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Neuroprotective Effects of the Psychoactive Compound Biatractylolide (BD) in Alzheimer's Disease. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27238294. [PMID: 36500385 PMCID: PMC9737891 DOI: 10.3390/molecules27238294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 11/19/2022] [Accepted: 11/23/2022] [Indexed: 11/29/2022]
Abstract
Mitochondria play a central role in the survival or death of neuronal cells, and they are regulators of energy metabolism and cell death pathways. Many studies support the role of mitochondrial dysfunction and oxidative damage in the pathogenesis of Alzheimer's disease. Biatractylolide (BD) is a kind of internal symmetry double sesquiterpene novel ester compound isolated from the Chinese medicinal plant Baizhu, has neuroprotective effects in Alzheimer's disease. We developed a systematic pharmacological model based on chemical pharmacokinetic and pharmacological data to identify potential compounds and targets of Baizhu. The neuroprotective effects of BD in PC12 (rat adrenal pheochromocytoma cells) and SH-SY5Y (human bone marrow neuroblastoma cells) were evaluated by in vitro experiments. Based on the predicted results, we selected 18 active compounds, which were associated with 20 potential targets and 22 signaling pathways. Compound-target, target-disease and target-pathway networks were constructed using Cytoscape 3.2.1. And verified by in vitro experiments that BD could inhibit Aβ by reducing oxidative stress and decreasing CytC release induced mPTP opening. This study provides a theoretical basis for the development of BD as an anti-Alzheimer's disease drug.
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Gadhave K, Kumar D, Uversky VN, Giri R. A multitude of signaling pathways associated with Alzheimer's disease and their roles in AD pathogenesis and therapy. Med Res Rev 2021; 41:2689-2745. [PMID: 32783388 PMCID: PMC7876169 DOI: 10.1002/med.21719] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 07/13/2020] [Accepted: 07/29/2020] [Indexed: 02/06/2023]
Abstract
The exact molecular mechanisms associated with Alzheimer's disease (AD) pathology continue to represent a mystery. In the past decades, comprehensive data were generated on the involvement of different signaling pathways in the AD pathogenesis. However, the utilization of signaling pathways as potential targets for the development of drugs against AD is rather limited due to the immense complexity of the brain and intricate molecular links between these pathways. Therefore, finding a correlation and cross-talk between these signaling pathways and establishing different therapeutic targets within and between those pathways are needed for better understanding of the biological events responsible for the AD-related neurodegeneration. For example, autophagy is a conservative cellular process that shows link with many other AD-related pathways and is crucial for maintenance of the correct cellular balance by degrading AD-associated pathogenic proteins. Considering the central role of autophagy in AD and its interplay with many other pathways, the finest therapeutic strategy to fight against AD is the use of autophagy as a target. As an essential step in this direction, this comprehensive review represents recent findings on the individual AD-related signaling pathways, describes key features of these pathways and their cross-talk with autophagy, represents current drug development, and introduces some of the multitarget beneficial approaches and strategies for the therapeutic intervention of AD.
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Affiliation(s)
- Kundlik Gadhave
- School of Basic Sciences, Indian Institute of Technology Mandi, Kamand, Himachal Pradesh, 175005, India
| | - Deepak Kumar
- School of Basic Sciences, Indian Institute of Technology Mandi, Kamand, Himachal Pradesh, 175005, India
| | - Vladimir N. Uversky
- Department of Molecular Medicine and Byrd Alzheimer’s Research Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America
- Laboratory of New Methods in Biology, Institute for Biological Instrumentation, Russian Academy of Sciences, Pushchino, Moscow Region, Russia
| | - Rajanish Giri
- School of Basic Sciences, Indian Institute of Technology Mandi, Kamand, Himachal Pradesh, 175005, India
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3
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Borden EA, Furey M, Gattone NJ, Hambardikar VD, Liang XH, Scoma ER, Abou Samra A, D-Gary LR, Dennis DJ, Fricker D, Garcia C, Jiang Z, Khan SA, Kumarasamy D, Kuppala H, Ringrose S, Rosenheim EJ, Van Exel K, Vudhayagiri HS, Zhang J, Zhang Z, Guitart-Mampel M, Urquiza P, Solesio ME. Is there a link between inorganic polyphosphate (polyP), mitochondria, and neurodegeneration? Pharmacol Res 2021; 163:105211. [PMID: 33010423 PMCID: PMC7855267 DOI: 10.1016/j.phrs.2020.105211] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 09/08/2020] [Accepted: 09/15/2020] [Indexed: 12/14/2022]
Abstract
Mitochondrial dysfunction - including increased apoptosis, calcium and protein dyshomeostasis within the organelle, and dysfunctional bioenergetics and oxidative status - is a common, early feature in all the major neurodegenerative diseases, including Alzheimer's Disease (AD) and Parkinson's Disease (PD). However, the exact molecular mechanisms that drive the organelle to dysfunction and ultimately to failure in these conditions are still not well described. Different authors have shown that inorganic polyphosphate (polyP), an ancient and well-conserved molecule, plays a key role in the regulation of mitochondrial physiology under basal conditions. PolyP, which is present in all studied organisms, is composed of chains of orthophosphates linked together by highly energetic phosphoanhydride bonds, similar to those found in ATP. This polymer shows a ubiquitous distribution, even if a high co-localization with mitochondria has been reported. It has been proposed that polyP might be an alternative to ATP for cellular energy storage in different organisms, as well as the implication of polyP in the regulation of many of the mitochondrial processes affected in AD and PD, including protein and calcium homeostasis. Here, we conduct a comprehensive review and discussion of the bibliography available regarding the role of polyP in the mitochondrial dysfunction present in AD and PD. Taking into account the data presented in this review, we postulate that polyP could be a valid, innovative and, plausible pharmacological target against mitochondrial dysfunction in AD and PD. However, further research should be conducted to better understand the exact role of polyP in neurodegeneration, as well as the metabolism of the polymer, and the effect of different lengths of polyP on cellular and mitochondrial physiology.
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Affiliation(s)
- Emily A Borden
- Department of Biology, College of Arts and Sciences, Rutgers University, NJ, USA
| | - Matthew Furey
- Department of Biology, College of Arts and Sciences, Rutgers University, NJ, USA
| | - Nicholas J Gattone
- Department of Biology, College of Arts and Sciences, Rutgers University, NJ, USA
| | | | - Xiao Hua Liang
- Department of Biology, College of Arts and Sciences, Rutgers University, NJ, USA
| | - Ernest R Scoma
- Department of Biology, College of Arts and Sciences, Rutgers University, NJ, USA
| | - Antonella Abou Samra
- Department of Biology, College of Arts and Sciences, Rutgers University, NJ, USA
| | - LaKeshia R D-Gary
- Department of Biology, College of Arts and Sciences, Rutgers University, NJ, USA
| | - Dayshaun J Dennis
- Department of Biology, College of Arts and Sciences, Rutgers University, NJ, USA
| | - Daniel Fricker
- Department of Biology, College of Arts and Sciences, Rutgers University, NJ, USA
| | - Cindy Garcia
- Department of Biology, College of Arts and Sciences, Rutgers University, NJ, USA
| | - ZeCheng Jiang
- Department of Biology, College of Arts and Sciences, Rutgers University, NJ, USA
| | - Shariq A Khan
- Department of Biology, College of Arts and Sciences, Rutgers University, NJ, USA
| | | | - Hasmitha Kuppala
- Department of Biology, College of Arts and Sciences, Rutgers University, NJ, USA
| | - Savannah Ringrose
- Department of Biology, College of Arts and Sciences, Rutgers University, NJ, USA
| | - Evan J Rosenheim
- Department of Biology, College of Arts and Sciences, Rutgers University, NJ, USA
| | - Kimberly Van Exel
- Center for Computational and Integrative Biology, Rutgers University, NJ, USA
| | | | - Jiarui Zhang
- Center for Computational and Integrative Biology, Rutgers University, NJ, USA
| | - Zhaowen Zhang
- Department of Biology, College of Arts and Sciences, Rutgers University, NJ, USA
| | | | - Pedro Urquiza
- Department of Biology, College of Arts and Sciences, Rutgers University, NJ, USA
| | - Maria E Solesio
- Department of Biology, College of Arts and Sciences, Rutgers University, NJ, USA; Center for Computational and Integrative Biology, Rutgers University, NJ, USA.
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4
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Hawkins KE, Duchen M. Modelling mitochondrial dysfunction in Alzheimer’s disease using human induced pluripotent stem cells. World J Stem Cells 2019; 11:236-253. [PMID: 31171953 PMCID: PMC6545525 DOI: 10.4252/wjsc.v11.i5.236] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 02/22/2019] [Accepted: 03/26/2019] [Indexed: 02/06/2023] Open
Abstract
Alzheimer’s disease (AD) is the most common form of dementia. To date, only five pharmacological agents have been approved by the Food and Drug Administration for clinical use in AD, all of which target the symptoms of the disease rather than the cause. Increasing our understanding of the underlying pathophysiology of AD will facilitate the development of new therapeutic strategies. Over the years, the major hypotheses of AD etiology have focused on deposition of amyloid beta and mitochondrial dysfunction. In this review we highlight the potential of experimental model systems based on human induced pluripotent stem cells (iPSCs) to provide novel insights into the cellular pathophysiology underlying neurodegeneration in AD. Whilst Down syndrome and familial AD iPSC models faithfully reproduce features of AD such as accumulation of Aβ and tau, oxidative stress and mitochondrial dysfunction, sporadic AD is much more difficult to model in this way due to its complex etiology. Nevertheless, iPSC-based modelling of AD has provided invaluable insights into the underlying pathophysiology of the disease, and has a huge potential for use as a platform for drug discovery.
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Affiliation(s)
- Kate Elizabeth Hawkins
- Cell and Developmental Biology, Division of Biosciences, University College London, London WC1E 6BT, United Kingdom
| | - Michael Duchen
- Cell and Developmental Biology, Division of Biosciences, University College London, London WC1E 6BT, United Kingdom
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5
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Chornenkyy Y, Wang W, Wei A, Nelson PT. Alzheimer's disease and type 2 diabetes mellitus are distinct diseases with potential overlapping metabolic dysfunction upstream of observed cognitive decline. Brain Pathol 2019; 29:3-17. [PMID: 30106209 PMCID: PMC6427919 DOI: 10.1111/bpa.12655] [Citation(s) in RCA: 114] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Accepted: 08/09/2018] [Indexed: 12/13/2022] Open
Abstract
Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are highly prevalent aging-related diseases associated with significant morbidity and mortality. Some findings in human and animal models have linked T2DM to AD-type dementia. Despite epidemiological associations between the T2DM and cognitive impairment, the interrelational mechanisms are unclear. The preponderance of evidence in longitudinal studies with autopsy confirmation have indicated that vascular mechanisms, rather than classic AD-type pathologies, underlie the cognitive decline often seen in self-reported T2DM. T2DM is associated with cardiovascular and cerebrovascular disease (CVD), and is associated with increased risk of infarcts and small vessel disease in the brain and other organs. Neuropathological examinations of post-mortem brains demonstrated evidence of cerebrovascular disease and little to no correlation between T2DM and β-amyloid deposits or neurofibrillary tangles. Nevertheless, the mechanisms upstream of early AD-specific pathology remain obscure. In this regard, there may indeed be overlap between the pathologic mechanisms of T2DM/"metabolic syndrome," and AD. More specifically, cerebral insulin processing, glucose metabolism, mitochondrial function, and/or lipid metabolism could be altered in patients in early AD and directly influence symptomatology and/or neuropathology.
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Affiliation(s)
| | - Wang‐Xia Wang
- University of Kentucky College of MedicineLexingtonKY
- Sanders‐Brown Center on Aging, Department of PathologyUniversity of KentuckyLexingtonKY
| | - Angela Wei
- Department of BiologyUniversity of KentuckyLexingtonKY
| | - Peter T. Nelson
- University of Kentucky College of MedicineLexingtonKY
- Sanders‐Brown Center on Aging, Department of PathologyUniversity of KentuckyLexingtonKY
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6
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Cui H, Deng M, Zhang Y, Yin F, Liu J. Geniposide Increases Unfolded Protein Response-Mediating HRD1 Expression to Accelerate APP Degradation in Primary Cortical Neurons. Neurochem Res 2018; 43:669-680. [DOI: 10.1007/s11064-018-2469-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 12/03/2017] [Accepted: 01/08/2018] [Indexed: 02/20/2023]
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Kosenko EA, Tikhonova LA, Montoliu C, Barreto GE, Aliev G, Kaminsky YG. Metabolic Abnormalities of Erythrocytes as a Risk Factor for Alzheimer's Disease. Front Neurosci 2018; 11:728. [PMID: 29354027 PMCID: PMC5760569 DOI: 10.3389/fnins.2017.00728] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Accepted: 12/13/2017] [Indexed: 01/02/2023] Open
Abstract
Alzheimer's disease (AD) is a slowly progressive, neurodegenerative disorder of uncertain etiology. According to the amyloid cascade hypothesis, accumulation of non-soluble amyloid β peptides (Aβ) in the Central Nervous System (CNS) is the primary cause initiating a pathogenic cascade leading to the complex multilayered pathology and clinical manifestation of the disease. It is, therefore, not surprising that the search for mechanisms underlying cognitive changes observed in AD has focused exclusively on the brain and Aβ-inducing synaptic and dendritic loss, oxidative stress, and neuronal death. However, since Aβ depositions were found in normal non-demented elderly people and in many other pathological conditions, the amyloid cascade hypothesis was modified to claim that intraneuronal accumulation of soluble Aβ oligomers, rather than monomer or insoluble amyloid fibrils, is the first step of a fatal cascade in AD. Since a characteristic reduction of cerebral perfusion and energy metabolism occurs in patients with AD it is suggested that capillary distortions commonly found in AD brain elicit hemodynamic changes that alter the delivery and transport of essential nutrients, particularly glucose and oxygen to neuronal and glial cells. Another important factor in tissue oxygenation is the ability of erythrocytes (red blood cells, RBC) to transport and deliver oxygen to tissues, which are first of all dependent on the RBC antioxidant and energy metabolism, which finally regulates the oxygen affinity of hemoglobin. In the present review, we consider the possibility that metabolic and antioxidant defense alterations in the circulating erythrocyte population can influence oxygen delivery to the brain, and that these changes might be a primary mechanism triggering the glucose metabolism disturbance resulting in neurobiological changes observed in the AD brain, possibly related to impaired cognitive function. We also discuss the possibility of using erythrocyte biochemical aberrations as potential tools that will help identify a risk factor for AD.
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Affiliation(s)
- Elena A Kosenko
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russia
| | - Lyudmila A Tikhonova
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russia
| | - Carmina Montoliu
- Fundación Investigación Hospital Clínico, INCLIVA Instituto Investigación Sanitaria, Valencia, Spain
| | - George E Barreto
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, Colombia.,Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile
| | - Gjumrakch Aliev
- GALLY International Biomedical Research Institute Inc., San Antonio, TX, United States
| | - Yury G Kaminsky
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russia
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8
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Abstract
The ketone body beta-hydroxybutyrate (βHB) is a histone deacetylase (HDAC) inhibitor and has been shown to be protective in many disease models, but its effects on aging are not well studied. Therefore we determined the effect of βHB supplementation on the lifespan of C. elegans nematodes. βHB supplementation extended mean lifespan by approximately 20%. RNAi knockdown of HDACs hda-2 or hda-3 also increased lifespan and further prevented βHB-mediated lifespan extension. βHB-mediated lifespan extension required the DAF-16/FOXO and SKN-1/Nrf longevity pathways, the sirtuin SIR-2.1, and the AMP kinase subunit AAK-2. βHB did not extend lifespan in a genetic model of dietary restriction indicating that βHB is likely functioning through a similar mechanism. βHB addition also upregulated βHB dehydrogenase activity and increased oxygen consumption in the worms. RNAi knockdown of F55E10.6, a short chain dehydrogenase and SKN-1 target gene, prevented the increased lifespan and βHB dehydrogenase activity induced by βHB addition, suggesting that F55E10.6 functions as an inducible βHB dehydrogenase. Furthermore, βHB supplementation increased worm thermotolerance and partially prevented glucose toxicity. It also delayed Alzheimer's amyloid-beta toxicity and decreased Parkinson's alpha-synuclein aggregation. The results indicate that D-βHB extends lifespan through inhibiting HDACs and through the activation of conserved stress response pathways.
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9
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Staging of cognitive deficits and neuropathological and ultrastructural changes in streptozotocin-induced rat model of Alzheimer’s disease. J Neural Transm (Vienna) 2015; 122:577-92. [DOI: 10.1007/s00702-015-1394-4] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Accepted: 03/09/2015] [Indexed: 12/22/2022]
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10
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Rodrigues R, Petersen RB, Perry G. Parallels between major depressive disorder and Alzheimer's disease: role of oxidative stress and genetic vulnerability. Cell Mol Neurobiol 2014; 34:925-49. [PMID: 24927694 DOI: 10.1007/s10571-014-0074-5] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Accepted: 05/14/2014] [Indexed: 12/19/2022]
Abstract
The thesis of this review is that oxidative stress is the central factor in major depressive disorder (MDD) and Alzheimer's disease (AD). The major elements involved are inflammatory cytokines, the hypothalamic-pituitary axis, the hypothalamic-pituitary gonadal, and arginine vasopressin systems, which induce glucocorticoid and "oxidopamatergic" cascades when triggered by psychosocial stress, severe life-threatening events, and mental-affective and somatic diseases. In individuals with a genomic vulnerability to depression, these cascades may result in chronic depression-anxiety-stress spectra, resulting in MDD and other known depressive syndromes. In contrast, in subjects with genomic vulnerability to AD, oxidative stress-induced brain damage triggers specific antioxidant defenses, i.e., increased levels of amyloid-β (Aβ) and aggregation of hyper-phosphorylated tau, resulting in paired helical filaments and impaired functions related to the ApoEε4 isoform, leading to complex pathological cascades culminating in AD. Surprisingly, all the AD-associated molecular pathways mentioned in this review have been shown to be similar or analogous to those found in depression, including structural damage, i.e., hippocampal and frontal cortex atrophy. Other interacting molecular signals, i.e., GSK-3β, convergent survival factors (brain-derived neurotrophic factor and heat shock proteins), and transition redox metals are also mentioned to emphasize the vast array of intermediates that could interact via comparable mechanisms in both MDD and AD.
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Affiliation(s)
- Roberto Rodrigues
- College of Sciences, The University of Texas at San Antonio, One UTSA Circle, San Antonio, TX, 78249, USA,
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11
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Castellani RJ, Zhu X, Lee HG, Moreira PI, Perry G, Smith MA. Neuropathology and treatment of Alzheimer disease: did we lose the forest for the trees? Expert Rev Neurother 2014; 7:473-85. [PMID: 17492899 DOI: 10.1586/14737175.7.5.473] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Although amyloid-beta-containing senile plaques and phospho-tau containing neurofibrillary tangles are hallmark lesions of Alzheimer disease (AD), neither is specific for AD, nor even a marker of AD. Rather, they are empirical lesions that require close correlation with age and clinical signs for optimal interpretation. In essence, these lesions represent the effect rather than the cause of disease. In this review, we discuss diagnostic criteria for AD, the relationship between pathology, pathogenesis and multiple treatment approaches that have so far been disappointing, including those that presume to address pathological lesions. An acceptance that lesion-based therapies do not address etiology or rate-limiting pathogenic factors is probably necessary for the best chance of significant advances that have thus far been elusive.
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Affiliation(s)
- Rudy J Castellani
- University of Maryland, Department of Pathology, Baltimore, MD 21201, USA.
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12
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Ríčný J. Overlooked Alzheimer's smoking gun? Neurochem Res 2013; 38:1774-6. [PMID: 23743622 DOI: 10.1007/s11064-013-1086-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Revised: 05/21/2013] [Accepted: 05/23/2013] [Indexed: 12/24/2022]
Abstract
Overview of Szutowicz et al. (Neurochem Res 38(8):1523-1542, 2013), is focusing on specific features of acetyl-CoA metabolism in the cholinergic compartment of the brain. Authors are suggesting that deficit of that metabolite can act as a trigger for several cholinergic encephalopathies, with special emphasis on Alzheimer disease (AD). Central role of acetyl-CoA and its metabolic paths in neurodegeneration are charted starting from its synthesis in mitochondria, followed by utilization in energy metabolism, as well as transport into cytoplasm and participation in the synthesis and turnover of neurotransmitter acetylcholine to emergence of diseased states. Various putative pathogenic signals are evaluated that might be responsible for acetyl-CoA deficit ending up in development of neurodegeneration, unraveling exceptional susceptibility of cholinergic system. They are discussed in context of other existing alternative hypotheses on AD etiology. Overview is thoroughly documented (178 references) and is supported by results accomplished by extensive research in Prof. Szutowicz's laboratory (approximately 25 original papers).
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Affiliation(s)
- Jan Ríčný
- Laboratory of Biochemistry and Brain Pathophysiology, Prague Psychiatric Center, Ústavní 91, 181 03, Prague, Czech Republic.
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13
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Chaari A, Hoarau-Véchot J, Ladjimi M. Applying chaperones to protein-misfolding disorders: molecular chaperones against α-synuclein in Parkinson's disease. Int J Biol Macromol 2013; 60:196-205. [PMID: 23748003 DOI: 10.1016/j.ijbiomac.2013.05.032] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2013] [Revised: 05/28/2013] [Accepted: 05/29/2013] [Indexed: 02/04/2023]
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the accumulation of a protein called α-synuclein (α-syn) into inclusions known as lewy bodies (LB) within neurons. This accumulation is also due to insufficient formation and activity of dopamine produced in certain neurons within the substantia nigra. Lewy bodies are the pathological hallmark of the idiopathic disorder and the cascade that allows α-synuclein to misfold, aggregate and form these inclusions has been the subject of intensive research. Targeting these early steps of oligomerization is one of the main therapeutic approaches in order to develop neurodegenerative-modifying agents. Because the folding and refolding of alpha synuclein is the key point of this cascade, we are interested in this review to summarize the role of some molecular chaperones proteins such as Hsp70, Hsp90 and small heat shock proteins (sHsp) and Hsp 104. Hsp70 and its co-chaperone, Hsp70 and small heat shock proteins can prevent neurodegeneration by preventing α-syn misfolding, oligomerization and aggregation in vitro and in Parkinson disease animal models. Hsp104 is able to resolve disordered protein aggregates and cross beta amyloid conformers. Together, these chaperones have a complementary effect and can be a target for therapeutic intervention in PD.
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Affiliation(s)
- Ali Chaari
- Department of Biochemistry, Weill Cornell Medical College in Qatar, Qatar Foundation, Education City, Doha, Qatar.
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14
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Liu HY, Pfleger CM. Mutation in E1, the ubiquitin activating enzyme, reduces Drosophila lifespan and results in motor impairment. PLoS One 2013; 8:e32835. [PMID: 23382794 PMCID: PMC3558519 DOI: 10.1371/journal.pone.0032835] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2012] [Accepted: 01/31/2012] [Indexed: 11/21/2022] Open
Abstract
Neurodegenerative diseases cause tremendous suffering for those afflicted and their families. Many of these diseases involve accumulation of mis-folded or aggregated proteins thought to play a causal role in disease pathology. Ubiquitinated proteins are often found in these protein aggregates, and the aggregates themselves have been shown to inhibit the activity of the proteasome. These and other alterations in the Ubiquitin Pathway observed in neurodegenerative diseases have led to the question of whether impairment of the Ubiquitin Pathway on its own can increase mortality or if ongoing neurodegeneration alters Ubiquitin Pathway function as a side-effect. To address the role of the Ubiquitin Pathway in vivo, we studied loss-of-function mutations in the Drosophila Ubiquitin Activating Enzyme, Uba1 or E1, the most upstream enzyme in the Ubiquitin Pathway. Loss of only one functional copy of E1 caused a significant reduction in adult lifespan. Rare homozygous hypomorphic E1 mutants reached adulthood. These mutants exhibited further reduced lifespan and showed inappropriate Ras activation in the brain. Removing just one functional copy of Ras restored the lifespan of heterozygous E1 mutants to that of wild-type flies and increased the survival of homozygous E1 mutants. E1 homozygous mutants also showed severe motor impairment. Our findings suggest that processes that impair the Ubiquitin Pathway are sufficient to cause early mortality. Reduced lifespan and motor impairment are seen in the human disease X-linked Infantile Spinal Muscular Atrophy, which is associated with mutation in human E1 warranting further analysis of these mutants as a potential animal model for study of this disease.
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Affiliation(s)
- Hsiu-Yu Liu
- Department of Oncological Sciences, The Mount Sinai School of Medicine, New York, New York, United States of America
| | - Cathie M. Pfleger
- Department of Oncological Sciences, The Mount Sinai School of Medicine, New York, New York, United States of America
- * E-mail:
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15
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Guo C, Wang P, Zhong ML, Wang T, Huang XS, Li JY, Wang ZY. Deferoxamine inhibits iron induced hippocampal tau phosphorylation in the Alzheimer transgenic mouse brain. Neurochem Int 2012; 62:165-72. [PMID: 23262393 DOI: 10.1016/j.neuint.2012.12.005] [Citation(s) in RCA: 153] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2012] [Revised: 11/21/2012] [Accepted: 12/10/2012] [Indexed: 01/19/2023]
Abstract
Prior work has shown that iron interacts with hyperphosphorylated tau, which contributes to the formation of neurofibrillary tangles (NFTs) in Alzheimer's disease (AD), whereas iron chelator desferrioxamine (DFO) slows down the clinical progression of the cognitive decline associated with this disease. However, the effects of DFO on tau phosphorylation in the presence or absence of iron have yet to be determined. Using amyloid precursor protein (APP) and presenilin 1 (PS1) double transgenic mouse brain as a model system, we investigated the effects and potential mechanisms of intranasal administration of DFO on iron induced abnormal tau phosphorylation. High-dose iron treatment markedly increased the levels of tau phosphorylation at the sites of Thr205, Thr231 and Ser396, whereas highly induced tau phosphorylation was abolished by intranasal administration of DFO in APP/PS1 transgenic mice. Moreover, DFO intranasal administration also decreases Fe-induced the activities of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3β (GSK3β), which in turn suppressing tau phosphorylation. Cumulatively, our data show that intranasal DFO treatment exerts its suppressive effects on iron induced tau phosphorylation via CDK5 and GSK3β pathways. More importantly, elucidation of DFO mechanism in suppressing tau phosphorylation may provide insights for developing therapeutic strategies to combat AD.
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Affiliation(s)
- Chuang Guo
- College of Life and Health Sciences, Northeastern University, Shenyang 110004, PR China
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16
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Jameson LP, Smith NW, Dzyuba SV. Dye-binding assays for evaluation of the effects of small molecule inhibitors on amyloid (aβ) self-assembly. ACS Chem Neurosci 2012; 3:807-19. [PMID: 23173064 DOI: 10.1021/cn300076x] [Citation(s) in RCA: 106] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2012] [Accepted: 08/06/2012] [Indexed: 01/07/2023] Open
Abstract
Dye-binding assays, such as those utilizing Congo red and thioflavin T, are among the most widely used tools to probe the aggregation of amyloidogenic biomolecules and for the evaluation of small molecule inhibitors of amyloid aggregation and fibrillization. A number of recent reports have indicated that these dye-binding assays could be prone to false positive effects when assessing inhibitors' potential toward Aβ peptides, species involved in Alzheimer's disease. Specifically, this review focuses on the application of thioflavin T for determining the efficiency of small molecule inhibitors of Aβ aggregation and addresses potential reasons that might be associated with the false positive effects in an effort to increase reliability of dye-binding assays.
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Affiliation(s)
- Laramie P. Jameson
- Department of Chemistry, Texas Christian University, Fort Worth, Texas 76129, United States
| | - Nicholas W. Smith
- Department of Chemistry, Texas Christian University, Fort Worth, Texas 76129, United States
| | - Sergei V. Dzyuba
- Department of Chemistry, Texas Christian University, Fort Worth, Texas 76129, United States
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17
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APOE and neuroenergetics: an emerging paradigm in Alzheimer's disease. Neurobiol Aging 2012; 34:1007-17. [PMID: 23159550 DOI: 10.1016/j.neurobiolaging.2012.10.011] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2012] [Revised: 10/13/2012] [Accepted: 10/15/2012] [Indexed: 12/29/2022]
Abstract
APOE is the major known genetic risk factor for late-onset Alzheimer's disease. Though relationships between APOE-encoded apolipoprotein E and β-amyloid are increasingly well described, mounting evidence supports wide-ranging effects of APOE on the brain. Specifically, APOE appears to affect brain network activity and closely related neuroenergetic functions that might be involved in vulnerability to neurodegenerative pathophysiology. These effects highlight the salience of further investigation into the diverse influences of APOE. Therefore, this article reviews the interplay between APOE and neuroenergetics and proposes areas for further investigation. This research might lead to the identification of novel therapeutic targets for the treatment and/or prevention of Alzheimer's disease.
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18
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Swerdlow RH. Alzheimer's disease pathologic cascades: who comes first, what drives what. Neurotox Res 2011; 22:182-94. [PMID: 21913048 DOI: 10.1007/s12640-011-9272-9] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2011] [Revised: 08/25/2011] [Accepted: 08/30/2011] [Indexed: 12/21/2022]
Abstract
This review discusses known and speculated relationships between Alzheimer's disease (AD) biochemical, molecular, and histologic phenomena. In the AD brain, various pathologies including neuritic plaques, neurofibrillary tangles, synaptic loss, oxidative stress, cell cycle re-entry, and mitochondrial changes have all been described. In an attempt to explain what exactly goes wrong in the AD brain various investigators have proposed different heuristic and hierarchical schemes. It is important to accurately define the AD pathology hierarchy because treatments targeting the true apex of its pathologic cascade arguably have the best chance of preventing, mitigating, or even curing this disease.
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Affiliation(s)
- Russell H Swerdlow
- Department of Neurology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
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19
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Conejero-Goldberg C, Hyde TM, Chen S, Dreses-Werringloer U, Herman MM, Kleinman JE, Davies P, Goldberg TE. Molecular signatures in post-mortem brain tissue of younger individuals at high risk for Alzheimer's disease as based on APOE genotype. Mol Psychiatry 2011; 16:836-47. [PMID: 20479757 PMCID: PMC2953572 DOI: 10.1038/mp.2010.57] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2010] [Revised: 03/17/2010] [Accepted: 04/12/2010] [Indexed: 11/09/2022]
Abstract
Alzheimer's disease (AD) is a neurodegenerative condition characterized histopathologically by neuritic plaques and neurofibrillary tangles. The objective of this transcriptional profiling study was to identify both neurosusceptibility and intrinsic neuroprotective factors at the molecular level, not confounded by the downstream consequences of pathology. We thus studied post-mortem cortical tissue in 28 cases that were non-APOE4 carriers (called the APOE3 group) and 13 cases that were APOE4 carriers. As APOE genotype is the major genetic risk factor for late-onset AD, the former group was at low risk for development of the disease and the latter group was at high risk for the disease. Mean age at death was 42 years and none of the brains had histopathology diagnostic of AD at the time of death. We first derived interregional difference scores in expression between cortical tissue from a region relatively invulnerable to AD (primary somatosensory cortex, BA 1/2/3) and an area known to be susceptible to AD pathology (middle temporal gyrus, BA 21). We then contrasted the magnitude of these interregional differences in between-group comparisons of the APOE3 (low risk) and APOE4 (high risk) genotype groups. We identified 70 transcripts that differed significantly between the groups. These included EGFR, CNTFR, CASP6, GRIA2, CTNNB1, FKBPL, LGALS1 and PSMC5. Using real-time quantitative PCR, we validated these findings. In addition, we found regional differences in the expression of APOE itself. We also identified multiple Kyoto pathways that were disrupted in the APOE4 group, including those involved in mitochondrial function, calcium regulation and cell-cycle reentry. To determine the functional significance of our transcriptional findings, we used bioinformatics pathway analyses to demonstrate that the molecules listed above comprised a network of connections with each other, APOE, and APP and MAPT. Overall, our results indicated that the abnormalities that we observed in single transcripts and in signaling pathways were not the consequences of diagnostic plaque and tangle pathology, but preceded it and thus may be a causative link in the long molecular prodrome that results in clinical AD.
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Affiliation(s)
- C Conejero-Goldberg
- The Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
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20
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del Valle J, Duran-Vilaregut J, Manich G, Pallàs M, Camins A, Vilaplana J, Pelegrí C. Cerebral amyloid angiopathy, blood-brain barrier disruption and amyloid accumulation in SAMP8 mice. NEURODEGENER DIS 2011; 8:421-9. [PMID: 21411981 DOI: 10.1159/000324757] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2010] [Accepted: 02/01/2011] [Indexed: 01/09/2023] Open
Abstract
Cerebrovascular dysfunction and β-amyloid peptide deposition on the walls of cerebral blood vessels might be an early event in the development of Alzheimer's disease. Here we studied the time course of amyloid deposition in blood vessels and blood-brain barrier (BBB) disruption in the CA1 subzone of the hippocampus of SAMP8 mice and the association between these two variables. We also studied the association between the amyloid deposition in blood vessels and the recently described amyloid clusters in the parenchyma, as well as the association of these clusters with vessels in which the BBB is disrupted. SAMP8 mice showed greater amyloid deposition in blood vessels than age-matched ICR-CD1 control mice. Moreover, at 12 months of age the number of vessels with a disrupted BBB had increased in both strains, especially SAMP8 animals. At this age, all the vessels with amyloid deposition showed BBB disruption, but several capillaries with an altered BBB showed no amyloid on their walls. Moreover, amyloid clusters showed no spatial association with vessels with amyloid deposition, nor with vessels in which the BBB had been disrupted. Finally, we can conclude that vascular amyloid deposition seems to induce BBB alterations, but BBB disruption may also be due to other factors.
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Affiliation(s)
- Jaume del Valle
- Departament de Fisiologia, Facultat de Farmàcia, Barcelona, Spain
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21
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Humpel C. Chronic mild cerebrovascular dysfunction as a cause for Alzheimer's disease? Exp Gerontol 2010; 46:225-32. [PMID: 21112383 PMCID: PMC3070802 DOI: 10.1016/j.exger.2010.11.032] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2010] [Revised: 11/17/2010] [Accepted: 11/19/2010] [Indexed: 02/08/2023]
Abstract
Alzheimer's disease (AD) is a progressive chronic disorder and is characterized by β-amyloid plaques and angiopathy, tau pathology, neuronal cell death, and inflammatory responses. The reasons for this disease are not known. This review proposes the hypothesis that a chronic mild longlasting cerebrovascular dysfunction could initiate a cascade of events leading to AD. It is suggested that (vascular) risk factors (e.g. hypercholesterolemia, type 2 diabetes, hyperhomocysteinemia) causes either damage of the cerebrovascular system including silent strokes or causes dysregulation of beta-amyloid clearance at the blood-brain barrier resulting in increased brain beta-amyloid. A cascade of subsequent downstream events may lead to disturbed metabolic changes, and neuroinflammation and tau pathology. The role of NGF on the cell death of cholinergic neurons is discussed. Additional risk factors (e.g. acidosis, metals) contribute to plaque development.
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Affiliation(s)
- Christian Humpel
- Laboratory of Psychiatry and Exp. Alzheimers Research, Department of Psychiatry and Psychotherapy, Innsbruck Medical University, Austria.
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22
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Grimm S, Hoehn A, Davies KJ, Grune T. Protein oxidative modifications in the ageing brain: consequence for the onset of neurodegenerative disease. Free Radic Res 2010; 45:73-88. [PMID: 20815785 DOI: 10.3109/10715762.2010.512040] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The free radical theory of ageing proposes the accumulation of altered, less active and toxic molecules of DNA, RNA, proteins and lipids caused by reactive oxygen species and reactive nitrogen species. Neurodegenerative disorders are characterized by an abnormal accumulation of oxidatively damaged macromolecules inside cells and in the extracellular space. Proteins involved in the formation of aggregates are β-amyloid, tau, α-synuclein, parkin, prion proteins and proteins containing polyglutamine. These abnormal aggregated proteins influence normal cellular metabolism. Additionally, deposition of abnormal proteins induces oxidative stress and proteasomal as well as mitochondrial dysfunction that ultimately lead to neuronal cell death. This review focuses on the impact of oxidative and nitrative stress in the ageing brain and, consequently, on the generation of modified proteins, as these post-translational modifications are assumed to play an important role in the development of neurodegenerative diseases.
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Affiliation(s)
- Stefanie Grimm
- Institute of Nutrition, Friedrich Schiller University Jena, Dornburger Straße 24, 07743 Jena, Germany
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23
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Candore G, Balistreri CR, Colonna-Romano G, Lio D, Listì F, Vasto S, Caruso C. Gender-Related Immune-Inflammatory Factors, Age-Related Diseases, and Longevity. Rejuvenation Res 2010; 13:292-7. [DOI: 10.1089/rej.2009.0942] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Affiliation(s)
- Giuseppina Candore
- Immunesenescence Unit, Department of Pathobiology and Biomedical Methodology, University of Palermo, Italy
| | - Carmela Rita Balistreri
- Immunesenescence Unit, Department of Pathobiology and Biomedical Methodology, University of Palermo, Italy
| | - Giuseppina Colonna-Romano
- Immunesenescence Unit, Department of Pathobiology and Biomedical Methodology, University of Palermo, Italy
| | - Domenico Lio
- Immunesenescence Unit, Department of Pathobiology and Biomedical Methodology, University of Palermo, Italy
| | - Florinda Listì
- Immunesenescence Unit, Department of Pathobiology and Biomedical Methodology, University of Palermo, Italy
| | - Sonya Vasto
- Immunesenescence Unit, Department of Pathobiology and Biomedical Methodology, University of Palermo, Italy
| | - Calogero Caruso
- Immunesenescence Unit, Department of Pathobiology and Biomedical Methodology, University of Palermo, Italy
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24
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Krüger J, Hinttala R, Majamaa K, Remes AM. Mitochondrial DNA haplogroups in early-onset Alzheimer's disease and frontotemporal lobar degeneration. Mol Neurodegener 2010; 5:8. [PMID: 20181062 PMCID: PMC2830999 DOI: 10.1186/1750-1326-5-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2009] [Accepted: 02/02/2010] [Indexed: 05/26/2023] Open
Abstract
Background Mitochondrial dysfunction, oxidative damage and the accumulation of somatic mutations in mitochondrial DNA (mtDNA) have been associated with certain neurodegenerative disorders. Previous studies have also provided controversial results on the association of mtDNA haplogroups with susceptibility to Alzheimer's disease (AD), but possible relationships between mtDNA and frontotemporal lobar degeneration (FTLD) have been less frequently studied. Methods We analysed the role of mtDNA and its maintenance enzymes in 128 early-onset AD (eoAD) and in 66 FTLD cases. Patients and 99 controls were collected from a defined region of Finland, that of Northern Ostrobothnia, for the determination of mtDNA haplogroups and the analysis of two common mtDNA mutations (m.3243A>G, m.8344A>G). In addition, screening was performed for five common POLG1 mutations (T251I, A467T, P587L, W748S and Y955C) and all the coding exons of the PEO1 and ANT1 genes were screened for mutations. Results The frequency of haplogroup cluster IWX was 2.3 fold higher among the FTLD cases than in the controls (OR 2.69, 95% CI 1.09-6.65, p = 0.028). The frequency of mtDNA haplogroups or clusters did not differ between the eoAD cases and controls. The two mtDNA mutations and five POLG1 mutations were absent in the eoAD and FTLD patients. No pathogenic mutations were found in the PEO1 or ANT1 genes. Conclusions We conclude that the haplogroup cluster IWX was associated with FTLD in our cohort. Further studies in other ethnically distinct cohorts are needed to clarify the contribution of mtDNA haplogroups to FTLD and AD.
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Affiliation(s)
- Johanna Krüger
- Institute of Clinical Medicine, Neurology, University of Oulu, Oulu, Finland.
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25
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Du H, Yan SS. Mitochondrial permeability transition pore in Alzheimer's disease: cyclophilin D and amyloid beta. BIOCHIMICA ET BIOPHYSICA ACTA 2010; 1802:198-204. [PMID: 19616093 PMCID: PMC3280723 DOI: 10.1016/j.bbadis.2009.07.005] [Citation(s) in RCA: 178] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/31/2009] [Revised: 07/06/2009] [Accepted: 07/07/2009] [Indexed: 10/20/2022]
Abstract
Amyloid beta (Abeta) plays a critical role in the pathophysiology of Alzheimer's disease. Increasing evidence indicates mitochondria as an important target of Abeta toxicity; however, the effects of Abeta toxicity on mitochondria have not yet been fully elucidated. Recent biochemical studies in vivo and in vitro implicate mitochondrial permeability transition pore (mPTP) formation involvement in Abeta-mediated mitochondrial dysfunction. mPTP formation results in severe mitochondrial dysfunction such as reactive oxygen species (ROS) generation, mitochondrial membrane potential dissipation, intracellular calcium perturbation, decrease in mitochondrial respiration, release of pro-apoptotic factors and eventually cell death. Cyclophilin D (CypD) is one of the more well-known mPTP components and recent findings reveal that Abeta has significant impact on CypD-mediated mPTP formation. In this review, the role of Abeta in the formation of mPTP and the potential of mPTP inhibition as a therapeutic strategy in AD treatment are examined.
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Affiliation(s)
- Heng Du
- Departments of Pathology and Cell Biology, Surgery, and The Taub institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons of Columbia University, 630 W. 168th Street, New York, NY 10032, USA
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26
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Estradiol and neurodegenerative oxidative stress. Front Neuroendocrinol 2008; 29:463-75. [PMID: 18275991 DOI: 10.1016/j.yfrne.2007.12.005] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2007] [Revised: 12/20/2007] [Accepted: 12/25/2007] [Indexed: 11/24/2022]
Abstract
Estradiol is a potent preventative against neurodegenerative disease, in part, by activating antioxidant defense systems scavenging reactive oxygen species, limiting mitochondrial protein damage, improving electron transport chain activity and reducing mitochondrial DNA damage. Estradiol also increases the activity of complex IV of the electron transport chain, improving mitochondrial respiration and ATP production under normal and stressful conditions. However, the high oxidative cellular environment present during neurodegeneration makes estradiol a poor agent for treatment of existing disease. Oxidative stress stimulates the production of the hydroperoxide-dependent hydroxylation of estradiol to the catecholestrogen metabolites, which can undergo reactive oxygen species producing redox cycling, setting up a self-generating toxic cascade offsetting any antioxidant/antiapoptotic effects generated by the parent estradiol. Additional disease-induced factors can further perpetuate this cycle. For example dysregulation of the catecholamine system could alter catechol-O-methyltransferase-catalyzed methylation, preventing removal of redox cycling catecholestrogens from the system enhancing pro-oxidant effects of estradiol.
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27
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Parihar MS, Kunz EA, Brewer GJ. Age-related decreases in NAD(P)H and glutathione cause redox declines before ATP loss during glutamate treatment of hippocampal neurons. J Neurosci Res 2008; 86:2339-52. [PMID: 18438923 DOI: 10.1002/jnr.21679] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Age-related glutamate excitotoxicity depends in an unknown manner on active mitochondria, which are key determinants of the cellular redox potential. Compared with embryonic and middle-aged neurons, old-aged rat hippocampal neurons have a lower resting reduced nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) and a lower redox ratio (NAD(P)H/flavin adenine nucleotide). Glutamate treatment resulted in an initial increase in NAD(P)H concentrations in all ages, followed by a profound calcium-dependent, age-related decline in NAD(P)H concentration and redox ratio. With complex I of the electron transport chain inhibited by rotenone, treatment with glutamate or ionomycin only resulted in the increase in NAD(P)H fluorescence. High-performance liquid chromatography analysis of adenine nucleotides in brain extracts showed 50% less nicotinamide adenine dinucleotide (NADH) and almost twice as much oxidized nicotinamide adenine dinucleotide, demonstrating a more oxidized ratio in old than middle-aged brain. Resting glutathione content also declined with age and further decreased with glutamate treatment without accompanying changes in adenosine triphosphate levels. We conclude that age does not affect production of NADH by dehydrogenases but that old-aged neurons consume more NADH and glutathione, leading to a catastrophic decline in redox ratio.
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Affiliation(s)
- Mordhwaj S Parihar
- Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois 62794-9626, USA
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28
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Wadsworth TL, Bishop JA, Pappu AS, Woltjer RL, Quinn JF. Evaluation of coenzyme Q as an antioxidant strategy for Alzheimer's disease. J Alzheimers Dis 2008; 14:225-34. [PMID: 18560133 PMCID: PMC2931577 DOI: 10.3233/jad-2008-14210] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Increasing evidence suggests that Alzheimer's disease (AD) is associated with oxidative damage that is caused in part by mitochondrial dysfunction. Here we investigated the feasibility of modifying Alzheimer pathology with the mitochondrial antioxidant coenzyme Q (CoQ). Exogenous CoQ protected MC65 neuroblastoma cells from amyloid-beta protein precursor C-terminal fragment (APP CTF)-induced neurotoxicity in a concentration dependent manner, with concentrations of 6.25 microM and higher providing near complete protection. Dietary supplementation with CoQ at a dose of 10 g/kg diet to C65/Bl6 mice for one month significantly suppressed brain protein carbonyl levels, which are markers of oxidative damage. Treatment for one month with 2 g lovastatin/kg diet, which interferes with CoQ synthesis, resulted in a significant lowering of brain CoQ10 levels. Mitochondrial energetics (brain ATP levels and mitochondrial membrane potential) were unaffected by either CoQ or lovastatin treatment. Our results suggest that oral CoQ may be a viable antioxidant strategy for neurodegenerative disease. Our data supports a trial of CoQ in an animal model of AD in order to determine whether a clinical trial is warranted.
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Affiliation(s)
- Teri L Wadsworth
- Department of Neurology, Oregon Health & Science University, Portland, OR 97239-3098, USA.
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29
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Stopa EG, Butala P, Salloway S, Johanson CE, Gonzalez L, Tavares R, Hovanesian V, Hulette CM, Vitek MP, Cohen RA. Cerebral Cortical Arteriolar Angiopathy, Vascular Beta-Amyloid, Smooth Muscle Actin, Braak Stage, and
APOE
Genotype. Stroke 2008; 39:814-21. [DOI: 10.1161/strokeaha.107.493429] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- Edward G. Stopa
- From the Departments of Pathology (E.G.S., P.B., R.T., V.H.), Psychiatry and Human Behavior (S.S., R.A.C.), and Clinical Neurosciences (E.G.S., S.S., C.E.J.), Warren Alpert Medical School of Brown University, Providence, RI; the Department of Computer Science and Statistics (L.G.), University of Rhode Island, Kingston, RI; and Departments of Medicine (Neurology Division) and Pathology (Neuropathology Division) (C.M.H., M.P.V.), Bryan Alzheimer Disease Research Center, Duke University School of
| | - Parag Butala
- From the Departments of Pathology (E.G.S., P.B., R.T., V.H.), Psychiatry and Human Behavior (S.S., R.A.C.), and Clinical Neurosciences (E.G.S., S.S., C.E.J.), Warren Alpert Medical School of Brown University, Providence, RI; the Department of Computer Science and Statistics (L.G.), University of Rhode Island, Kingston, RI; and Departments of Medicine (Neurology Division) and Pathology (Neuropathology Division) (C.M.H., M.P.V.), Bryan Alzheimer Disease Research Center, Duke University School of
| | - Stephen Salloway
- From the Departments of Pathology (E.G.S., P.B., R.T., V.H.), Psychiatry and Human Behavior (S.S., R.A.C.), and Clinical Neurosciences (E.G.S., S.S., C.E.J.), Warren Alpert Medical School of Brown University, Providence, RI; the Department of Computer Science and Statistics (L.G.), University of Rhode Island, Kingston, RI; and Departments of Medicine (Neurology Division) and Pathology (Neuropathology Division) (C.M.H., M.P.V.), Bryan Alzheimer Disease Research Center, Duke University School of
| | - Conrad E. Johanson
- From the Departments of Pathology (E.G.S., P.B., R.T., V.H.), Psychiatry and Human Behavior (S.S., R.A.C.), and Clinical Neurosciences (E.G.S., S.S., C.E.J.), Warren Alpert Medical School of Brown University, Providence, RI; the Department of Computer Science and Statistics (L.G.), University of Rhode Island, Kingston, RI; and Departments of Medicine (Neurology Division) and Pathology (Neuropathology Division) (C.M.H., M.P.V.), Bryan Alzheimer Disease Research Center, Duke University School of
| | - Liliana Gonzalez
- From the Departments of Pathology (E.G.S., P.B., R.T., V.H.), Psychiatry and Human Behavior (S.S., R.A.C.), and Clinical Neurosciences (E.G.S., S.S., C.E.J.), Warren Alpert Medical School of Brown University, Providence, RI; the Department of Computer Science and Statistics (L.G.), University of Rhode Island, Kingston, RI; and Departments of Medicine (Neurology Division) and Pathology (Neuropathology Division) (C.M.H., M.P.V.), Bryan Alzheimer Disease Research Center, Duke University School of
| | - Rosemarie Tavares
- From the Departments of Pathology (E.G.S., P.B., R.T., V.H.), Psychiatry and Human Behavior (S.S., R.A.C.), and Clinical Neurosciences (E.G.S., S.S., C.E.J.), Warren Alpert Medical School of Brown University, Providence, RI; the Department of Computer Science and Statistics (L.G.), University of Rhode Island, Kingston, RI; and Departments of Medicine (Neurology Division) and Pathology (Neuropathology Division) (C.M.H., M.P.V.), Bryan Alzheimer Disease Research Center, Duke University School of
| | - Virginia Hovanesian
- From the Departments of Pathology (E.G.S., P.B., R.T., V.H.), Psychiatry and Human Behavior (S.S., R.A.C.), and Clinical Neurosciences (E.G.S., S.S., C.E.J.), Warren Alpert Medical School of Brown University, Providence, RI; the Department of Computer Science and Statistics (L.G.), University of Rhode Island, Kingston, RI; and Departments of Medicine (Neurology Division) and Pathology (Neuropathology Division) (C.M.H., M.P.V.), Bryan Alzheimer Disease Research Center, Duke University School of
| | - Christine M. Hulette
- From the Departments of Pathology (E.G.S., P.B., R.T., V.H.), Psychiatry and Human Behavior (S.S., R.A.C.), and Clinical Neurosciences (E.G.S., S.S., C.E.J.), Warren Alpert Medical School of Brown University, Providence, RI; the Department of Computer Science and Statistics (L.G.), University of Rhode Island, Kingston, RI; and Departments of Medicine (Neurology Division) and Pathology (Neuropathology Division) (C.M.H., M.P.V.), Bryan Alzheimer Disease Research Center, Duke University School of
| | - Michael P. Vitek
- From the Departments of Pathology (E.G.S., P.B., R.T., V.H.), Psychiatry and Human Behavior (S.S., R.A.C.), and Clinical Neurosciences (E.G.S., S.S., C.E.J.), Warren Alpert Medical School of Brown University, Providence, RI; the Department of Computer Science and Statistics (L.G.), University of Rhode Island, Kingston, RI; and Departments of Medicine (Neurology Division) and Pathology (Neuropathology Division) (C.M.H., M.P.V.), Bryan Alzheimer Disease Research Center, Duke University School of
| | - Ronald A. Cohen
- From the Departments of Pathology (E.G.S., P.B., R.T., V.H.), Psychiatry and Human Behavior (S.S., R.A.C.), and Clinical Neurosciences (E.G.S., S.S., C.E.J.), Warren Alpert Medical School of Brown University, Providence, RI; the Department of Computer Science and Statistics (L.G.), University of Rhode Island, Kingston, RI; and Departments of Medicine (Neurology Division) and Pathology (Neuropathology Division) (C.M.H., M.P.V.), Bryan Alzheimer Disease Research Center, Duke University School of
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Rak M, Del Bigio MR, Mai S, Westaway D, Gough K. Dense-core and diffuse Abeta plaques in TgCRND8 mice studied with synchrotron FTIR microspectroscopy. Biopolymers 2007; 87:207-17. [PMID: 17680701 DOI: 10.1002/bip.20820] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Plaques composed of the Abeta peptide are the main pathological feature of Alzheimer's disease. Dense-core plaques are fibrillar deposits of Abeta, showing all the classical properties of amyloid including beta-sheet secondary structure, while diffuse plaques are amorphous deposits. We studied both plaque types, using synchrotron infrared (IR) microspectroscopy, a technique that allows the chemical composition and average protein secondary structure to be investigated in situ. We examined plaques in hippocampal, cortical and caudal tissue from 5- to 21-month-old TgCRND8 mice, a transgenic model expressing doubly mutant amyloid precursor protein, and displaying impaired hippocampal function and robust pathology from an early age. Spectral analysis confirmed that the congophilic plaque cores were composed of protein in a beta-sheet conformation. The amide I maximum of plaque cores was at 1623 cm(-1), and unlike for in vitro Abeta fibrils, the high-frequency (1680-1690 cm(-1)) component attributed to antiparallel beta-sheet was not observed. A significant elevation in phospholipids was found around dense-core plaques in TgCRND8 mice ranging in age from 5 to 21 months. In contrast, diffuse plaques were not associated with IR detectable changes in protein secondary structure or relative concentrations of any other tissue components.
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Affiliation(s)
- Margaret Rak
- Department of Chemistry, University of Manitoba, Winnipeg, MB, Canada R3T 2N2
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31
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Fesahat F, Houshmand M, Panahi MSS, Gharagozli K, Mirzajani F. Do haplogroups H and U act to increase the penetrance of Alzheimer's disease? Cell Mol Neurobiol 2007; 27:329-34. [PMID: 17186363 PMCID: PMC11881813 DOI: 10.1007/s10571-006-9126-9] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2006] [Accepted: 10/06/2006] [Indexed: 11/26/2022]
Abstract
1. Alzheimer's disease (AD) is the most common form of dementia in the elderly in which interplay between genes and the environment is supposed to be involved. Mitochondrial DNA (mtDNA) has the only noncoding regions at the displacement loop (D-loop) region that contains two hypervariable segments (HVS-I and HVS-II) with high polymorphism. mtDNA has already been fully sequenced and many subsequent publications have shown polymorphic sites, haplogroups, and haplotypes. Haplogroups could have important implications to understand the association between mutability of the mitochondrial genome and the disease.2. To assess the relationship between mtDNA haplogroup and AD, we sequenced the mtDNA HVS-I in 30 AD patients and 100 control subjects. We could find that haplogroups H and U are significantly more abundant in AD patients (P = 0.016 for haplogroup H and P = 0.0003 for haplogroup U), Thus, these two haplogroups might act synergistically to increase the penetrance of AD disease.
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Affiliation(s)
- Farzaneh Fesahat
- Khatam University, Tehran, Iran
- Department of Medical Genetics, National Institute for Genetic Engineering and Biotechnology, Tehran, Iran
| | - Massoud Houshmand
- Department of Medical Genetics, National Institute for Genetic Engineering and Biotechnology, Tehran, Iran
- Department of Medical Genetics, National Institute for Genetic Engineering and Biotechnology, P.O. Box 14155-6343, Tehran, Iran
| | - Mehdi Shafa Shariat Panahi
- Department of Medical Genetics, National Institute for Genetic Engineering and Biotechnology, Tehran, Iran
| | | | - Farzaneh Mirzajani
- Department of Medical Genetics, National Institute for Genetic Engineering and Biotechnology, Tehran, Iran
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Zhang S, Zhang Z, Sandhu G, Ma X, Yang X, Geiger JD, Kong J. Evidence of oxidative stress-induced BNIP3 expression in amyloid beta neurotoxicity. Brain Res 2007; 1138:221-30. [PMID: 17274962 DOI: 10.1016/j.brainres.2006.12.086] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2006] [Revised: 12/25/2006] [Accepted: 12/27/2006] [Indexed: 11/16/2022]
Abstract
The formation of Abeta and its subsequent deposition in senile plaques are considered to be initial events that lead to a cascade of pathological changes in AD. Mediators of Abeta-induced oxidative stress are known to cause oxidative damage to macromolecules. However, the molecular mechanisms by which Abeta-induced oxidative stress leads to neuronal cell death are not fully understood. Here we show that Abeta-induced oxidative stress activates the pro-death gene BNIP3. Abeta treatment results in mitochondrial dysfunction, accumulation of reactive oxygen species, and subsequent expression of BNIP3 in rat primary cortical neurons. Pretreatment with antioxidants abolished Abeta-induced BNIP3 expression and attenuated cell death, demonstrating the role of oxidative stress in BNIP3 induction. Abeta-induced BNIP3 expression may be mediated by hypoxia-inducible factor-1 (HIF-1) because Abeta-treatment induced accumulation and nuclear translocation of HIF-1 and knock-down of HIF-1 by RNAi inhibited BNIP3 expression. Finally, knockdown of BNIP3 reduced Abeta-induced neuronal death. Together, these results suggest a potential pathological role of BNIP3 in the etiology of AD.
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Affiliation(s)
- Surong Zhang
- Department of Human Anatomy and Cell Science, University of Manitoba Faculty of Medicine, 730 William Avenue, Winnipeg, Manitoba, Canada R3E 0W3
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33
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Rui Y, Tiwari P, Xie Z, Zheng JQ. Acute impairment of mitochondrial trafficking by beta-amyloid peptides in hippocampal neurons. J Neurosci 2006; 26:10480-7. [PMID: 17035532 PMCID: PMC6674697 DOI: 10.1523/jneurosci.3231-06.2006] [Citation(s) in RCA: 206] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Defects in axonal transport are often associated with a wide variety of neurological diseases including Alzheimer's disease (AD). Beta-amyloid (Abeta) is a major component of neuritic plaques associated with pathological conditions of AD brains. Here, we report that a brief exposure of cultured hippocampal neurons to Abeta molecules resulted in rapid and severe impairment of mitochondrial transport without inducing apparent cell death and significant morphological changes. Such acute inhibition of mitochondrial transport was not associated with a disruption of mitochondria potential nor involved aberrant cytoskeletal changes. Abeta also did not elicit significant Ca2+ signaling to affect mitochondrial trafficking. However, stimulation of protein kinase A (PKA) by forskolin, cAMP analogs, or neuropeptides effectively alleviated the impairment. We also show that Abeta inhibited mitochondrial transport by acting through glycogen synthase kinase 3beta (GSK3beta). Given that mitochondria are crucial organelles for many cellular functions and survival, our findings thus identify an important acute action of Abeta molecules on nerve cells that could potentially contribute to various abnormalities of neuronal functions under AD conditions. Manipulation of GSK3beta and PKA activities may represent a key approach for preventing and alleviating Abeta cytotoxicity and AD pathological conditions.
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Affiliation(s)
- Yanfang Rui
- Department of Biological Science and Biotechnology, State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua University, Beijing, China 100084, and
| | - Priyanka Tiwari
- Department of Neuroscience and Cell Biology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854
| | - Zuoping Xie
- Department of Biological Science and Biotechnology, State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua University, Beijing, China 100084, and
| | - James Q. Zheng
- Department of Neuroscience and Cell Biology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854
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34
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Nilsen J, Chen S, Irwin RW, Iwamoto S, Brinton RD. Estrogen protects neuronal cells from amyloid beta-induced apoptosis via regulation of mitochondrial proteins and function. BMC Neurosci 2006; 7:74. [PMID: 17083736 PMCID: PMC1636062 DOI: 10.1186/1471-2202-7-74] [Citation(s) in RCA: 127] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2006] [Accepted: 11/03/2006] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Neurodegeneration in Alzheimer's disease is associated with increased apoptosis and parallels increased levels of amyloid beta, which can induce neuronal apoptosis. Estrogen exposure prior to neurotoxic insult of hippocampal neurons promotes neuronal defence and survival against neurodegenerative insults including amyloid beta. Although all underlying molecular mechanisms of amyloid beta neurotoxicity remain undetermined, mitochondrial dysfunction, including altered calcium homeostasis and Bcl-2 expression, are involved in neurodegenerative vulnerability. RESULTS In this study, we investigated the mechanism of 17beta-estradiol-induced prevention of amyloid beta-induced apoptosis of rat hippocampal neuronal cultures. Estradiol treatment prior to amyloid beta exposure significantly reduced the number of apoptotic neurons and the associated rise in resting intracellular calcium levels. Amyloid beta exposure provoked down regulation of a key antiapoptotic protein, Bcl-2, and resulted in mitochondrial translocation of Bax, a protein known to promote cell death, and subsequent release of cytochrome c. E2 pretreatment inhibited the amyloid beta-induced decrease in Bcl-2 expression, translocation of Bax to the mitochondria and subsequent release of cytochrome c. Further implicating the mitochondria as a target of estradiol action, in vivo estradiol treatment enhanced the respiratory function of whole brain mitochondria. In addition, estradiol pretreatment protected isolated mitochondria against calcium-induced loss of respiratory function. CONCLUSION Therefore, we propose that estradiol pretreatment protects against amyloid beta neurotoxicity by limiting mitochondrial dysfunction via activation of antiapoptotic mechanisms.
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Affiliation(s)
- Jon Nilsen
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, 90033, USA
| | - Shuhua Chen
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, 90033, USA
| | - Ronald W Irwin
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, 90033, USA
| | - Sean Iwamoto
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, 90033, USA
| | - Roberta Diaz Brinton
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, 90033, USA
- Program in Neuroscience, University of Southern California, Los Angeles, California, 90033, USA
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35
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Pai AS, Rubinstein I, Onyüksel H. PEGylated phospholipid nanomicelles interact with beta-amyloid((1-42)) and mitigate its beta-sheet formation, aggregation and neurotoxicity in vitro. Peptides 2006; 27:2858-66. [PMID: 16762454 DOI: 10.1016/j.peptides.2006.04.022] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2006] [Revised: 04/18/2006] [Accepted: 04/19/2006] [Indexed: 11/26/2022]
Abstract
beta-Amyloid (Abeta) is a hydrophobic peptide that drives the pathogenesis of Alzheimer's disease (AD) due to its aberrant aggregation. Inhibition of Abeta aggregation process is one of the most promising strategies for therapeutic intervention in AD. Here, we demonstrate that sterically stabilized (PEGylated) phospholipid nanomicelles (SSM) are effective in mitigating Abeta-42 aggregation using several deterministic techniques such as (1) Turbidimetry (2) Congo red binding (3) Thioflavine-T binding (4) Laser light scattering and (5) Electron Microscopy. alpha-Helicity of Abeta-42 is significantly augmented in the presence of SSM as demonstrated by circular dichroism (p<0.05). Cytotoxicity studies, employing human neuroblastoma SHSY-5Y cells, established that PEGylated phospholipid associated peptide demonstrated significantly lower neurotoxicity compared to lipid untreated Abeta-42 (p<0.05). Collectively, our results establish that PEGylated phospholipids abrogate transformation of Abeta-42 to amyloidogenic beta-sheeted form and impart neuroprotection in vitro. This study provides a foundation for designing nanoconstructs of PEGylated phospholipid nanomicelles in conjunction with a therapeutic agent for multitargeting the different pathophysiologies associated with AD.
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Affiliation(s)
- Ashwini S Pai
- Department of Biopharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA
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36
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Gregersen N. Protein misfolding disorders: pathogenesis and intervention. J Inherit Metab Dis 2006; 29:456-70. [PMID: 16763918 DOI: 10.1007/s10545-006-0301-4] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2005] [Accepted: 02/02/2006] [Indexed: 11/26/2022]
Abstract
Newly synthesized proteins in the living cell must go through a folding process to attain their functional structure. To achieve this in an efficient fashion, all organisms, including humans, have evolved a large set of molecular chaperones that assist the folding as well as the maintenance of the functional structure of cellular proteins. Aberrant proteins, the result of production errors, inherited or acquired amino acid substitutions or damage, especially oxidative modifications, can in many cases not fold correctly and will be trapped in misfolded conformations. To rid the cell of misfolded proteins, the living cell contains a large number of intracellular proteases, e.g. the proteasome, which together with the chaperones comprise the cellular protein quality control systems. Many inherited disorders due to amino acid substitutions exhibit loss-of-function pathogenesis because the aberrant protein is eliminated by one of the protein quality control systems. Examples are cystic fibrosis and phenylketonuria. However, not all aberrant proteins can be eliminated and the misfolded protein may accumulate and form toxic oligomeric and/or aggregated inclusions. In this case the loss of function may be accompanied by a gain-of-function pathogenesis, which in many cases determines the pathological and clinical features. Examples are Parkinson and Huntington diseases. Although a number of strategies have been tried to decrease the amounts of accumulated and aggregated proteins, a likely future strategy seems to be the use of chemical or pharmacological chaperones with specific effects on the misfolded protein in question. Positive examples are enzyme enhancement in a number of lysosomal disorders.
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Affiliation(s)
- N Gregersen
- Research Unit for Molecular Medicine, Institute of Clinical Medicine, Aarhus University Hospital, Skejby Sygehus, 8200, Aarhus N, Denmark
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37
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Elson JL, Herrnstadt C, Preston G, Thal L, Morris CM, Edwardson JA, Beal MF, Turnbull DM, Howell N. Does the mitochondrial genome play a role in the etiology of Alzheimer's disease? Hum Genet 2006; 119:241-54. [PMID: 16408223 DOI: 10.1007/s00439-005-0123-8] [Citation(s) in RCA: 77] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2005] [Accepted: 12/12/2005] [Indexed: 10/25/2022]
Abstract
We report here the analyses of complete mtDNA coding region sequences from more than 270 Alzheimer's disease (AD) patients and normal controls to determine if inherited mtDNA mutations contribute to the etiology of AD. The AD patients and normal individuals were carefully screened and drawn from two populations of European descent in an effort to avoid spurious effects due to local population anomalies. Overall, there were no significant haplogroup associations in the combined AD and normal control sequence sets. Reduced median network analysis revealed that the AD mtDNA sequences contained a higher number of substitutions in tRNA genes, and that there was an elevated frequency of replacement substitutions in the complex I genes of the control sequences. Analysis of the replacement substitutions indicated that those arising in the AD mtDNAs were no more deleterious, on average, than those in the control mtDNAs. The only evidence for the synergistic action of mutations was the presence of both a rare non-conservative replacement substitution and a tRNA mutation in 2 AD mtDNAs, from a total of 145, whereas such a combination of mutations was not observed in the control sequences. Overall, the results reported here indicate that pathogenic inherited mtDNA mutations do not constitute a major etiological factor in sporadic AD. At most, a small proportion of AD patients carry a pathogenic mtDNA mutation and a small proportion of cognitively normal aged individuals carry a mtDNA mutation that reduces the risk of AD.
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Affiliation(s)
- Joanna L Elson
- Mitochondrial Research Group, School of Neurology, Neurobiology, and Psychiatry, The University of Newcastle upon Tyne, and Institute for the Health of the Elderly, Newcastle General Hospital, Newcastle upon Tyne, United Kingdom
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38
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Aisen PS. The development of anti-amyloid therapy for Alzheimer's disease : from secretase modulators to polymerisation inhibitors. CNS Drugs 2006; 19:989-96. [PMID: 16332141 DOI: 10.2165/00023210-200519120-00002] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
The leading hypothesis of the pathophysiology of Alzheimer's disease holds that the pivotal event is cleavage of the amyloid precursor protein to release intact the 42-amino-acid amyloid-beta peptide (Abeta); this hypothesis best explains the known genetic causes of Alzheimer's disease. If this theory is correct, optimal strategies for altering the disease process should be directed toward modifying the generation, clearance and/or toxicity of Abeta. Abeta is highly aggregable, spontaneously assuming a beta-sheet conformation and polymerising into oligomers, protofibrils, fibrils and plaques. The relative contribution of the various forms of Abeta to neuronal dysfunction in Alzheimer's disease remains uncertain; however, recent evidence implicates diffusible oligomeric species. This article reviews the range of strategies that have been investigated to target Abeta to slow the progression of Alzheimer's disease, from secretase modulators to anti-polymerisation agents. One amyloid-binding drug, tramiprosate (3-amino-1-propanesulfonic acid; Alzhemed), which is effective in reducing polymerisation in vitro and plaque deposition in animals, has now reached phase III clinical trials. Thus, it is plausible that an effective anti-amyloid strategy will become available for the treatment of Alzheimer's disease within the next few years.
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Affiliation(s)
- Paul S Aisen
- Department of Neurology, Georgetown University Medical Center, Washington DC, USA.
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39
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Fearon IM, Brown ST, Hudasek K, Scragg JL, Boyle JP, Peers C. Mitochondrial ROS production initiates Abeta1-40-mediated up-regulation of L-type Ca2+ channels during chronic hypoxia. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2006; 580:197-201; discussion 351-9. [PMID: 16683719 DOI: 10.1007/0-387-31311-7_30] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/09/2023]
Affiliation(s)
- Ian M Fearon
- Faculty of Life Sciences, The University of Manchester, Manchester M13 9PT, UK
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40
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Reddy PH, Beal MF. Are mitochondria critical in the pathogenesis of Alzheimer's disease? ACTA ACUST UNITED AC 2005; 49:618-32. [PMID: 16269322 DOI: 10.1016/j.brainresrev.2005.03.004] [Citation(s) in RCA: 206] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2004] [Revised: 03/11/2005] [Accepted: 03/14/2005] [Indexed: 12/11/2022]
Abstract
This review summarizes recent findings that suggest a causal connection between mitochondrial abnormalities and sporadic Alzheimer's disease (AD). Genetic causes of AD are known only for a small proportion of familial AD patients, but for a majority of sporadic AD patients, genetic causal factors are still unknown. Currently, there are no early detectable biomarkers for sporadic AD, and there is a lack of understanding of the pathophysiology of the disease. Findings from recent genetic studies of AD pathogenesis suggest that mitochondrial defects may play an important role in sporadic AD progression, and that mitochondrial abnormalities and oxidative damage may play a significant role in the progression of familial AD. Findings from biochemical studies, in vitro studies, gene expression studies, and animal model studies of AD are reviewed, and the possible contribution of mitochondrial mutations to late-onset sporadic AD is discussed.
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Affiliation(s)
- P Hemachandra Reddy
- Neurogenetics Laboratory, Neurological Sciences Institute, Oregon Health and Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA.
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41
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Brown ST, Scragg JL, Boyle JP, Hudasek K, Peers C, Fearon IM. Hypoxic Augmentation of Ca2+ Channel Currents Requires a Functional Electron Transport Chain. J Biol Chem 2005; 280:21706-12. [PMID: 15824110 DOI: 10.1074/jbc.m503144200] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
The incidence of Alzheimer disease is increased following ischemic episodes, and we previously demonstrated that following chronic hypoxia (CH), amyloid beta (Abeta) peptide-mediated increases in voltage-gated L-type Ca(2+) channel activity contribute to the Ca(2+) dyshomeostasis seen in Alzheimer disease. Because in certain cell types mitochondria are responsible for detecting altered O(2) levels we examined the role of mitochondrial oxidant production in the regulation of recombinant Ca(2+) channel alpha(1C) subunits during CH and exposure to Abeta-(1-40). In wild-type (rho(+)) HEK 293 cells expressing recombinant L-type alpha(1C) subunits, Ca(2+) currents were enhanced by prolonged (24 h) exposure to either CH (6% O(2)) or Abeta-(1-40) (50 nm). By contrast the response to CH was absent in rho(0) cells in which the mitochondrial electron transport chain (ETC) was depleted following long term treatment with ethidium bromide or in rho(+) cells cultured in the presence of 1 microm rotenone. CH was mimicked in rho(0) cells by the exogenous production of O2(-.). by xanthine/xanthine oxidase. Furthermore Abeta-(1-40) enhanced currents in rho(0) cells to a degree similar to that seen in cells with an intact ETC. The antioxidants ascorbate (200 microm) and Trolox (500 microm) ablated the effect of CH in rho(+) cells but were without effect on Abeta-(1-40)-mediated augmentation of Ca(2+) current in rho(0) cells. Thus oxidant production in the mitochondrial ETC is a critical factor, acting upstream of amyloid beta peptide production in the up-regulation of Ca(2+) channels in response to CH.
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Affiliation(s)
- Stephen T Brown
- Department of Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada
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42
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Liu Q, Smith MA, Avilá J, DeBernardis J, Kansal M, Takeda A, Zhu X, Nunomura A, Honda K, Moreira PI, Oliveira CR, Santos MS, Shimohama S, Aliev G, de la Torre J, Ghanbari HA, Siedlak SL, Harris PLR, Sayre LM, Perry G. Alzheimer-specific epitopes of tau represent lipid peroxidation-induced conformations. Free Radic Biol Med 2005; 38:746-54. [PMID: 15721985 DOI: 10.1016/j.freeradbiomed.2004.11.005] [Citation(s) in RCA: 93] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2004] [Accepted: 11/01/2004] [Indexed: 11/21/2022]
Abstract
Several recent studies support a link between tau protein phosphorylation and adduction of tau by reactive carbonyls. Indeed, the phosphorylation-dependent adduction of tau by carbonyl products resulting from lipid peroxidation creates the neurofibrillary tangle-related antigen, Alz50. To determine whether epitopes of carbonyl-modified tau are major conformational changes associated with neurofibrillary tangle formation, we examined seven distinct antibodies raised against neurofibrillary tangles that recognize unique epitopes of tau in Alzheimer disease. Consistently, all seven antibodies recognize tau more strongly (4- to 34-fold) after treatment of normal tau with the reactive carbonyl, 4-hydroxy-2-nonenal (HNE), but only when tau is in the phosphorylated state. These findings not only support the idea that oxidative stress is involved in neurofibrillary tangle formation occurring in brains of Alzheimer disease patients, but also show, for the first time, that HNE modifications of tau promote and contribute to the generation of the major conformational properties defining neurofibrillary tangles.
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Affiliation(s)
- Quan Liu
- Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106, USA
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Teng FYH, Tang BL. Widespread γ-secretase activity in the cell, but do we need it at the mitochondria? Biochem Biophys Res Commun 2005; 328:1-5. [PMID: 15670741 DOI: 10.1016/j.bbrc.2004.12.131] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2004] [Indexed: 12/16/2022]
Abstract
gamma-Secretase cleavage of the amyloid precursor protein already subjected to a prior beta-secretase cleavage generates beta-amyloid (Abeta) peptide fragments, which are major constituents of the amyloid plagues found in Alzheimer's disease brain tissues. gamma-Secretase activity and components of the gamma-secretase complex are found in the endoplasmic reticulum-Golgi intermediate compartment, the Golgi, the trans-Golgi network, the plasma membrane, the endosomal-lysosomal system and recently, the mitochondria. Abeta fragments have been shown to be neurotoxic, leading to mitochondrial dysfunction and enhanced apoptotic cell death. However, if Abeta fragments are indeed detrimental to neurons, the widespread presence of enzymatic activity that would result in their generation in the cell appears to make little sense. The presence of a gamma-secretase complex in the mitochondrion, an organelle that is particularly susceptible to Abeta toxicity, is even more puzzling. Emerging evidence suggests that both secreted and intracellular Abeta fragments have endogenous functions. Also, while the fibrillogenic Abeta1-42 is clearly neurotoxic, the more abundant and soluble Abeta1-40 is an antioxidant and could potentially be neuroprotective in several ways. A "physiological" amount of Abeta1-40 production by cellular gamma-secretase activity may be part of the neuron's natural counter against oxidative damage, in addition to endogenous roles in neuronal survival and modulation of synaptic transmission. In any case, whether Abeta is produced locally in the mitochondria and the function for mitochondrial Abeta, if produced, is yet unclear.
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Affiliation(s)
- Felicia Yu Hsuan Teng
- Department of Biochemistry and Programme in Neurobiology and Aging, National University of Singapore, 8 Medical Drive, Singapore 117597, Singapore
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44
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Canu N, Calissano P. In vitro cultured neurons for molecular studies correlating apoptosis with events related to Alzheimer disease. THE CEREBELLUM 2004; 2:270-8. [PMID: 14964686 DOI: 10.1080/14734220310004289] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
This short review analyses the possible molecular events linking a general program of death such as apoptosis to highly specific intracellular pathways involving the function and degradation of two proteins--tau and amyloid precursor protein--which in their aggregated state constitute the hallmark of Alzheimer disease. By surveying the recent studies carried out in 'in vitro' neuronal cultures--with special emphasis to cerebellar granule neurons--the apparent correlation between onset of apoptosis, tau cleavage with formation of potential toxic fragments, and activation of an amyloidogenic route are discussed. Within this framework, proteasomes seem to play a crucial role upstream of the proteolytic cascade involving calpain(s) and caspase(s) by contributing to tau and amyloid precursor protein-altered breakdown and consequent tendency to aggregation of their degradation fragments. Thus, apoptotic death due to altered supply of anti apoptotic agents, neurotrophic factors, deafferentiation or other causes, may constitute a major trigger of the onset of Alzheimer disease.
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Affiliation(s)
- Nadia Canu
- Department of Neuroscience, University of Tor Vergata, Rome, Italy.
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45
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Vásquez GB, Zullo SJ, Barker PE. Standards requirements for systems biology approaches to health care: mitochondrial proteomics. Mitochondrion 2004; 3:205-15. [PMID: 16120355 DOI: 10.1016/j.mito.2003.11.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2003] [Revised: 10/02/2003] [Accepted: 11/05/2003] [Indexed: 10/26/2022]
Abstract
A review of the standards needs of the mitochondrial proteomics communities is presented based on the presentations and discussions at National Institute of Standards and Technology (NIST) workshop, Systems Biology Approaches to Health Care: Mitochondrial Proteomics, held on September 17-18, 2002. The mitochondrial proteomics areas addressed for standards needs are model systems, methods and data. This review outlines the challenges in the field, proposes standards efforts that the community would like to see pursued to meet those challenges, and is followed by a summary and NIST's planned efforts to address these standards requirements.
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Affiliation(s)
- Gregory B Vásquez
- Biotechnology Division, National Institute of Standards and Technology, 100 Bureau Drive, Gaithersburg, MD 20899-8313, USA.
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46
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Blanchard V, Moussaoui S, Czech C, Touchet N, Bonici B, Planche M, Canton T, Jedidi I, Gohin M, Wirths O, Bayer TA, Langui D, Duyckaerts C, Tremp G, Pradier L. Time sequence of maturation of dystrophic neurites associated with Abeta deposits in APP/PS1 transgenic mice. Exp Neurol 2004; 184:247-63. [PMID: 14637096 DOI: 10.1016/s0014-4886(03)00252-8] [Citation(s) in RCA: 230] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Several novel transgenic mouse models expressing different mutant APPs in combination with mutant PS1 have been developed. These models have been analyzed to investigate the formation and progressive alterations of dystrophic neurites (DNs) in relation to Abeta deposits. In the most aggressive model, Abeta deposits appear as early as 2.5 months of age. Maturation of DNs was qualitatively quite similar among models and in some respect reminiscent of human AD pathology. From the onset of deposition, most if not all Abeta deposits were decorated with a high number of APP-, ubiquitin-, and MnSOD-immunoreactive DNs. Phosphorylated Tau DNs, however, appeared at a much slower rate and were more restricted. Mitochondrial dysfunction markers were observed in DNs: the frequency and the density per deposit of DNs accumulating cytochrome c, cytochrome oxidase 1, and Bax progressively increased with age. Later, the burden of reactive DNs was reduced around large compact/mature deposits. In addition, the previously described phenomenon of early intraneuronal Abeta accumulation in our models was associated with altered expression of APP protein as well as oxidative and mitochondrial stress markers occasionally in individual neurons. The present study demonstrates that oxidative and mitochondrial stress factors are present at several phases of Abeta pathology progression, confirming the neuronal dysfunction in APP transgenic mice.
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Affiliation(s)
- Véronique Blanchard
- Neurodegenerative Disease Group, Centre de Recherche de Paris, Aventis Pharma 94403, Vitry sur Seine Cedex, France.
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47
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Datki Z, Juhász A, Gálfi M, Soós K, Papp R, Zádori D, Penke B. Method for measuring neurotoxicity of aggregating polypeptides with the MTT assay on differentiated neuroblastoma cells. Brain Res Bull 2003; 62:223-9. [PMID: 14698355 DOI: 10.1016/j.brainresbull.2003.09.011] [Citation(s) in RCA: 117] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Reliable in vitro assays are essential for study of the effects of neurotoxic compounds such as beta-amyloid peptides (Abeta). The MTT assay has been used in cultures of different cells, e.g. SH-SY5Y neuroblastoma cells, for the quantitative measurement of Abeta toxicity. In our laboratory differentiated SH-SY5Y cells were used in the MTT assay. Cell differentiation with 10 microM all-trans-retinoic acid resulted in a constant cell number. The cells possess highly developed neurites and exhibit high sensitivity against Abeta. Owing to the constant cell number in differentiated SH-SY5Y cultures the decrease of the redox activity is directly proportional to the neurotoxicity of the substances, no correction is needed. The results of the MTT assay of Abeta peptides on differentiated SH-SY5Y cells displayed a good correlation also with the in vivo results. The present experiments reveal an effective assay for the study of potentially neurotoxic compounds.
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Affiliation(s)
- Zsolt Datki
- Department of Medical Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary.
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48
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Abstract
Emerging therapies for Alzheimer's disease offer hope to patients and their caregivers. Future treatments will probably include combination approaches with agents that modify amyloid processing, deposition, and clearance. One example, the AD vaccine, reduced amyloid burden and changed behavior in animal models of AD, but the human trial was halted when several subjects developed brain inflammation. Anti-inflammatory agents have epidemiologic support, but clinical trials have been disappointing, possibly related to inadequate study with anti-inflammatory agents that modify amyloid processing. Agents that target known cardiovascular risk factors, such as hypercholesterolemia, hypertension, and insulin resistance, have epidemiologic, preclinical, and clinical evidence to warrant further investigation. Heavy metal chelators, antioxidants, neurotrophic factors, glutaminergic modulators, and agents that modify hyperphosphorylation of Tau are other approaches in research and development.
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Affiliation(s)
- Steven C Samuels
- Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA.
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Abstract
Amyloid plaques and neurofibrillary tangles are the neuropathological hallmarks of Alzheimer's disease (AD), but no conclusive evidence has emerged showing that these hallmarks are the cause and not a product of the disease. Many studies have implicated oxidation and inflammation in the AD process, and there is growing evidence that abnormalities of lipid metabolism also play a role. Using epidemiology to elucidate risk factors and histological changes to suggest possible mechanisms, the hypothesis is advanced that dietary lipids are the principal risk factor for the development of late-onset sporadic AD. The degree of saturation of fatty acids and the position of the first double bond in essential fatty acids are the most critical factors determining the effect of dietary fats on the risk of AD, with unsaturated fats and n-3 double bonds conferring protection and an overabundance of saturated fats or n-6 double bonds increasing the risk. The interaction of dietary lipids and apolipoprotein E isoforms may determine the risk and rate of sustained autoperoxidation within cellular membranes and the efficacy of membrane repair. Interventions involving dietary lipids and lipid metabolism show great promise in slowing or possibly averting the development of AD, including dietary changes, cholesterol-modifying agents and antioxidants.
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Affiliation(s)
- Janelle L Cooper
- The Memory Center, Affinity Health System, Oshkosh, Wisconsin 54902, USA.
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50
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Kuperstein F, Yavin E. Pro-apoptotic signaling in neuronal cells following iron and amyloid beta peptide neurotoxicity. J Neurochem 2003; 86:114-25. [PMID: 12807431 DOI: 10.1046/j.1471-4159.2003.01831.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In a previous report, we characterized several oxidative stress parameters during the course of amyloid beta (Abeta) peptide/Fe2+-induced apoptotic death in neuronal cells. In extending these findings, we now report a marked decrease in protein kinase C (PKC) isoforms, reduced Akt serine/threonine kinase activity, Bcl 2-associated death promoter (BAD) phosphorylation and enhanced p38 mitogen-activated protein kinase (MAPK) and caspase-9 and -3 activation, 12 h after addition of both 5 micro m Abeta and 5 micro m Fe2+. These activities reminiscent for a pro-apoptotic cellular course were blocked in the presence of the iron chelator deferroxamine. Abeta alone, increased PKC isoform levels between three- and four-fold after 12 h, enhanced Akt activity approximately eight-fold and Ser136 BAD phosphorylation two-fold, suggesting that by itself is not toxic. Fe2+ alone transiently enhanced p38 MAPK and caspase-9 and -3 enzymes indicative for cell damage, but was not sufficient to cause cell death as previously indicated. GF, a PKC inhibitor or wortmannin, a blocker of the Akt pathway enhanced Abeta/Fe2+-induced toxicity, while SB, a p38 MAPK inhibitor, prevented cell damage and apoptosis. These findings further support the hypothesis that metal ion chelation and inhibitors of pro-apoptotic kinase cascades may be beneficial for Alzheimer's disease therapy.
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Affiliation(s)
- Faina Kuperstein
- Department of Neurobiology, The Weizmann Institute of Science, Rehovot, Israel
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