Detection of Amyloid Beta 42 aggregation intermediates
(2020) KEMP30 20201Department of Chemistry
- Abstract
- Amyloid β 42 (Aβ42) is one of the peptides associated with Alzheimer's Disease (AD) due to its aggregation propensity which in the end causes neuronal damage. Much is yet to be understood on how the aggregation processes occurs but most importantly the toxic species responsible have not been identified yet. It is believed that transient oligomeric species are involved in the process. The lack of methods capable of detecting these species, which structurally vary from mature fibrils, makes it hard to analyze them and fully comprehend the mechanisms involved and possibly the toxicity. Thus, new fluorescent dyes, Luminescent Conjugated Oligotiophens (LCOs), are being developed with the aim of identifying structural differences in amyloids. In... (More)
- Amyloid β 42 (Aβ42) is one of the peptides associated with Alzheimer's Disease (AD) due to its aggregation propensity which in the end causes neuronal damage. Much is yet to be understood on how the aggregation processes occurs but most importantly the toxic species responsible have not been identified yet. It is believed that transient oligomeric species are involved in the process. The lack of methods capable of detecting these species, which structurally vary from mature fibrils, makes it hard to analyze them and fully comprehend the mechanisms involved and possibly the toxicity. Thus, new fluorescent dyes, Luminescent Conjugated Oligotiophens (LCOs), are being developed with the aim of identifying structural differences in amyloids. In this work, the LCOs are being applied in order to observe the Amyloid$\beta$42 aggregation process. The goal is to identify candidates which are able to detect transient species. The study focuses on the aggregation process at pH 6.8 with a 10 μM concentration in a 20 mM phosphate buffer. These conditions, previously applied, have identified novel intermediate structures in which fibrils are covered by protrusions, thus making sure that an intermediate specie is being formed. Our findings, based on linear combination models of fluorescence spectra, indicate that hFTAA and HS310 are promising dyes at the aforementioned conditions. Additionally, the aggregation process has been tested at pH 8 where qFTAA generated the most promising results. (Less)
- Popular Abstract
- Alzheimer’s Disease (AD) is the most common form of dementia, which causes the patient to lose cognitive abilities such as short-term memory caused by neuronal damage. The illness now days is categorized as incurable due to the lack of treatments. In order to resolve this problematic situation, it is necessary to fully comprehend the molecular mechanisms involved in this disease. Such knowledge can allow scientist to develop targeted approaches, which can cure or prevent the occurrence of such illness.
One of the hallmarks of AD is the presence of clumps in the brain tissue. These features are known as plaques and their main components are amyloid-beta proteins. Further more, the most common peptide found in the plaques is known as... (More) - Alzheimer’s Disease (AD) is the most common form of dementia, which causes the patient to lose cognitive abilities such as short-term memory caused by neuronal damage. The illness now days is categorized as incurable due to the lack of treatments. In order to resolve this problematic situation, it is necessary to fully comprehend the molecular mechanisms involved in this disease. Such knowledge can allow scientist to develop targeted approaches, which can cure or prevent the occurrence of such illness.
One of the hallmarks of AD is the presence of clumps in the brain tissue. These features are known as plaques and their main components are amyloid-beta proteins. Further more, the most common peptide found in the plaques is known as Amyloid β 42 (Aβ42). This small protein is present in all humans and, by itself, hasnot shown signs of toxicity. The peptide has a great tendency to aggregate in fibrillar structures which can be found in the plaques. Many studies have demonstrated that these fibrils are not toxic for neurons and therefore cannot be responsible for AD. On the contrary, studies have correlated the Aβ42 peptide with neuronal damage. Hence it is believed that the toxicity derives from intermediate species that form while the peptide is aggregating. The exact morphology, structure or composition of these species has not been identified jet.
This work aims at finding a method capable of detecting transient species. The success would allow scientists to easily detect the intermediates in tissue samples or in in vitro studies. Having a mean to identify these species will make it easier to study them in order comprehend whether they are toxic and to analyze the mechanism associated with them.
The method implemented in this study involves using different molecules called Luminescent Conjugated Oligotiophenes (LCOs). These molecules are fluorescent, which mean that they are able to absorb specific light and emit a different kind of light. This emission is studied by collecting spectra which indicate how much light is emitted at different wavelengths. The reason why these LCOs have been used is because they are capable of binding the fibrils formed by the Aβ42 peptide. By doing so their conformation changes and subsequently also the emission spectra changes. What we are looking for, is an LCO which is able to generate three, or more, district spectra: one associated with the free LCO, one associated with the LCO bound to the fibrils and one associated with the LCO bound to the intermediate specie. The reason why this can happen is because the molecule is able to exist in distinct conformations; free, bound to the fibrils and bound to the intermediate specie. This work has identified three promising LCOs (hFTAA, HS310 and qFTAA) which have been able to generate three district spectra. (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/9026579
- author
- Mazzotta, Francesca LU
- supervisor
-
- Sara Linse LU
- organization
- course
- KEMP30 20201
- year
- 2020
- type
- L3 - Miscellaneous, Projetcs etc.
- subject
- keywords
- Alzheimer’s Disease, LCOs, Fluorescence
- language
- English
- id
- 9026579
- date added to LUP
- 2020-10-12 15:41:52
- date last changed
- 2020-10-12 15:41:52
@misc{9026579,
abstract = {{Amyloid β 42 (Aβ42) is one of the peptides associated with Alzheimer's Disease (AD) due to its aggregation propensity which in the end causes neuronal damage. Much is yet to be understood on how the aggregation processes occurs but most importantly the toxic species responsible have not been identified yet. It is believed that transient oligomeric species are involved in the process. The lack of methods capable of detecting these species, which structurally vary from mature fibrils, makes it hard to analyze them and fully comprehend the mechanisms involved and possibly the toxicity. Thus, new fluorescent dyes, Luminescent Conjugated Oligotiophens (LCOs), are being developed with the aim of identifying structural differences in amyloids. In this work, the LCOs are being applied in order to observe the Amyloid$\beta$42 aggregation process. The goal is to identify candidates which are able to detect transient species. The study focuses on the aggregation process at pH 6.8 with a 10 μM concentration in a 20 mM phosphate buffer. These conditions, previously applied, have identified novel intermediate structures in which fibrils are covered by protrusions, thus making sure that an intermediate specie is being formed. Our findings, based on linear combination models of fluorescence spectra, indicate that hFTAA and HS310 are promising dyes at the aforementioned conditions. Additionally, the aggregation process has been tested at pH 8 where qFTAA generated the most promising results.}},
author = {{Mazzotta, Francesca}},
language = {{eng}},
note = {{Student Paper}},
title = {{Detection of Amyloid Beta 42 aggregation intermediates}},
year = {{2020}},
}