Investigating The Role Of Amyloid Beta Peptides In Inflammation And Alzheimers Disease Pathogenesis
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Apolipoprotein E and Alzheimer’s Disease
| Author | : A.D. Roses |
| Publisher | : Springer Science & Business Media |
| Total Pages | : 208 |
| Release | : 2012-12-06 |
| Genre | : Medical |
| ISBN | : 3642801099 |
There is now considerable genetic evidence that the type 4 allele of the apolipoprotein E gene is a major susceptibility factor associated with late-onset Alzheimer's disease, the common form of the disease defined as starting after sixty years of age. The role of apolipoprotein E in normal brain metabolism and in the pathogenesis of Alzheimer's disease are new and exciting avenues of research. This book, written by the most outstanding scientists in this new filed, is the first presentation of results concerning the implications of apolipoprotein E on the genetics, cell biology, neuropathology, biochemistry, and therapeutic management of Alzheimer's disease.
Potential Covalent Modification of Amyloid-beta Protein and Its Effect on Aggregation
| Author | : Izzeddin Alsalahat |
| Publisher | : |
| Total Pages | : |
| Release | : 2012 |
| Genre | : |
| ISBN | : |
The pathogenesis of Alzheimer's disease (AD) is mainly correlated to the misfolding and aggregation of the beta-amyloid peptide. This causes extracellular amyloid-beta peptide deposition as monomers, oligomers, fibrils and plaques in the brain. Compounds that may covalently interact with amyloid-beta protein might have a role in altering the pathogenesis of AD. Some beta-lactam antibiotics (e.g. amoxicillin), orlistat, resveratrol, vanillin, o-vanillin and ethyl vanillin have been shown to modulate the process of amyloid-beta peptide aggregation using a range of techniques. Several approaches have been used to investigate modulation of amyloid-beta peptide by these compounds. These methods include molecular modelling using both covalent and non-covalent docking, investigation of covalent interaction by MALDI and LC-MS/MS mass spectrometry, and synthesis of model peptides representing key motifs in the amyloid-beta peptide, aggregation studies of amyloid-beta peptide by using the thioflavin T (ThT) fluorescence assay, studying the morphology of aggregation by atomic force microscopy (AFM), and investigating their ability to inhibit amyloid-beta peptide cell toxicity by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell toxicity assay. In non-covalent docking, amoxicillin gave the best results after curcumin when docked with amyloid-beta peptides, while in covalent docking, the binding of vanillin with Lys16 in amyloid-beta peptide was favourable. Except orlistat and resveratrol, the other compounds were found to modulate amyloid-beta peptide aggregation by covalent interaction as confirmed by mass spectrometry. Vanillin derivatives were found to interact with Lys16 in the full length amyloid-beta peptide and synthesised model peptide fragments of amyloid-beta peptide. Penicillins were also shown to covalently interact with amyloid-beta peptide, probably by interacting with a serine residue in the amyloid-beta peptide. Surprisingly, orlistat and resveratrol were shown to induce hydrolysis of amyloid-beta peptide after 10 days of incubation. All of the compounds were found to inhibit aggregation of amyloid-beta peptide as confirmed by both the ThT fluorescence assay and AFM. In addition, the compounds showed significant cytoprotective activity against amyloid-beta peptide (A[beta](1-42)) cell toxicity as shown by the MTT cell toxicity assay. The best inhibitor was orlistat, with complete cell protection, and then resveratrol. Vanillin derivatives showed similar activity, whilst the weakest inhibitor was amoxicillin.
Tau oligomers
| Author | : Jesus Avila |
| Publisher | : Frontiers E-books |
| Total Pages | : 114 |
| Release | : 2014-08-18 |
| Genre | : Medicine (General) |
| ISBN | : 288919261X |
Neurofibrillary tangles (NFTs) composed of intracellular aggregates of tau protein are a key neuropathological feature of Alzheimer’s Disease (AD) and other neurodegenerative diseases, collectively termed tauopathies. The abundance of NFTs has been reported to correlate positively with the severity of cognitive impairment in AD. However, accumulating evidences derived from studies of experimental models have identified that NFTs themselves may not be neurotoxic. Now, many of tau researchers are seeking a “toxic” form of tau protein. Moreover, it was suggested that a “toxic” tau was capable to seed aggregation of native tau protein and to propagate in a prion-like manner. However, the exact neurotoxic tau species remain unclear. Because mature tangles seem to be non-toxic component, “tau oligomers” as the candidate of “toxic” tau have been investigated for more than one decade. In this topic, we will discuss our consensus of “tau oligomers” because the term of “tau oligomers” [e.g. dimer (disulfide bond-dependent or independent), multimer (more than dimer), granular (definition by EM or AFM) and maybe small filamentous aggregates] has been used by each researchers definition. From a biochemical point of view, tau protein has several unique characteristics such as natively unfolded conformation, thermo-stability, acid-stability, and capability of post-translational modifications. Although tau protein research has been continued for a long time, we are still missing the mechanisms of NFT formation. It is unclear how the conversion is occurred from natively unfolded protein to abnormally mis-folded protein. It remains unknown how tau protein can be formed filaments [e.g. paired helical filament (PHF), straight filament and twisted filament] in cells albeit in vitro studies confirmed tau self-assembly by several inducing factors. Researchers are still debating whether tau oligomerization is primary event rather than tau phosphorylation in the tau pathogenesis. Inhibition of either tau phosphorylation or aggregation has been investigated for the prevention of tauopathies, however, it will make an irrelevant result if we don’t know an exact target of neurotoxicity. It is a time to have a consensus of definition, terminology and methodology for the identification of “tau oligomers”.
Pathobiology of Alzheimer's Disease
| Author | : |
| Publisher | : Elsevier |
| Total Pages | : 273 |
| Release | : 1995-10-17 |
| Genre | : Medical |
| ISBN | : 0080538495 |
Neuroscience Perspectives provides multidisciplinary reviews of topics in one of the most diverse and rapidly advancing fields in the life sciences.Whether you are a new recruit to neuroscience, or an established expert, look to this series for 'one-stop' sources of the historical, physiological, pharmacological, biochemical, molecular biological and therapeutic aspects of chosen research areas.The last decade has seen tremendous advances in our understanding of the pathobiology of Alzheimer's disease. These will lead to the first generation of drugs aimed at prevention rather than cure. This book covers some of the most important and exciting of these advances, with chapters written by many of the leading researchers in the field.With genetic studies as a backbone to this volume many chapters are devoted to the function and regulation of amyloid b-protein precursor (APP) and apolipoprotein E (ApoE). Other chapters describe cell biological approaches helping to piece together the link between the genetic alterations and the phenotype we call Alzheimer's disease.Although APP and its proteolytic cleavage product, amyloid b-protein, do not answer all the questions, detailed research into this system has undoubtedly increased our knowledge of the pathobiology of AD and has lead to the identification of other risk factors. Understanding the role of ApoE in the pathology of Alzheimer's disease promises to open a whole new field in AD research.* * Reviews the current knowledge of the pathogenesis of Alzheimer's Disease from a clinical perspective to a genetic and cell biological perspective* A comprehensive description of the role of amyloid B-protein precursor in Alzheimer's disease.* Up-to-date research data* Clear illustrations complement the text
The Biology of Alzheimer Disease
| Author | : Dennis J. Selkoe |
| Publisher | : Cold Spring Harbor Perspective |
| Total Pages | : 0 |
| Release | : 2012 |
| Genre | : Medical |
| ISBN | : 9781936113446 |
Alzheimer disease causes the gradual deterioration of cognitive function, including severe memory loss and impairments in abstraction and reasoning. Understanding the complex changes that occur in the brain as the disease progressesincluding the accumulation of amyloid plaques and neurofibrillary tanglesis critical for the development of successful therapeutic approaches. Written and edited by leading experts in the field, this collection from Cold Spring Harbor Perspectives in Medicine includes contributions covering all aspects of Alzheimer disease, from our current molecular understanding to therapeutic agents that could be used to treat and, ultimately, prevent it. Contributors discuss the biochemistry and cell biology of amyloid -protein precursor (APP), tau, presenilin, -secretase, and apolipoprotein E and their involvement in Alzheimer disease. They also review the clinical, neuropathological, imaging, and biomarker phenotypes of the disease; genetic alterations associated with the disorder; and epidemiological insights into its causation and pathogenesis. This comprehensive volume, which includes discussions of therapeutic strategies that are currently used or under development, is a vital reference for neurobiologists, cell biologists, pathologists, and other scientists pursuing the biological basis of Alzheimer disease, as well as investigators, clinicians, and students interested in its pathogenesis, treatment, and prevention.
Examining an Unexpected Protective Role of Amyloid-beta in Experimental Autoimmune Encephalomyelitis
| Author | : Ms. Jacqueline Leigh Grant |
| Publisher | : |
| Total Pages | : |
| Release | : 2012 |
| Genre | : |
| ISBN | : |
[Beta]-amyloid-42 (A[beta]42) and [beta]-amyloid-40 (A[beta]40), major components of senile plaque deposits in Alzheimer's disease (AD), are considered neurotoxic and pro-inflammatory. In Multiple Sclerosis (MS), A[beta]42 is upregulated in brain lesions and damaged axons. Here we found, unexpectedly, that treatment with either A[beta]42 or A[beta]40 peptides reduced motor paralysis and brain inflammation in four different models of experimental autoimmune encephalomyelitis (EAE) with attenuation of motor paralysis, reduction of inflammatory lesions in the central nervous system (CNS), and suppression of lymphocyte activation. A[beta]42 and A[beta]40 treatments were effective in reducing ongoing paralysis induced with adoptive transfer of either autoreactive Th1 or Th17 cells. High-dimensional 14-parameter flow cytometry of peripheral immune cell populations after in vivo A[beta]2 and A[beta]40 treatment revealed substantial modulations in the percentage of lymphoid and myeloid subsets during EAE. Major pro-inflammatory cytokines and chemokines were reduced in the blood following A[beta] peptide treatment. Protection conferred by A[beta] treatment did not require its delivery to the brain: adoptive transfer with lymphocytes from donors treated with A[beta]42 attenuated EAE in WT recipient mice and A[beta] deposition in the brain was not detected in treated EAE mice by immunohistochemical analysis. In contrast to the improvement in EAE with A[beta]-treatment, EAE was worse in mice with genetic deletion of the amyloid precursor protein. Therefore, in the absence of A[beta] there is exacerbated clinical EAE disease progression. Since A[beta]42 and A[beta]40 ameliorate experimental autoimmune inflammation targeting the CNS, we might now consider its potential anti-inflammatory role in other neuropathological conditions.
Developments in Tryptophan and Serotonin Metabolism
| Author | : Graziella Allegri |
| Publisher | : Springer Science & Business Media |
| Total Pages | : 810 |
| Release | : 2004-01-15 |
| Genre | : Science |
| ISBN | : 9780306477553 |
This volume contains the proceedings of the Tenth International Meeting of the International Study Group for Tryptophan Research (ISTR V), held at the University of Padova, Padova, Italy, from 25-29 June, 2002 under the auspices of the Ministry of Education, University and Research (MIUR) in Roma, the University of Padova, the Italian Chemical Society - Division of Pharmaceutical Chemistry, the Veneto Region and the City of Padova. The meeting was organized to cover the recent developments in the field of tryptophan research. Weare very honoured that so many speakers accepted our invitation to give plenary lectures which, with the other communications, demonstrated the high scientific value of the Meeting. The publications in this volume are subdivided into nine main chapters, and cover all the major aspects in immunology, neurobiology, psychiatry, pathology, clinics, metabolism, enzymology, pharmacology, toxicology, melatonin, exercise and analytical chemistry. The volume includes the contributions of 325 scientists from 24 countries, and the Musajo Memorial Lecture delivered by Prof. Osamu Hayaishi during the Opening Ceremony.
Handbook of Infection and Alzheimer's Disease
| Author | : J. Miklossy |
| Publisher | : IOS Press |
| Total Pages | : 420 |
| Release | : 2017-03-10 |
| Genre | : Medical |
| ISBN | : 1614997063 |
Alzheimer’s disease is one of the biggest emerging public health problems in the world. Although the last four decades have yielded important insights into the pathogenesis of Alzheimer’s disease, its cause is still unclear, and if it is not discovered the world will face an unprecedented healthcare problem by the middle of this century. In recent years, evidence of the microbial origin of various chronic inflammatory disorders – including several neurodegenerative, neuropsychiatric and other systemic disorders – has been steadily growing. Accumulating new and historic observations are providing evidence of an association between Alzheimer’s disease and certain infectious agents, and may offer new opportunities for ground-breaking healthcare solutions. This handbook assembles and connects findings with regard to the infectious origin of Alzheimer’s disease, and the data presented in its chapters deserves the attention of the neuroscience community, physicians and the health departments of governments worldwide by virtue of its amount and quality. This handbook offers a comprehensive overview of the current knowledge regarding the topic of infection and Alzheimer’s disease, which could pinpoint the cause of this disease. Influential diagnosis, treatment and prevention strategies may also emerge from this crucial research area.
Investigating the Role of the Amyloid Precursor Protein in the Pathogenesis of Alzheimer's Disease
| Author | : Roger Lefort |
| Publisher | : |
| Total Pages | : |
| Release | : 2011 |
| Genre | : |
| ISBN | : |
We also found that dimerization of APP is sufficient to promote the amyloidogenic pathway, by increasing levels of the Î2-secretase BACE1, resulting in increased AÎ2 production. Finally, we found that dimerization of APP triggered caspase-dependent cleavage of APP and the formation of a second neurotoxic fragment, termed C31, which also mimics the effects of AÎ2 in hippocampal neurons. Taken together, our data provides support for the occurrence of a positive pathogenic feedback loop involving AÎ2, APP and C31 in neurons.
