidation and storage of nondeclarative memories in the brain.
MeSH term(s)	Analysis of Variance ; Animals ; Avoidance Learning/drug effects ; Avoidance Learning/physiology ; Behavior, Animal/physiology ; Cerebral Cortex/anatomy & histology ; Cerebral Cortex/physiology ; Conditioning (Psychology) ; Extracellular Matrix Proteins/genetics ; Extracellular Matrix Proteins/metabolism ; Gene Expression Regulation/physiology ; Green Fluorescent Proteins/biosynthesis ; Integrases/genetics ; Lithium Chloride/pharmacology ; Long-Term Potentiation/drug effects ; Long-Term Potentiation/physiology ; Memory/drug effects ; Memory/physiology ; Mice ; Mice, Transgenic ; Protein-Lysine 6-Oxidase/genetics ; Protein-Lysine 6-Oxidase/metabolism ; Receptors, N-Methyl-D-Aspartate/deficiency ; Receptors, N-Methyl-D-Aspartate/genetics ; Receptors, N-Methyl-D-Aspartate/physiology ; Saccharin/pharmacology ; Sweetening Agents/pharmacology ; Taste/drug effects ; Taste/physiology ; Time Factors
Chemical Substances	Extracellular Matrix Proteins ; NR1 NMDA receptor ; Receptors, N-Methyl-D-Aspartate ; Sweetening Agents ; Green Fluorescent Proteins (147336-22-9) ; Lox protein, mouse (149137-54-2) ; Protein-Lysine 6-Oxidase (EC 1.4.3.13) ; Cre recombinase (EC 2.7.7.-) ; Integrases (EC 2.7.7.-) ; Saccharin (FST467XS7D) ; Lithium Chloride (G4962QA067)
Language	English
Publishing date	2005-08
Publishing country	France
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	645180-9
ISSN	1460-9568 ; 0953-816X
ISSN (online)	1460-9568
ISSN	0953-816X
DOI	10.1111/j.1460-9568.2005.04257.x
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Article ; Online: Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system.

Journal of neurovirology

2014 Volume 20, Issue 1, Page(s) 39–53

Abstract: HIV-associated neurocognitive disorder (HAND), characterized by a wide spectrum of behavioral, cognitive, and motor dysfunctions, continues to affect approximately 50 % of HIV(+) patients despite the success of combination antiretroviral drug therapy ( ... ...

Abstract	HIV-associated neurocognitive disorder (HAND), characterized by a wide spectrum of behavioral, cognitive, and motor dysfunctions, continues to affect approximately 50 % of HIV(+) patients despite the success of combination antiretroviral drug therapy (cART) in the periphery. Of note, potential toxicity of antiretroviral drugs in the central nervous system (CNS) remains remarkably underexplored and may contribute to the persistence of HAND in the cART era. Previous studies have shown antiretrovirals (ARVs) to be neurotoxic in the peripheral nervous system in vivo and in peripheral neurons in vitro. Alterations in lipid and protein metabolism, mitochondrial damage, and oxidative stress all play a role in peripheral ARV neurotoxicity. We hypothesized that ARVs also induce cellular stresses in the CNS, ultimately leading to neuronal damage and contributing to the changing clinical and pathological picture seen in HIV-positive patients in the cART era. In this report, we show that ARVs are neurotoxic in the CNS in both pigtail macaques and rats in vivo. Furthermore, in vitro, ARVs lead to accumulation of reactive oxygen species (ROS), and ultimately induction of neuronal damage and death. Whereas ARVs alone caused some activation of the endogenous antioxidant response in vitro, augmentation of this response by a fumaric acid ester, monomethyl fumarate (MMF), blocked ARV-induced ROS generation, and neuronal damage/death. These findings implicate oxidative stress as a contributor to the underlying mechanisms of ARV-induced neurotoxicity and will provide an access point for adjunctive therapies to complement ARV therapy and reduce neurotoxicity in this patient population.
MeSH term(s)	AIDS Dementia Complex/pathology ; Animals ; Anti-Retroviral Agents/toxicity ; Blotting, Western ; Brain/drug effects ; Brain/pathology ; Brain/virology ; Cell Death/drug effects ; Disease Models, Animal ; Enzyme-Linked Immunosorbent Assay ; Female ; Fluorescent Antibody Technique ; Macaca ; Male ; Neurons/drug effects ; Neurons/pathology ; Oxidative Stress/drug effects ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Reverse Transcriptase Polymerase Chain Reaction
Chemical Substances	Anti-Retroviral Agents ; Reactive Oxygen Species
Language	English
Publishing date	2014-01-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1283265-0
ISSN	1538-2443 ; 1355-0284
ISSN (online)	1538-2443
ISSN	1355-0284
DOI	10.1007/s13365-013-0227-1
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Article: Expression of Nrf2 in neurodegenerative diseases.

Ramsey, Chenere P / Glass, Charles A / Montgomery, Marshall B / Lindl, Kathryn A / Ritson, Gillian P / Chia, Luis A / Hamilton, Ronald L / Chu, Charleen T / Jordan-Sciutto, Kelly L

Journal of neuropathology and experimental neurology

2007 Volume 66, Issue 1, Page(s) 75–85

Abstract: In response to oxidative stress, the nuclear factor E2-related factor 2 (Nrf2) transcription factor translocates from the cytoplasm into the nucleus and transactivates expression of genes with antioxidant activity. Despite this cellular mechanism, ... ...

Abstract	In response to oxidative stress, the nuclear factor E2-related factor 2 (Nrf2) transcription factor translocates from the cytoplasm into the nucleus and transactivates expression of genes with antioxidant activity. Despite this cellular mechanism, oxidative damage is abundant in Alzheimer and Parkinson disease (AD and PD). To investigate mechanisms by which Nrf2 activity may be aberrant or insufficient in neurodegenerative conditions, we assessed Nrf2 localization in affected brain regions of AD, Lewy body variant of AD (LBVAD), and PD. By immunohistochemistry, Nrf2 is expressed in both the nucleus and the cytoplasm of neurons in normal hippocampi with predominant expression in the nucleus. In AD and LBVAD, Nrf2 was predominantly cytoplasmic in hippocampal neurons and was not a major component of beta amyloid plaques or neurofibrillary tangles. By immunoblotting, we observed a significant decrease in nuclear Nrf2 levels in AD cases. In contrast, Nrf2 was strongly nuclear in PD nigral neurons but cytoplasmic in substantia nigra of normal, AD, and LBVAD cases. These findings suggest that Nrf2-mediated transcription is not induced in neurons in AD despite the presence of oxidative stress. In PD, nuclear localization of Nrf2 is strongly induced, but this response may be insufficient to protect neurons from degeneration.
MeSH term(s)	Aged ; Aged, 80 and over ; Case-Control Studies ; Cell Nucleus/metabolism ; Cytoplasm/metabolism ; Gene Expression/physiology ; Glial Fibrillary Acidic Protein/metabolism ; Hippocampus/metabolism ; Hippocampus/pathology ; Humans ; Immunohistochemistry/methods ; Microscopy, Confocal/methods ; Middle Aged ; NF-E2-Related Factor 2/metabolism ; Neurodegenerative Diseases/metabolism ; Neurodegenerative Diseases/pathology ; Neurodegenerative Diseases/physiopathology ; Neurons/metabolism ; Neurons/pathology ; Postmortem Changes ; Substantia Nigra/metabolism ; Substantia Nigra/pathology
Chemical Substances	Glial Fibrillary Acidic Protein ; NF-E2-Related Factor 2 ; NFE2L2 protein, human
Language	English
Publishing date	2007-01
Publishing country	England
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3088-0
ISSN	1554-6578 ; 0022-3069
ISSN (online)	1554-6578
ISSN	0022-3069
DOI	10.1097/nen.0b013e31802d6da9
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Article: Activation of cyclin-dependent kinase 5 by calpains contributes to human immunodeficiency virus-induced neurotoxicity.

Wang, Ying / White, Michael G / Akay, Cagla / Chodroff, Rebecca A / Robinson, Jonathan / Lindl, Kathryn A / Dichter, Marc A / Qian, Yang / Mao, Zixu / Kolson, Dennis L / Jordan-Sciutto, Kelly L

Journal of neurochemistry

2007 Volume 103, Issue 2, Page(s) 439–455

Abstract: Although the specific mechanism of neuronal damage in human immunodeficiency virus (HIV) -associated dementia is not known, a prominent role for NMDA receptor (NMDAR)-induced excitotoxicity has been demonstrated in neurons exposed to HIV-infected/ ... ...

Abstract	Although the specific mechanism of neuronal damage in human immunodeficiency virus (HIV) -associated dementia is not known, a prominent role for NMDA receptor (NMDAR)-induced excitotoxicity has been demonstrated in neurons exposed to HIV-infected/activated macrophages. We hypothesized NMDAR-mediated activation of the calcium-dependent protease, calpain, would contribute to cell death by induction of cyclin-dependent kinase 5 (CDK5) activity. Using an in vitro model of HIV neurotoxicity, in which primary rat cortical cultures are exposed to supernatants from primary human HIV-infected macrophages, we have observed increased calpain-dependent cleavage of the CDK5 regulatory subunit, p35, to the constitutively active isoform, p25. Formation of p25 is dependent upon NMDAR activation and calpain activity and is coincident with increased CDK5 activity in this model. Further, inhibition of CDK5 by roscovitine provided neuroprotection in our in vitro model. Consistent with our observations in vitro, we have observed a significant increase in calpain activity and p25 levels in midfrontal cortex of patients infected with HIV, particularly those with HIV-associated cognitive impairment. Taken together, our data suggest calpain activation of CDK5, a pathway activated in HIV-infected individuals, can mediate neuronal damage and death in a model of HIV-induced neurotoxicity.
MeSH term(s)	AIDS Dementia Complex/metabolism ; AIDS Dementia Complex/pathology ; Animals ; Blotting, Western ; Calpain/pharmacology ; Cell Count ; Cell Death ; Cells, Cultured ; Coloring Agents ; Cyclin-Dependent Kinase 5/metabolism ; Enzyme Activation/drug effects ; Enzyme-Linked Immunosorbent Assay ; HIV-1 ; Indicators and Reagents ; Mitogen-Activated Protein Kinase 1/metabolism ; Monocytes/chemistry ; Neurons/pathology ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate/drug effects ; Receptors, N-Methyl-D-Aspartate/physiology ; Reverse Transcriptase Polymerase Chain Reaction ; Subcellular Fractions/metabolism
Chemical Substances	Coloring Agents ; Indicators and Reagents ; Receptors, N-Methyl-D-Aspartate ; Cyclin-Dependent Kinase 5 (EC 2.7.11.1) ; Mitogen-Activated Protein Kinase 1 (EC 2.7.11.24) ; Calpain (EC 3.4.22.-)
Language	English
Publishing date	2007-10
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80158-6
ISSN	1471-4159 ; 0022-3042 ; 1474-1644
ISSN (online)	1471-4159
ISSN	0022-3042 ; 1474-1644
DOI	10.1111/j.1471-4159.2007.04746.x
Database	MEDical Literature Analysis and Retrieval System OnLINE

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