Investigating the process of fibril formation of the Iowa mutant of the Alzheimer\u27s peptide

The purpose of this study is to determine how the length of the beta-amyloid peptide, the specific region of the peptide, and a single point mutation affect the behavior of Alzheimer’s beta-amyloid. The beta-amyloid peptide, which is a 40 residue peptide that has been implicated as a potential cause of Alzheimer’s disease, has been shown to undergo a fibrillization process that involves numerous intermediate stages. One of the intermediate stages has revealed a high neurotoxicity and is believed to be the cause of neurodegeneration associated with Alzheimer’s disease. Various point mutations of the beta-amyloid peptide are responsible for the many familial forms of Alzheimer’s. Although familial diseases account for only a small percentage of Alzheimer’s cases, the study of their behavior can elucidate the mechanism through which fibrillization occurs by determining how each mutation, and its location, affect fibrillization. For the Iowa mutation, residue 23 in the amyloid beta peptide is changed from aspartic acid to asparagine. Residue 23 bonds with residue 28, enabling the peptide to misfold. Although the Iowa mutant undergoes the same general fibrillization process as the wild type, it has a different kinetic profile. This study focuses on a smaller fragment of the beta-amyloid peptide, Aβ22-35, which encompasses the hair-pin turn and the beta-sheet region of the peptide after the hair-pin turn. The point mutation can affect the fibrillization, structure, kinetics, and solubility of the peptide relative to that of the wild type

Inhibition of beta amyloid fibril formation to prevent development of Alzheimer's disease [abstract]

Abstract only availableFaculty Mentor: Dr. Renee JiJi, ChemistryStudies have indicated that Alzheimer's disease may be caused by the buildup of plaques in the brain, both intraneuronal and extracellular (Tanzi, 1989). The buildup of these plaques is caused by the aggregation of the beta amyloid peptide that is normally found in its monomeric form in the human blood stream. Development of a viable inhibitor to the aggregation of this peptde could result in a pharmaceutical application capable of preventing the onset of Alzheimer's disease. Several candidates for inhibitors were proposed, one of which was myricetin. Myricetin is a flavonoid that occurs naturally, found in some fruits and vegetables. To determine the inhibitive properties of myricetin, beta amyloid peptide was dissolved into a solution under conditions intended to mimic those of the human body. After various incubation periods, a fluorescent indicator that would only bind with the aggregated peptide was added, allowing for the quantification of the degree of aggregation that occurred in the solution.Studies have indicated that Alzheimer's disease may be caused by the buildup of plaques in the brain, both intraneuronal and extracellular (Tanzi, 1989). The buildup of these plaques is caused by the aggregation of the beta amyloid peptide that is normally found in its monomeric form in the human blood stream. Development of a viable inhibitor to the aggregation of this peptde could result in a pharmaceutical application capable of preventing the onset of Alzheimer's disease. Several candidates for inhibitors were proposed, one of which was myricetin. Myricetin is a flavonoid that occurs naturally, found in some fruits and vegetables. To determine the inhibitive properties of myricetin, beta amyloid peptide was dissolved into a solution under conditions intended to mimic those of the human body. After various incubation periods, a fluorescent indicator that would only bind with the aggregated peptide was added, allowing for the quantification of the degree of aggregation that occurred in the solution

Genomic profiling of cortical neurons following exposure to β-amyloid

In vitro and in vivo studies have shown that beta-amyloid peptide induces neuronal cell death. To explore the molecular basis underlying beta-amyloid-induced toxicity, we analyzed gene expression profiles of cultured rat cortical neurons treated for 24 and 48 h with synthetic beta-amyloid peptide. From the 8740 genes interrogated by oligonucleotide microarray analysis, 241 genes were found to be differentially expressed and segregated into distinct clusters. Functional clustering based on gene ontologies showed coordinated expression of genes with common biological functions and metabolic pathways. The comparison with genes differentially expressed in cerebellar granule neurons following serum and potassium deprivation indicates the existence of common regulatory mechanisms underlying neuronal cell death. Our results offer a genomic view of the changes that accompany beta-amyloid-induced neurodegeneration

Spectroscopic investigations of the beta-amyloid peptide

The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file.Title from title screen of research.pdf file (viewed on August 14, 2009)Includes bibliographical references.Thesis (M.S.) University of Missouri-Columbia 2008.Dissertations, Academic -- University of Missouri--Columbia -- Chemistry.The focus of this project is two-fold: examining the native structures of three different fragments of the beta-amyloid (A[beta]) peptide, and attempting to overcome some of the difficulties encountered in such an examination. The first part uses two different spectroscopic methods to compare the native structures of the hydrophilic [alpha beta] (1-16) fragment, the hydrophobic A[beta] (25-40) fragment, and the longer A[beta] (1-40) fragment. The second part focuses on replacing the counter-ion used in peptide purifications, including the purification of the A[beta] peptide, with a counter-ion that is less likely to alter the secondary structure and will not interfere with vibration-based spectroscopic studies. The third part highlights an attempt to improve upon current methods of peptide concentration estimation. Many experimental measurements require an accurate estimate of peptide concentration, which can prove to be particularly problematic for peptides such as A[beta] that are not easily soluble in aqueous solvents

Aloe arborescens Extract Protects IMR-32 Cells against Alzheimer Amyloid Beta Peptide via Inhibition of Radical Peroxide Production.

Aloe arborescens is commonly used as a pharmaceutical ingredient for its effect in burn treatment and ability to increase skin wound healing properties. Besides, it is well known to have beneficial phytotherapeutic, anticancer, and radio-protective properties. In this study, we first provided evidence that A. arborescens extract protects IMR32, a neuroblastoma human cellular line, from toxicity induced by beta amyloid, the peptide responsible for Alzheimer's disease. In particular, pretreatment with A. arborescens maintains an elevated cell viability and exerts a protective effect on mitochondrial functionality, as evidenced by oxygen consumption experiments. The protective mechanism exerted by A. arborescens seems be related to lowering of oxidative potential of the cells, as demonstrated by the ROS measurement compared with the results obtained in the presence of amyloid beta (1–42) peptide alone. Based on these preliminary observations we suggest that use of A. arborescens extract could be developed as agents for the management of AD

Influence of surface chemistry on the aggregation of beta amyloid peptide

Alzheimer\u27s disease is a progressive neurological ailment affecting 4.5 million aging Americans. The disease is characterized by the presence in the brain of self-assembled fibrils consisting of beta amyloid protein (Aβ). Soluble Aβ protein is present in normal human cerebrospinal fluid, but it is unclear what makes the protein aggregate into insoluble plaques. There is evidence that the Aβ fibril assembly is affected by interactions with biological surfaces, such as neuronal membranes. Here, surfaces consisting of self-assembled alkanethiol monolayers with different end groups were used to test the effect of surface chemistry on the structure and morphology of aggregates formed from the Aβ peptide. Reflection-absorption infrared spectroscopy and scanning force microscopy (SFM) were used to examine the interactions of the protein with the monolayers. It was found that the surfaces have a seeding effect on the Aβ protein in solution and can actually induce aggregation of the Aβ protein over time. The outcomes are important, because the work described here is the first attempt at relating the chemical makeup of supported, model monolayer surfaces and their propensity to interact with Aβ peptide in solution. Patterned surfaces consisting of fouling and non-fouling monolayers were constructed to determine how these different areas would affect the deposition and aggregation of the Aβ protein. It appeared that the Aβ protein adsorbed onto the ethylene glycol even though the ethylene glycol-terminated monolayers alone were previously seen to be non-fouling. This was important because it appears that the fouling monolayer can induce a change in conformation that allows the protein to stick to what are normally non-fouling surfaces. Mica-supported lipid bilayers consisting of 1-Palmitoyl-2-Oleoyl-sn-Glycero-3-Phosphocholine (POPC) and 1-Oleoyl-2-[12-[(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]dodecanoyl]-sn-Glycero-3-Phosphocholine (NBD-PC) were also used as a simple cell membrane model system. Fluorescence photobleaching recovery and SFM were used to determine the effects of association of the fibrils with the bilayers. It was found that the Aβ peptide affected the fluidity of the lipid bilayers and inserted itself into the lipid bilayer. This experiment was important because it offers information about the insertion of the Aβ peptide into cell membranes that could potentially be toxic to cells

Implications of gut and oral microbiota in neuroinflammatory responses in Alzheimer's disease

[EN] A diverse and stable microbiota promotes a healthy state, nevertheless, an imbalance in gut or oral bacterial composition, called dysbiosis, can cause gastrointestinal disorders, systemic inflammatory states and oxidative stress, among others. Recently, gut and oral dysbiosis has been linked to Alzheimer's disease (AD), which is considered the most common form of dementia and a public health priority due to its high prevalence and incidence. The aim of this review is to highlight the implications of gut and oral microbiota in the neuroinflammation characteristic of AD pathology and the subsequent cognitive impairment. It is a systematic review of the current literature obtained by searching the PubMed, Web of Science and Scopus databases. The characteristic intestinal dysbiosis in AD patients leads to increased permeability of the intestinal barrier and activates immune cells in the central nervous system due to translocation of microbiota-derived metabolites and/or bacteria into the circulation leading to increased neuroinflammation and neuronal loss, thus generating the cognitive impairment characteristic of AD. The presence in the central nervous system of Porphyromonas gingivalis can cause an increased neuroinflammation and beta-amyloid peptide accumulation.S