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Tuesday, November 1, 2016
Highlighted Article: DNA Double Strand Breaks: A Common Theme in Neurodegenerative Diseases
DNA Double Strand Breaks: A Common Theme in Neurodegenerative Diseases
Author(s):
Daniela Merlo, Cristiana Mollinari, Mauro Racaniello, Enrico Garaci and Alessio Cardinale Pages 1208 - 1218 ( 11 )
Abstract:
Accumulation of DNA damage and impairment of DNA repair systems are involved in the pathogenesis of different neurodegenerative diseases. Whenever DNA damage is too extensive, the DNA damage response pathway provides for triggering cellular senescence and/or apoptosis. However, whether the increased level of DNA damage in neurodegenerative disorders is a cause rather than the consequence of neurodegenerative events remains to be established. Among possible DNA lesions, DNA double strand breaks (DSBs) are rare events, nevertheless they are the most lethal form of DNA damage. In neurons, DSBs are particularly deleterious because of their reduced DNA repair capability as compared to proliferating cells.
Here, we provide a description of DSB repair systems and describe human studies showing the presence of several types of DNA lesions in three major neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD). Then, we analyze the role of DSB accumulation and deficiency of DSB repair systems in neurodegeneration by examining studies on animal models of neurodegenerative diseases.
Keywords:
Alzheimer's disease, DNA damage, DNA repair, DNA double strand breaks, Huntington's disease, neurodegenerative diseases, Parkinson's disease.
Affiliation:
Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Rome, Italy.
For More Information Please Visit Our Website Current Alzheimer Research
Monday, October 24, 2016
Most Cited Article: Identification of Human ABAD Inhibitors for Rescuing Aβ-Mediated Mitochondrial Dysfunction
Identification of
Human ABAD Inhibitors for Rescuing Aβ-Mediated Mitochondrial Dysfunction
Author(s):
Koteswara R. Valaasani, Qinru Sun, Gang Hu,
Jianping Li, Fang Du, Yaopeng Guo, Emily A. Carlson, Xueqi Gan and Shirley S.
YanPages 128-136 (9)
Abstract:
Amyloid beta (Aβ ) binding alcohol dehydrogenase (ABAD) is a cellular cofactor for promoting (Aβ )-mediated mitochondrial and neuronal dysfunction, and cognitive decline in transgenic Alzheimer’s disease (AD) mouse models. Targeting mitochondrial ABAD may represent a novel therapeutic strategy against AD. Here, we report the biological activity of small molecule ABAD inhibitors. Using in vitro surface plasmon resonance (SPR) studies, we synthesized compounds with strong binding affinities for ABAD. Further, these ABAD inhibitors (ABAD-4a and 4b) reduced ABAD enzyme activity and administration of phosphonate derivatives of ABAD inhibitors antagonized calcium-mediated mitochondrial swelling. Importantly, these compounds also abolished A β-induced mitochondrial dysfunction as shown by increased cytochrome c oxidase activity and adenosine-5'-triphosphate levels, suggesting protective mitochondrial function effects of these synthesized compounds. Thus, these compounds are potential candidates for further pharmacologic development to target ABAD to improve mitochondrial function.
Keywords:
ABAD inhibitors, adenosine-5'-triphosphate,
amyloid beta, benzothiazole amino phosphonates, cytochrome c oxidase,
mitochondrial dysfunction.
Affiliation:
2099 Constant Avenue, University of Kansas,
Lawrence, KS 66047, USA.
For More Information Please Visit Our Website Current Alzheimer Research
Tuesday, October 18, 2016
The BET-Bromodomain Inhibitor JQ1 Reduces Inflammation and Tau Phosphorylation at Ser396 in the Brain of the 3xTg Model of Alzheimer’s Disease
Article Details
The BET-Bromodomain Inhibitor JQ1 Reduces Inflammation and Tau
Phosphorylation at Ser396 in the Brain of the 3xTg Model of Alzheimer’s Disease
Author(s):
Marco Magistri, Dmitry Velmeshev, Madina
Makhmutova, Prutha Patel, Gregory C. Sartor, Claude-Henry Volmar, Claes
Wahlestedt and Mohammad Ali FaghihiPages 985-995 (11)
Abstract:
Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by welldefined neuropathological brain changes including amyloid plaques, neurofibrillary tangles and the presence of chronic neuroinflammation. Objective: The brain penetrant BET bromodomain inhibitor JQ1 has been shown to regulate inflammation responses in vitro and in vivo, but its therapeutic potential in AD is currently unknown. Method: Three-month-old 3xTg mice were injected once a day with JQ1 (50 mg/kg) or vehicle for 15 weeks. At the end of the treatment learning and memory was assessed using the modified Barnes maze and the Y maze behavioral tests. Tissue from the brain and other organs was collected for molecular evaluation of neuroinflammation tau pathology and amyloid β. Results: JQ1 treatment reduced splenomegaly and neuroinflammation in the brain of treated mice where we observed a reduction in the expression of the pro-inflammatory modulators Il-1b, Il-6, Tnfa, Ccl2, Nos2 and Ptgs2. Additionally, JQ1-treated mice showed a reduction of tau phosphorylation at Ser396 in the hippocampus and frontal cortex while total levels of tau remained unaffected. On the other hand, JQ1 did not ameliorate learning and memory deficits in 7-month-old 3xTg mice. Conclusion: Taken together, our data suggest that BET bromodomain inhibitors hold the promise to be used for the treatment of neurological disorders characterized by neuroinflammation.
Keywords:
Alzheimer’s disease, astrocytes, inflammation,
microglia, neuroinflammation, bromodomain, JQ1, splenomegaly.
Affiliation:
Center for Therapeutic Innovation & Department
of Psychiatry and Behavioral Sciences, University of Miami Miller School of
Medicine, 1501 NW 10th Ave, BRB 508, Miami, FL 33136, USA.
For more information please visit out website Current
Alzheimer Research
Sunday, October 9, 2016
Neuropsychiatric Disturbances in Alzheimer’s Disease: What Have We Learned from Neuropathological Studies?
Neuropsychiatric Disturbances in Alzheimer’s Disease: What Have We Learned from Neuropathological Studies?
[ Vol. 13 , Issue. 10 ]
Author(s):
Debby Van Dam, Yannick Vermeiren, Alain D. Dekker, Petrus J.W. Naudé and Peter P. De DeynPages 1145-1164 (20)
Abstract:
Neuropsychiatric symptoms (NPS) are an integral part of the dementia syndrome and were therefore recently included in the core diagnostic criteria of dementia. The near universal prevalence of NPS in Alzheimer’s disease (AD), combined with their disabling effects on patients and caregivers, is contrasted by the fact that few effective and safe treatments exist, which is in part to be attributed to our incomplete understanding of the neurobiology of NPS. In this review, we describe the pathological alterations typical for AD, including spreading and evolution of burden, effect on the molecular and cellular integrity, functional consequences and atrophy of NPS-relevant brain regions and circuits in correlation with specific NPS assessments. It is thereby clearly established that NPS are fundamental expressions of the underlying neurodegenerative brain disease and not simply reflect the patients’ secondary response to their illness. Neuropathological studies, moreover, include a majority of end-stage patient samples, which may not correctly represent the pathophysiological environment responsible for particular NPS that may already be present in an early stage, or even prior to AD diagnosis. The burdensome nature and high prevalence of NPS, in combination with the absence of effective and safe pharmacotherapies, provide a strong incentive to continue neuropathological and neurochemical, as well as imaging and other relevant approaches to further improve our apprehension of the neurobiology of NPS.
Keywords:
Aggression, amyloid, depression, neurofibrillary tangles, neuronal loss, psychosis, neurotransmitter.
Affiliation:
Laboratory of Neurochemistry and Behaviour, Institute Born-Bunge, Department of Biomedical Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, and, Faculty of Medical and Health Care Sciences, University of Antwerp, Universiteitsplein 1, BE-2610 Wilrijk (Antwerp), Belgium.
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Tuesday, October 4, 2016
Current Alzheimer Research, 13 Issue 10
Current Alzheimer Research publishes peer-reviewed frontier review, research, drug clinical trial studies and letter articles on all areas of Alzheimer’s disease. This multidisciplinary journal will help in understanding the neurobiology, genetics, pathogenesis, and treatment strategies of Alzheimer’s disease. The journal publishes objective reviews written by experts and leaders actively engaged in research using cellular, molecular, and animal models. The journal also covers original articles on recent research in fast emerging areas of molecular diagnostics, brain imaging, drug development and discovery, and clinical aspects of Alzheimer’s disease.
Articles from the journal Current Alzheimer Research, Volume 13 Issue 10:
- Neuropsychiatric Disturbances in Mild Cognitive Impairment (MCI): A Systematic Review of Population-Based Studies
- Suicide Risk in Alzheimer’s Disease: A Systematic Review
- Psychological Interventions for Neuropsychiatric Disturbances in Mild and Moderate Alzheimer’s Disease: Current Evidences and Future Directions
- Physical Exercise for the Treatment of Neuropsychiatric Disturbances in Alzheimer’s Dementia: Possible Mechanisms, Current Evidence and Future Directions
- The Treatment of Behavioral and Psychological Symptoms of Dementia: Weighing Benefits and Risks
- Pharmacological Management of Agitation and Aggression in Alzheimer’s Disease: A Review of Current and Novel Treatments
- Neuropsychiatric Disturbances in Alzheimer’s Disease: What Have We Learned from Neuropathological Studies?
- Alzheimer’s Disease is Associated with Increased Risk of Osteoporosis: The Chongqing Aging Study
- Butyrylcholinesterase as a Diagnostic and Therapeutic Target for Alzheimer’s Disease
- The Brainstem Tau Cytoskeletal Pathology of Alzheimer’s Disease: A Brief Historical Overview and Description of its Anatomical Distribution Pattern, Evolutional Features, Pathogenetic and Clinical Relevance
For details on the articles, please visit this link :: http://bit.ly/2bNrjaP
courtesy by : Bentham Insight
Current Alzheimer Research , 13 Issue 9
Current Alzheimer Research publishes peer-reviewed frontier review, research, drug clinical trial studies and letter articles on all areas of Alzheimer’s disease. This multidisciplinary journal will help in understanding the neurobiology, genetics, pathogenesis, and treatment strategies of Alzheimer’s disease. The journal publishes objective reviews written by experts and leaders actively engaged in research using cellular, molecular, and animal models. The journal also covers original articles on recent research in fast emerging areas of molecular diagnostics, brain imaging, drug development and discovery, and clinical aspects of Alzheimer’s disease. Manuscripts are encouraged that relate to the synergistic mechanism of Alzheimer’s disease with other dementia and neurodegenerative disorders. Book reviews, meeting reports and letters-to-the-editor are also published. The journal is essential reading for researchers, educators and physicians with interest in age-related dementia and Alzheimer’s disease. Current Alzheimer Research provides a comprehensive ‘bird’s-eye view’ of the current state of Alzheimer’s research for neuroscientists, clinicians, health science planners, granting, caregivers and families of this devastating disease.
Articles from the journal Current Alzheimer Research , Volume 13 Issue 9:
- Molecular Basis of Familial and Sporadic Alzheimer’s Disease
- Substance P and Alzheimer’s Disease: Emerging Novel Roles
- Lipid Raft Alterations in Aged-Associated Neuropathologies
- The BET-Bromodomain Inhibitor JQ1 Reduces Inflammation and Tau Phosphorylation at Ser396 in the Brain of the 3xTg Model of Alzheimer’s Disease
- Connections Between Herpes Simplex Virus Type 1 and Alzheimer’s Disease Pathogenesis
- Misoprostol Reverse Hippocampal Neuron Cyclooxygenase-2 Downstream Signaling Imbalance in Aluminum-Overload Rats
- Rhein-Huprine Derivatives Reduce Cognitive Impairment, Synaptic Failure and Amyloid Pathology in AβPPswe/PS-1 Mice of Different Ages
- Altered Arginine Metabolism in Cells Transfected with Human Wild-Type Beta Amyloid Precursor Protein (βAPP)
- Decreased Myelinated Fibers in the Hippocampal Dentate Gyrus of the Tg2576 Mouse Model of Alzheimer’s Disease
- APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice
- Inflammation, Oxidation, Caloric Expenditure and Cognitive Impairment in Brazilian Elderly Assisted at Primary Care
For details on the articles, please visit this link :: http://bit.ly/2b8FpWA
courtesy by : Bentham Insight
Current Alzheimer Research 13, Issue 8
Current Alzheimer Research publishes peer-reviewed frontier review, research, drug clinical trial studies and letter articles on all areas of Alzheimer’s disease. This multidisciplinary journal will help in understanding the neurobiology, genetics, pathogenesis, and treatment strategies of Alzheimer’s disease. The journal publishes objective reviews written by experts and leaders actively engaged in research using cellular, molecular, and animal models. The journal also covers original articles on recent research in fast emerging areas of molecular diagnostics, brain imaging, drug development and discovery, and clinical aspects of Alzheimer’s disease. Manuscripts are encouraged that relate to the synergistic mechanism of Alzheimer’s disease with other dementia and neurodegenerative disorders. Book reviews, meeting reports and letters-to-the-editor are also published. The journal is essential reading for researchers, educators and physicians with interest in age-related dementia and Alzheimer’s disease. Current Alzheimer Research provides a comprehensive ‘bird’s-eye view’ of the current state of Alzheimer’s research for neuroscientists, clinicians, health science planners, granting, caregivers and families of this devastating disease.
Articles from the journal Current Alzheimer Research, Volume 13, Issue 8:
- Editorial (Thematic Issue: Neuroprotective Effects of Li – It is Elementary)
- Lithium Distinctly Modulates the Secretion of Pro- and Anti- Inflammatory Interleukins in Co-Cultures of Neurons and Glial Cells at Therapeutic and Sub-Therapeutic Concentrations
- The Putative Use of Lithium in Alzheimer’s Disease
- Neuroprotective Effects of Lithium in Human Brain? Food for Thought
- Population Studies of Association Between Lithium and Risk of Neurodegenerative Disorders
- Lithium, a Therapy for AD: Current Evidence from Clinical Trials of Neurodegenerative Disorders
- Effect of Lithium on Neurocognitive Functioning
- Glial Cells – The Key Elements of Alzheimer´s Disease
- Association of Apolipoprotein E (ApoE) Polymorphism with Alzheimer’s Disease in Chinese Population
- An Anti-apoE4 Specific Monoclonal Antibody Counteracts the Pathological Effects of apoE4 In Vivo
- Mitochondrial Respiration in the Platelets of Patients with Alzheimer’s Disease
- Influence of Genetic Background on Apathy-Like Behavior in Triple Transgenic AD Mice
For details on the articles, please visit this link :: http://bit.ly/2auH77b
courtesy by : Bentham Insight
Current Alzheimer Research, 13 Issue 3
Current Alzheimer Research publishes peer-reviewed frontier review, research, drug clinical trial studies and letter articles on all areas of Alzheimer’s disease. This multidisciplinary journal will help in understanding the neurobiology, genetics, pathogenesis, and treatment strategies of Alzheimer’s disease. The journal publishes objective reviews written by experts and leaders actively engaged in research using cellular, molecular, and animal models. The journal also covers original articles on recent research in fast emerging areas of molecular diagnostics, brain imaging, drug development and discovery, and clinical aspects of Alzheimer’s disease. Manuscripts are encouraged that relate to the synergistic mechanism of Alzheimer’s disease with other dementia and neurodegenerative disorders. Book reviews, meeting reports and letters-to-the-editor are also published. The journal is essential reading for researchers, educators and physicians with interest in age-related dementia and Alzheimer’s disease. Current Alzheimer Research provides a comprehensive ‘bird’s-eye view’ of the current state of Alzheimer’s research for neuroscientists, clinicians, health science planners, granting, caregivers and families of this devastating disease.
Articles from the journal in Current Alzheimer Research, 13 Issue 3
- Testosterone, Estradiol, and Sex Hormone-Binding Globulin in Alzheimer’s Disease: A Meta
- Peripheral Blood Adipokines and Insulin Levels in Patients with Alzheimer’s Disease: A Replication Study and Meta-Analysis
- Functional Activity and Connectivity Differences of Five Resting-State Networks in Patients with Alzheimer’s Disease or Mild Cognitive Impairment
- The Relationship Between Plasma Aβ Levels, Cognitive Function and Brain Volumetrics: Sydney Memory and Ageing Study
- Structural MRI Biomarkers of Mild Cognitive Impairment from Young Elders to Centenarians
- Cytoskeletal Pathologies of Age-Related Diseases between Elderly Sri Lankan (Colombo) and Indian (Bangalore) Brain Samples
- Defining the earliest pathological changes of Alzheimer’s disease
- Triptolide Rescues Spatial Memory Deficits and Amyloid-β Aggregation Accompanied by Inhibition of Inflammatory Responses and MAPKs Activity in APP/PS1 Transgenic Mice
- SS31, a Small Molecule Antioxidant Peptide, Attenuates β-Amyloid Elevation, Mitochondrial/Synaptic Deterioration and Cognitive Deficit in SAMP8 Mice
- Perspectives on the Tertiary Prevention Strategy for Alzheimer’s Disease
For details on the articles, please visit this link :: http://bit.ly/1XulpwZ
courtesy by : Bentham Insight
Highlighted Article Flyer for the journal “Current Alzheimer Research”
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Friday, August 12, 2016
Friday, June 24, 2016
Neuropsychiatric Disturbances in Alzheimer’s Disease: What have We Learned from Neuropathological Studies?
Author(s):
Debby Van Dam, Yannick Vermeiren, Alain D. Dekker, Petrus J.W. Naudé and Peter P. De DeynPages 1-20 (20)
Abstract:
Neuropsychiatric symptoms (NPS) are an integral part of the dementia syndrome and were therefore recently included in the core diagnostic criteria of dementia. The near universal prevalence of NPS in Alzheimer’s disease (AD), combined with their disabling effects on patients and caregivers, is contrasted by the fact that few effective and safe treatments exist, which is in part to be attributed to our incomplete understanding of the neurobiology of NPS. In this review, we describe the pathological alterations typical for AD, including spreading and evolution of burden, effect on the molecular and cellular integrity, functional consequences and atrophy of NPS-relevant brain regions and circuits in correlation with specific NPS assessments. It is thereby clearly established that NPS are fundamental expressions of the underlying neurodegenerative brain disease and not simply reflect the patients’ secondary response to their illness. Neuropathological studies, moreover, include a majority of end-stage patient samples, which may not correctly represent the pathophysiological environment responsible for particular NPS that may already be present in an early stage, or even prior to AD diagnosis. The burdensome nature and high prevalence of NPS, in combination with the absence of effective and safe pharmacotherapies, provide a strong incentive to continue neuropathological and neurochemical, as well as imaging and other relevant approaches to further improve our apprehension of the neurobiology of NPS.
Keywords:
Aggression, amyloid, depression, neurofibrillary tangles, neuronal loss, psychosis, neurotransmitter
Affiliation:
Laboratory of Neurochemistry and Behaviour, Institute Born-Bunge, Department of Biomedical Sciences, University of Antwerp, Wilrijk, Belgium
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Decreased Myelinated Fibers in the Hippocampal Dentate Gyrus of the Tg2576 Mouse Model of Alzheimer’s Disease
Author(s):
Wei Lu, Shu Yang, Lei Zhang, Lin Chen, Feng-lei Chao, Yan-min Luo, Qian Xiao, Heng-wei Gu, Rong Jiang and Yong TangPages 1-8 (8)
Abstract:
Alzheimer’s disease (AD), the most common cause of dementia in the elderly, is characterized by deficits in cognition and memory. Although amyloid-β (Aβ) accumulation is known to be the earliest pathological event that triggers subsequent neurodegeneration, how Aβ accumulation causes behavioral deficits remains incompletely understood. In this study, using the Morris water maze test, ELISA and stereological methods, we examined spatial learning and memory performance, the soluble Aβ concentration and the myelination of fibers in the hippocampus of 4-, 6-, 8- and 10-month-old Tg2576 AD model mice. Our results showed that spatial learning and memory performance was significantly impaired in the Tg2576 mice compared to the WT controls and that the myelinated fiber length in the hippocampal dentate gyrus (DG) was markedly decreased from 0.33 ± 0.03 km in the WT controls to 0.17 ± 0.02 km in the Tg2576 mice at 10 months of age. However, the concentrations of soluble Aβ40 and Aβ42 were significantly increased as early as 4-6 months of age. The decreased myelinated fiber length in the DG may contribute to the spatial learning and memory deficits of Tg2576 mice. Therefore, we suggest that the significant accumulation of soluble Aβ may serve as a preclinical biomarker for AD diagnosis and that protecting myelinated fibers may represent a novel strategy for delaying the progression of early-stage AD.
Affiliation:
Department of Histology and Embryology, Chongqing Medical University, Chongqing 400016, PR China
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Defining the earliest pathological changes of Alzheimer’s disease
Author(s):
James C. Vickers, Stan Mitew, Adele Woodhouse, Carmen M. Fernandez-Martos, Mathew T. Kirkcaldie, Alison J. Canty, Graeme H. McCormack and Anna E. KingPages 281-287 (7)
Abstract:
The prospects for effectively treating well-established dementia, such as Alzheimer’s disease (AD), are slim, due to the destruction of key brain pathways that underlie higher cognitive function. There has been a substantial shift in the field towards detecting conditions such as AD in their earliest stages, which would allow preventative or therapeutic approaches to substantially reduce risk and/or slow the progression of disease. AD is characterized by hallmark pathological changes such as extracellular Aβ plaques and intracellular neurofibrillary pathology, which selectively affect specific subclasses of neurons and brain circuits. Current evidence indicates that Aβ plaques begin to form many years before overt dementia, a gradual and progressive pathology which offers a potential target for early intervention. Early Aβ changes in the brain result in localized damage to dendrites, axonal processes and synapses, to which excitatory synapses and the processes of projection neurons are highly vulnerable. Aβ pathology is replicated in a range of transgenic models overexpressing mutant human familial AD genes (eg APP and presenilin 1). Studying the development of aberrant regenerative and degenerative changes in neuritic processes associated with Aβ plaques may represent the best opportunity to understand the relationship between the pathological hallmarks of AD and neuronal damage, and to develop early interventions to prevent, slow down or mitigate against Aβ pathology and/or the neuronal alterations that leads to cognitive impairment.
Keywords:
Alzheimer’s disease, amyloid precursor protein, Aß, plaque, dystrophic neurite, selective vulnerability, transgenic mice.
Affiliation:
Wicking Dementia Research and Education Centre, Faculty of Health, University of Tasmania, Hobart, Tasmania 7000, Australia.
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Perspectives on the Tertiary Prevention Strategy for Alzheimer’s Disease
Author(s):
Xian-Le Bu, Shu-Sheng Jiao, Yan Lian and Yan-Jiang WangPages 307-316 (10)
Abstract:
Amyloid-beta (Aβ) plays a pivotal role in Alzheimer’s disease (AD) pathogenesis, and is the most promising disease-modifying target for AD. A succession of failures in Aβ-targeting clinical trials, however, has prompted questions on whether Aβ is the true cause of AD and a valid therapeutic target. Therefore, current therapeutic targets and intervention strategies must be reconsidered. In addition to Aβ, multiple pathological events such as tau hyperphosphorylation, oxidative stress and neuroinflammation are involved in the disease pathogenesis and cause cross-talk between these pathological pathways, which synergistically drive disease progression. Increasing evidence also reveals that the pathogenesis varies at different stages of the disease. Therefore, targeting Aβ alone at all stages of the disease would not be sufficient to halt or reverse disease progression. In the light of the pathophysiologic similarities between the development of ischemic stroke and AD, we can formulate management strategies for AD from the successful practice of ischemic stroke management, namely the tertiary prevention strategy. These new perspectives of tertiary prevention target both Aβ and different pathological pathways of AD pathogenesis at different stages of the disease, and may represent a promising avenue for the effective prevention and treatment of AD.
Keywords:
Alzheimer's disease, beta-amyloid, tau hyperphosphorylation, stroke, therapeutic strategy.
Affiliation:
Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, China.
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Oral Triphenylmethane Food Dye Analog, Brilliant Blue G, Prevents Neuronal Loss in APPSwDI/NOS2-/- Mouse Model
Author(s):
Jacob A. Irwin, Alev Erisir and Inchan KwonPages 663-677 (15)
Abstract:
Reducing amyloid-β (Aβ) accumulation is a promising strategy for developing Alzheimer’s Disease (AD) therapeutics. We recently reported that a triphenylmethane food dye analog, Brilliant Blue G (BBG), is a dose-dependent modulator of in vitro amyloid-β aggregation and cytotoxicity in cell-based assays. Following up on this recent work, we sought to further evaluate this novel modulator in a therapeutically-relevant AD transgenic mouse model. BBG was orally administered to APPSwDI/NOS2-/- mice for three months in order to assess its biocompatibility, its permeability across the blood-brain barrier, and its efficacy at rescuing AD pathology. The results showed that BBG was well-tolerated, caused no significant weight change/unusual behavior, and was able to significantly cross the AD blood-brain barrier in APPSwDI/NOS2-/- mice. Immunohistochemical and electron microscopic analysis of the brain sections revealed that BBG was able to significantly prevent neuronal loss and reduce intracellular APP/Aβ in hippocampal neurons. This is the first report of 1) the effect of Brilliant Blue G on neuronal loss in a transgenic animal model of AD, 2) oral administration of BBG to affect a protein conformation/aggregation disease, and 3) electron microscopic ultrastructural analysis of AD pathology in APPSwDI/NOS2-/- mice.
Keywords:
Alzheimer’s Disease, amyloid-β, blood-brain barrier, intracellular amyloid-β, neuronal loss, triphenylmethane dye.
Affiliation:
102 Gilmer Hall, PO Box 400400, Department of Psychology, University of Virginia, Charlottesville, Virginia 22904, USA., School of Materials Science and Engineering, Gwangju Institute of Science and Technology, 123 Cheomdan-gwagiro, Buk-gu, Gwangju 61005, Republic of Korea.
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