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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)
AMYLOIDOGENICITY OF THE PEPTIDE FRAGMENT IN MICROTUBULE BINDING REPEAT DOMAIN OF TAU
Title
AMYLOIDOGENICITY OF THE PEPTIDE FRAGMENT IN MICROTUBULE BINDING REPEAT DOMAIN OF TAU.
Creator
Islam, Majedul, Du, Deguo, Florida Atlantic University, Department of Chemistry and Biochemistry, Charles E. Schmidt College of Science
Abstract/Description
Tau, a microtubule-associated protein, is involved in more than 20 different tauopathic disorders characterized by aberrant intracellular aggregation of tau in the brain. However, it is still unclear how this highly soluble tau protein aggregates inside the brain. Thus, understanding the mechanistic details of tau aggregation is critical for unraveling the underlying pathology of tauopathies and developing effective strategies to inhibit tau aggregation. Herein, we investigated the...
Show moreTau, a microtubule-associated protein, is involved in more than 20 different tauopathic disorders characterized by aberrant intracellular aggregation of tau in the brain. However, it is still unclear how this highly soluble tau protein aggregates inside the brain. Thus, understanding the mechanistic details of tau aggregation is critical for unraveling the underlying pathology of tauopathies and developing effective strategies to inhibit tau aggregation. Herein, we investigated the aggregation of a novel 20-residue model peptide, tau₂₉₈₋₃₁₇, derived from the key microtubule-binding domain of the full sequence tau. Our study demonstrates that tau₂₉₈₋₃₁₇ highly mimics full-length tau's physical and aggregation properties. The fibrillation of the peptide is strongly dependent on external factors. The presence of polyanionic heparin (Hep) significantly promotes the aggregation of this peptide to form amyloid fibrils. The Hep-induced aggregation is sensitive to the ionic strength of the solution, suggesting an important role of electrostatic interactions in the mechanism of Hep-mediated aggregation. In addition, two positively charged polysaccharides, chitosan (CHT) and its quaternary derivative N-trimethyl chitosan (TMC), effectively inhibit Hep-induced aggregation of tau₂₉₈₋₃₁₇ in a concentration-dependent manner. Attractive electrostatic interactions between the positively charged moieties in CHT/TMC and the negatively charged residues of Hep play a critical role in inhibiting Hep–peptide interactions and suppressing peptide aggregation.
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Date Issued
2023
PURL
http://purl.flvc.org/fau/fd/FA00014211
Subject Headings
tau Proteins, Tauopathies, Amyloidogenic Proteins
Format
Document (PDF)
DISSECTING THE MECHANISTIC ROLES OF REGULATORS IN MEDIATING AMYLOID-BETA AMYLOIDOGENESIS
Title
DISSECTING THE MECHANISTIC ROLES OF REGULATORS IN MEDIATING AMYLOID-BETA AMYLOIDOGENESIS.
Creator
Shen, Fengyun, Du, Deguo, Florida Atlantic University, Department of Chemistry and Biochemistry, Charles E. Schmidt College of Science
Abstract/Description
Alzheimer’s disease (AD) is a common neurodegenerative disorder. The most recognized disease pathology is the Amyloid-β (Aβ) cascade hypothesis which states that the accumulation of Aβ plaques might be the cause of AD. In the AD brain, Aβ plaques stockpile a variety of molecular components including metals, lipids, nucleic acids, carbohydrates, and peptides, indicating Aβ aggregation might be influenced by these modulators. In this dissertation, we investigated the effects of Zn2+ and...
Show moreAlzheimer’s disease (AD) is a common neurodegenerative disorder. The most recognized disease pathology is the Amyloid-β (Aβ) cascade hypothesis which states that the accumulation of Aβ plaques might be the cause of AD. In the AD brain, Aβ plaques stockpile a variety of molecular components including metals, lipids, nucleic acids, carbohydrates, and peptides, indicating Aβ aggregation might be influenced by these modulators. In this dissertation, we investigated the effects of Zn2+ and carnosine, phospholipids, and β-hairpins on Aβ aggregation to dissect their mechanistic roles in the amyloidogenesis of Aβ. We first systematically studied the kinetic impact of Zn2+ on the aggregation of Aβ40 and Aβ40-M. Our results show that the presence of Zn2+ transforms the Aβ40 aggregation kinetics from a single sigmoidal to a biphasic process, while the aggregation of Aβ40-M is significantly suppressed by Zn2+. We also found that a nature dipeptide, carnosine, remarkably decreases the activity of Zn2+ on modulating Aβ aggregation, although it has a weak direct effect on the peptide aggregation kinetics. Second, we investigated the activities of Aβ40 and Aβ42 in inducing membrane damage and the effects of lipid membranes on the aggregation of these peptides using liposome models containing mitochondrial-specific phospholipid–cardiolipin (CL).
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Date Issued
2023
PURL
http://purl.flvc.org/fau/fd/FA00014314
Subject Headings
Alzheimer's disease, Amyloid beta-Peptides, 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)
HUMAN CALCITONIN: AN INVESTIGATION OF AMYLOID FORMATION AND INHIBITION
Title
HUMAN CALCITONIN: AN INVESTIGATION OF AMYLOID FORMATION AND INHIBITION.
Creator
Lantz, Richard, Du, Deguo, Florida Atlantic University, Department of Chemistry and Biochemistry, Charles E. Schmidt College of Science
Abstract/Description
Human calcitonin (hCT) is a peptide hormone that is produced by the thyroid gland where it regulates blood calcium and stimulates bone formation. However, increased concentrations can cause hCT to aggregate into amyloid fibrils where they can cause cellular toxicity. In this dissertation, we investigated the role of the N-terminal intramolecular disulfide bond, the effects cholesterol derivatives, the inhibitory effects of a group of polyphenolic molecules, and membrane interactions on hCT...
Show moreHuman calcitonin (hCT) is a peptide hormone that is produced by the thyroid gland where it regulates blood calcium and stimulates bone formation. However, increased concentrations can cause hCT to aggregate into amyloid fibrils where they can cause cellular toxicity. In this dissertation, we investigated the role of the N-terminal intramolecular disulfide bond, the effects cholesterol derivatives, the inhibitory effects of a group of polyphenolic molecules, and membrane interactions on hCT amyloid formation. To better understand hCT amyloid formation, we investigated the role of the N-terminal intramolecular disulfide bond has on the aggregation kinetics of hCT. Our results demonstrated that the presence of the disulfide bond is key to the formation of the oligomeric nucleus that is needed for amyloid formation. We also investigated the role of cholesterol, cholesterol sulfate, and 3β-[N-(dimethylaminoethane)carbamoyl]-cholesterol (DC-cholesterol) in moderating hCT fibril formation. We showed that cholesterol does not significantly affect hCT fibrillization while high concentrations of cholesterol sulfate has a moderate inhibiting effect. However, DC-cholesterol strongly inhibits hCT fibril formation in a concentration-dependent manner suggesting the role of electrostatic and hydrogen bonding interactions have in moderating the interactivity between hCT and the surface of DC-cholesterol vesicles. We also probed the inhibitory effects of a group of polyphenolic molecules on hCT fibril formation. Our results showed that molecules containing vicinal hydroxyl groups on the phenyl ring effectively inhibits hCT fibril formation though a plausible covalent linkage between the oxidized polyphenol and hCT.
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Date Issued
2020
PURL
http://purl.flvc.org/fau/fd/FA00013514
Subject Headings
Calcitonin, Amyloid
Format
Document (PDF)
INVESTIGATING THE AMYLOIDOGENESIS OF A PRION PEPTIDE (106-128)
Title
INVESTIGATING THE AMYLOIDOGENESIS OF A PRION PEPTIDE (106-128).
Creator
Regmi, Deepika, Du, Deguo, Florida Atlantic University, Department of Chemistry and Biochemistry, Charles E. Schmidt College of Science
Abstract/Description
The misfolding of native, cellular prion protein (PrPc) to a conformationally altered pathogenic isoform, designated scrapie PrPsc, is the main molecular process involved in the pathogenesis of prion diseases. Prion diseases are marked by the accumulation of conformationally modified forms of cellular prion protein. An N-terminal portion of the prion protein, PrP (106-128), is a 23-residue peptide fragment and is characterized by an amphipathic structure with two domains: a hydrophilic N...
Show moreThe misfolding of native, cellular prion protein (PrPc) to a conformationally altered pathogenic isoform, designated scrapie PrPsc, is the main molecular process involved in the pathogenesis of prion diseases. Prion diseases are marked by the accumulation of conformationally modified forms of cellular prion protein. An N-terminal portion of the prion protein, PrP (106-128), is a 23-residue peptide fragment and is characterized by an amphipathic structure with two domains: a hydrophilic N-terminal domain and a hydrophobic C-terminal domain. In this study, the aggregation characteristics of the PrP (106-128) peptide were investigated using a combination of biophysical approaches. We investigated the effect of different factors including concentrations, pH, and metal ions, on the aggregation of the peptide. Our results demonstrated that the peptide steadily aggregates at concentrations higher than 25 M. The aggregation propensity and fibril formation is higher at pH 7.4 and pH 8.1, and the aggregation is inhibited at pH lower than 6. Furthermore, our results indicate that the Cu2+ has much less effect on the peptide amyloidogenesis, while Zn2+ has a significant influence on the PrP (106-128) amyloidogenesis. We further presented a systematic analysis of the impact of phospholipid liposomes of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1’-racglycerol) (POPG) in the absence or presence of cholesterol, on the amyloidogenesis of PrP (106-128). The results showed that POPC vesicles does not significantly influence the aggregation kinetics of the peptide. However, the anionic lipid POPG delays the aggregation in a concentration-dependent manner, whereas the addition of POPG with the cholesterol shows fast kinetics of fibrillization, thus reducing the lag time of the aggregation kinetics. We also monitored the effect of cholesterol and its derivatives including cholesterol-SO4 and DC-cholesterol on PrP (106-128) amyloidogenesis. Our results showed that the cholesterol inhibits the peptide aggregation and delays the formation of fibrils in a concentration-dependent manner. Cholesterol-SO4 dramatically facilitates the aggregation at high concentrations but has the potential to slow down the fibrillization at low concentrations, whereas cationic DC-cholesterol vesicles can effectively inhibit peptide fibril formation at high concentrations.
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Date Issued
2020
PURL
http://purl.flvc.org/fau/fd/FA00013565
Subject Headings
Prion Diseases, Prions--pathogenicity, Amyloid, Peptides, Prions
Format
Document (PDF)
PRION FRAGMENT 106-128: AN INVESTIGATION OF AMYLOID FORMATION AND INHIBITION
Title
PRION FRAGMENT 106-128: AN INVESTIGATION OF AMYLOID FORMATION AND INHIBITION.
Creator
Regmi, Deepika, Du, Deguo, Florida Atlantic University, Department of Chemistry and Biochemistry, Charles E. Schmidt College of Science
Abstract/Description
Misfolding and aggregation of Cellular Prion Protein (PrPc) is a major molecular process involved in the pathogenesis of Prion diseases. An N-terminal portion of the Prion protein, PrP106-128, is a 23-residue peptide fragment characterized by an amphipathic structure with two domains: a hydrophilic N-terminal domain and a hydrophobic C-terminal domain. Here, we studied the aggregation properties of the prion fragment peptide PrP106-128. The results show that the peptide aggregates in a...
Show moreMisfolding and aggregation of Cellular Prion Protein (PrPc) is a major molecular process involved in the pathogenesis of Prion diseases. An N-terminal portion of the Prion protein, PrP106-128, is a 23-residue peptide fragment characterized by an amphipathic structure with two domains: a hydrophilic N-terminal domain and a hydrophobic C-terminal domain. Here, we studied the aggregation properties of the prion fragment peptide PrP106-128. The results show that the peptide aggregates in a concentration-dependent manner in an aqueous solution and that the aggregation is sensitive to pH and the preformed amyloid seeds.Furthermore, we show that the zwitterionic POPC liposomes moderately inhibit the aggregation of PrP(106–128), whereas POPC/cholesterol (8:2) vesicles facilitate peptide aggregation likely due to the increase of the lipid packing order and membrane rigidity in the presence of cholesterol. In addition, anionic lipid vesicles of POPG and POPG/cholesterol above a certain concentration accelerate the aggregation of the peptide remarkably. The strong electrostatic interactions between the N-terminal region of the peptide and POPG may constrain the conformational plasticity of the peptide, preventing insertion of the peptide into the inner side of the membrane and thus promoting fibrillation on the membrane surface. The results suggest that the charge properties of the membrane, the composition of the liposomes, and the rigidity of lipid packing are critical in determining peptide adsorption on the membrane surface and the efficiency of the membrane in catalyzing peptide oligomeric nucleation and amyloid formation.
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Date Issued
2023
PURL
http://purl.flvc.org/fau/fd/FA00014356
Subject Headings
Prion Proteins, Prion diseases, Epigallocatechin gallate, Amyloid
Format
Document (PDF)
Role of the N-Terminal Hydrophilic Region of Amyloid Beta Peptide in Amyloidogenesis, Membrane Interaction and Toxicity Associated with Alzheimer’s Disease
Title
Role of the N-Terminal Hydrophilic Region of Amyloid Beta Peptide in Amyloidogenesis, Membrane Interaction and Toxicity Associated with Alzheimer’s Disease.
Creator
Morris, Clifford M., Du, Deguo, Florida Atlantic University, Charles E. Schmidt College of Science, Department of Chemistry and Biochemistry
Abstract/Description
Alzheimer’s disease (AD) is a deleterious neurodegenerative disease caused in major part by the aberrant processing and accumulation of amyloid beta peptides. In this dissertation, we systematically investigated the role of N-terminal region (NTR) residues of amyloid (1-40) (Aβ40) peptide in amyloidogenesis, lipid bilayer membrane interaction and damage, as well as neurotoxicity. Herein, we investigated the role of NTR residues on the aggregation and amyloid fibril formation process, to gain...
Show moreAlzheimer’s disease (AD) is a deleterious neurodegenerative disease caused in major part by the aberrant processing and accumulation of amyloid beta peptides. In this dissertation, we systematically investigated the role of N-terminal region (NTR) residues of amyloid (1-40) (Aβ40) peptide in amyloidogenesis, lipid bilayer membrane interaction and damage, as well as neurotoxicity. Herein, we investigated the role of NTR residues on the aggregation and amyloid fibril formation process, to gain understanding on the electrostatic and hydrophobic constituents of the mechanism. This was achieved by substituting specific charged residues located in the NTR of Aβ40 and investigating their effects through a variety of techniques. We also investigated the role of NTR charged residues in their interaction with supported phospholipid bilayer membranes through the use of Quartz Crystal Microbalance with Dissipation (QCM-D) monitoring to gain insight on the mechanistic details of the interaction. To further understand the implications of substituting charged NTR residues on membrane interaction, pore formation and damage, we utilized a carboxyfluorescein dye leakage assay to quantify the membrane damage caused by Aβ40 and the NTR mutants. We also performed neurotoxicity assay with SH-SY5Y neuroblastoma cells to shed light on the effects of NTR substitutions on cellular toxicity. Finally, we synthesized a polymer, trimethyl chitosan (TMC), and utilized it as a polyelectrolyte monitor of electrostatic interactions occurring between TMC and the NTR of Aβ40. Our results demonstrate that the NTR charged residues of Aβ40 contribute significantly to the aggregation process, amyloidogenesis, and phospholipid membrane interaction and perturbation by means of electrostatic, thermodynamic and hydrophobic forces.
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Date Issued
2019
PURL
http://purl.flvc.org/fau/fd/FA00013246
Subject Headings
Alzheimer's disease, Amyloid beta-Peptides, Amyloid
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)
Studying the Effects of Lipid Membranes and Polysaccharides on the Amyloidogenicity of Fragments of Amyloid Beta
Title
Studying the Effects of Lipid Membranes and Polysaccharides on the Amyloidogenicity of Fragments of Amyloid Beta.
Creator
Petersen, Katherine, Du, Deguo, Florida Atlantic University, Department of Chemistry and Biochemistry, Charles E. Schmidt College of Science
Abstract/Description
The amyloid beta (Aβ) peptide has been linked to Alzheimer’s Disease (AD) since the early 1990s. Since then, many studies have characterized the peptide and examined its aggregation process. Aβ is a 40 or 42-residue peptide, composed of a charged N-terminal and hydrophobic C-terminal, that aggregates into characteristic β-sheets forming insoluble plaques in the brains of (AD) patients. In recent years an intermediate oligomeric species has been shown to interact with lipid membranes, largely...
Show moreThe amyloid beta (Aβ) peptide has been linked to Alzheimer’s Disease (AD) since the early 1990s. Since then, many studies have characterized the peptide and examined its aggregation process. Aβ is a 40 or 42-residue peptide, composed of a charged N-terminal and hydrophobic C-terminal, that aggregates into characteristic β-sheets forming insoluble plaques in the brains of (AD) patients. In recent years an intermediate oligomeric species has been shown to interact with lipid membranes, largely resulting in the etiology of AD. In this study, two fragments are used, the 23-residue N-terminal fragment, Aβ23 and the 30-residue C-terminal fragment, Aβ11-40, to better understand the role of the N and C-terminus in the aggregation of Aβ peptide. Aβ11-40 has also been found in the brains of AD patients, playing a biological role in the disease. This study used analytical and biophysical techniques to systematically synthesize, purify, characterize, and study these fragments' aggregation in different conditions. We investigated the effects of lipid membranes on the aggregation of Aβ23 and Aβ11-40 and the activities of these peptides in inducing membrane damage. The results show that the aggregation of Aβ23 was increased in the presence of lipid membranes, likely due to favorable electrostatic interactions. However, the aggregation of Aβ11-40 was not influenced by lipid membranes. A dye leakage study was carried out to study the membrane damage occurring as a result of fragments' interaction with lipid membranes. The results showed that neither fragment had a profound effect on membrane destruction, although the charge of the lipid head seemed to play a role. This work's second study focused on the effect of three specific polysaccharides, heparin, chitosan (CHT), and trimethyl chitosan (TMC), on the aggregation of Aβ23 and Aβ11-40. The results showed that for Aβ23, heparin increased aggregation, while both CHT and TMC decreased aggregation. However, for Aβ11-40, both heparin and CHT did not affect aggregation, while TMC decreased aggregation.
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Date Issued
2023
PURL
http://purl.flvc.org/fau/fd/FA00014294
Subject Headings
Amyloid beta-Peptides, Alzheimer's disease
Format
Document (PDF)