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Amyloid Cascade Hypothesis Perspective on Alzheimer's Disease
Title
Amyloid Cascade Hypothesis Perspective on Alzheimer's Disease.
Creator
Elsouri, Kawther, Kantorow, Marc, Florida Atlantic University, Charles E. Schmidt College of Medicine, Department of Biomedical Science
Abstract/Description
Alzheimer’s disease (AD) has been defined as a type of dementia that causes problems with memory, thinking, and behavior. AD is characterized by tau tangles and Aβ plaques in and around neurons, respectively. The impact this disease has on its victims’ health, both physically and mentally, is unimaginable and the rate of progression is not expected to decrease any time soon. This threat to our minds encourages the importance of understanding AD. Amongst the theories as to what bio mechanisms...
Show moreAlzheimer’s disease (AD) has been defined as a type of dementia that causes problems with memory, thinking, and behavior. AD is characterized by tau tangles and Aβ plaques in and around neurons, respectively. The impact this disease has on its victims’ health, both physically and mentally, is unimaginable and the rate of progression is not expected to decrease any time soon. This threat to our minds encourages the importance of understanding AD. Amongst the theories as to what bio mechanisms cause the brain to intertwine is the amyloid cascade hypothesis. The purpose of this thesis is to review the amyloid cascade hypothesis and discuss treatments which utilize this model. We also wish to examine social aspects such as loneliness and socioeconomic factors which are associated with the progression of AD. Research presented provides evidence that targeting the accumulation of Aβ in the brain will prevent further biochemical responses to form neurodegenerative pathology. From the collected data, we observe that therapies targeting the amyloidogenic pathway have received positive feedback in the medical community. Amongst them, an Aβ synthetic peptide vaccine which made history in vaccine development due to their responder rate. The impact of social factors such as loneliness in the advancement of AD is also supported by research. While it is acknowledged that any neurodegenerative disease is far too complex to narrow its cause specifically, this thesis provides an association with multiple aspects that can be understood and applied to future research in this field.
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Date Issued
2018
PURL
http://purl.flvc.org/fau/fd/FA00005986
Subject Headings
Alzheimer Disease--etiology, Amyloid, Amyloid beta-protein
Format
Document (PDF)
Aggregation kinetics of A\U+fffd\ peptides and the inhibition effects of small molecules on A\U+fffd\ peptide aggregation
Title
Aggregation kinetics of A\U+fffd\ peptides and the inhibition effects of small molecules on A\U+fffd\ peptide aggregation.
Creator
Hijazi, Ahmad Alex., Charles E. Schmidt College of Science, Department of Chemistry and Biochemistry
Abstract/Description
The pathology of Alzheimer's disease (AD) remains elusive. Competing evidence links amylois \U+fffd\-peptide (A\U+fffd\) amyloid formation to the phenotype of AD (1). The mechanism of amyloid fibril formation has been an ongoing investigation for many years. A\U+fffd\10-23 peptide, a fragment of A\U+fffd\1-42 peptide, contained crucial hydrophobic core residues (2). In this study, an investigation was launched to study the aggreagation process of A\U+fffd\1023 peptide and its ability to form...
Show moreThe pathology of Alzheimer's disease (AD) remains elusive. Competing evidence links amylois \U+fffd\-peptide (A\U+fffd\) amyloid formation to the phenotype of AD (1). The mechanism of amyloid fibril formation has been an ongoing investigation for many years. A\U+fffd\10-23 peptide, a fragment of A\U+fffd\1-42 peptide, contained crucial hydrophobic core residues (2). In this study, an investigation was launched to study the aggreagation process of A\U+fffd\1023 peptide and its ability to form amyloid fibrils. Furthermore, the presence of its hydrophobic core showed importance for its ability to aggregate and form amyloid fibrils. Thereafter, the inhibition of A\U+fffd\1-42 peptide aggregation was studied by using pyrimidine-based compounds. A\U+fffd\1-42 peptides, known to be neurotoxic, aggregate to form amyloid fibrils (3). This investigation may provide insight into the development of novel small molecular candidates to treat AD.
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Date Issued
2012
PURL
http://purl.flvc.org/FAU/3358550
Subject Headings
Amyloid beta-protein, Proteins, Metabolism, Disorders, Prions, Alzheimer's disease
Format
Document (PDF)
Aggregation Inhibition and Detection of Alzheimer’s Amyloidogenic and Oligomeric Peptides
Title
Aggregation Inhibition and Detection of Alzheimer’s Amyloidogenic and Oligomeric Peptides.
Creator
Elbassal, Esmail A. E., Du, Deguo, Florida Atlantic University, Charles E. Schmidt College of Science, Department of Chemistry and Biochemistry
Abstract/Description
Protein aggregation, oligomer and fibril formation is one of the dominant characteristics in the pathogenesis of a number of neurodegenerative diseases, such as Alzheimer’s disease (AD). Inhibition of toxic oligomer and fibril formation is one of the approaches to find potential drug candidates for AD. Additionally, early diagnosis of these amyloid species can provide mechanistic understanding of protein aggregation and thus can pave the way for preventing the onset of AD. The aim of this...
Show moreProtein aggregation, oligomer and fibril formation is one of the dominant characteristics in the pathogenesis of a number of neurodegenerative diseases, such as Alzheimer’s disease (AD). Inhibition of toxic oligomer and fibril formation is one of the approaches to find potential drug candidates for AD. Additionally, early diagnosis of these amyloid species can provide mechanistic understanding of protein aggregation and thus can pave the way for preventing the onset of AD. The aim of this dissertation was 1) to explore the effects of charged cholesterol derivatives on the aggregation kinetic behavior of Amyloid-β40 (Aβ40), 2) to probe Aβ40 oligomer and amyloid formation in vitro using gold nanoparticles (AuNPs), and 3) to monitor the kinetic effect of various natural product molecules on Aβ40 aggregation in vitro. In the first chapter, a general introduction about AD as an amyloidogenic disease, amyloid cascade hypothesis, and the manipulation of Aβ peptides aggregation kinetics using different approaches was presented. In the second chapter, we studied the effects of oppositely charged cholesterol derivatives on the aggregation kinetics of Aβ. In the third chapter, we developed a gold nanoparticles (AuNPs) assay to probe Aβ40 oligomers and amyloid formation. In chapter IV, we monitored the effects of various small molecules on the aggregation kinetics of Aβ40. In chapter V, we discussed the methods and experimental details.
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Date Issued
2018
PURL
http://purl.flvc.org/fau/fd/FA00013009
Subject Headings
Alzheimer's disease, Amyloid beta-protein, Oligomers, Protein Aggregates, Neurodegenerative Diseases
Format
Document (PDF)
Effects of small molecule modulators and Phospholipid Liposomes on βeta-amyloid (1-40) Amyloidogenesis
Title
Effects of small molecule modulators and Phospholipid Liposomes on βeta-amyloid (1-40) Amyloidogenesis.
Creator
Morris, Clifford, Du, Deguo, Florida Atlantic University, Charles E. Schmidt College of Science, Department of Chemistry and Biochemistry
Abstract/Description
Beta-Amyloid (1-40) (Aβ40) is an aggregation prone protein, which undergoes a nucleation-dependent aggregation process causing the pathological neurodegeneration by amyloid plaque formation implicated in Alzheimer’s disease. In this thesis, we investigated the effects of small molecule modulators extracted from the marine invertebrate Pseudopterogorgia elisabethae on the Aβ40 amyloidogenic process using in- vitro ThT fluorescence assay and atomic force microscopy. We also investigated the...
Show moreBeta-Amyloid (1-40) (Aβ40) is an aggregation prone protein, which undergoes a nucleation-dependent aggregation process causing the pathological neurodegeneration by amyloid plaque formation implicated in Alzheimer’s disease. In this thesis, we investigated the effects of small molecule modulators extracted from the marine invertebrate Pseudopterogorgia elisabethae on the Aβ40 amyloidogenic process using in- vitro ThT fluorescence assay and atomic force microscopy. We also investigated the effects of neutral and anionic phospholipid liposomes on Aβ40 aggregation. Our results show that a marine natural product Pseudopterosin-A and its derivatives can suppress and modulate the Aβ40 aggregation process. Furthermore, our results demonstrate that a neutral phospholipid liposome inhibits Aβ40 fibril formation, whereas the anionic liposomes promote it.
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Date Issued
2015
PURL
http://purl.flvc.org/fau/fd/FA00004453, http://purl.flvc.org/fau/fd/FA00004453
Subject Headings
Aggregation (Chemistry), Alzheimer's disease -- Pathogenesis, Alzheimer's disease -- Research, Amyloid beta protein, Molecular biology, Molecular dynamics, Prions, Proteins -- Metabolism -- Disorders
Format
Document (PDF)
Studies of Site-Specific Dynamics of Aβ Amyloid Formation and Effect of Macromolecules on Aβ Amyloidogenesis
Title
Studies of Site-Specific Dynamics of Aβ Amyloid Formation and Effect of Macromolecules on Aβ Amyloidogenesis.
Creator
Liu, Haiyang, Du, Deguo, Florida Atlantic University, Charles E. Schmidt College of Science, Department of Chemistry and Biochemistry
Abstract/Description
The aim of this dissertation was 1) to explore early stage aggregation kinetic behavior of Amyloid-β 1-40 (Aβ1-40) by incorporation of unnatural amino acid pcyanophenylalanine as a site-specific fluorescence reporter, 2) to explore the effect of macromolecules on the aggregation of Aβ1-40. Chapter One provides an introduction of Alzheimer’s disease as an amyloidogenic disease, amyloidogenic peptide and amyloid formation. Details were shown about the research progress of Aβ1-40 aggregation and...
Show moreThe aim of this dissertation was 1) to explore early stage aggregation kinetic behavior of Amyloid-β 1-40 (Aβ1-40) by incorporation of unnatural amino acid pcyanophenylalanine as a site-specific fluorescence reporter, 2) to explore the effect of macromolecules on the aggregation of Aβ1-40. Chapter One provides an introduction of Alzheimer’s disease as an amyloidogenic disease, amyloidogenic peptide and amyloid formation. Details were shown about the research progress of Aβ1-40 aggregation and Aβ1-40’s interaction with polyelectrolytes, and how treatments studies were designed. In Chapter two, using Aβ1-23 as a model molecule, the distinct site-specific dynamics was identified, during amyloid formation, and the structural characteristics of amyloid fibrils were defined by using an unnatural amino acid, p-cyanophenylalanine, as a sensitive fluorescent and Raman probe. The results reveal distinct local environmental changes of specific residues during the aggregation of Aβ1-23. The results also suggest that an edge-to-face aromatic interaction between the F4 and F19 residues from the adjacent in-register β-strands plays a key role in the conformational conversion to form and stabilize β-sheet structure. In Chapter Three, p-cyanophenylalanine was incorporated in the full sequence of Aβ1-40. Site-specific information from p-cyanophenylalanine fluorescence was studied and summarized. In Chapter Four, the inhibiting effect of an anionic polyelectrolyte poly(4- styrenesulfonate) (PSS) on the aggregation of Aβ1-40 peptide was reported. The results demonstrate the strong inhibition potential of PSS on the aggregation of Aβ1-40. Additional studies indicate that the presence of both aliphatic backbone as well as aromatic side chain group in PSS is essential for its inhibition activity. In Chapter Five, it was investigated the effect of two polyelectrolytes, chitosan (CHT) and N-trimethyl chitosan chloride (TMC), on the aggregation of Aβ1-40. Results show that both CHT and TMC exhibit a concentration-dependent decrease of amyloid aggregation suggesting their application as amyloid assembly inhibitors. Their binding mechanism was investigated by computational modeling which shows that Aβ1-40 monomer was primarily stabilized by electrostatic interactions with charged amine and quaternary amines of CHT and TMC respectively. Chapter Six, describes all experimental procedures and instrument setup in detail.
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Date Issued
2016
PURL
http://purl.flvc.org/fau/fd/FA00004769, http://purl.flvc.org/fau/fd/FA00004769
Subject Headings
Alzheimer's disease--Research., Alzheimer's disease--Pathogenesis., Molecular biology., Molecular dynamics., Prions., Amyloid beta-protein.
Format
Document (PDF)