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Infectious origin of Alzheimer’s disease: Amyloid beta as a component of brain antimicrobial immunity

The amyloid cascade hypothesis, focusing on pathological proteins aggregation, has so far failed to uncover the root cause of Alzheimer’s disease (AD), or to provide an effective therapy. This traditional paradigm essentially explains a mechanism involved in the development of sporadic AD rather tha...

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Autores principales: Vojtechova, Iveta, Machacek, Tomas, Kristofikova, Zdenka, Stuchlik, Ales, Petrasek, Tomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9671327/
https://www.ncbi.nlm.nih.gov/pubmed/36395147
http://dx.doi.org/10.1371/journal.ppat.1010929
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author Vojtechova, Iveta
Machacek, Tomas
Kristofikova, Zdenka
Stuchlik, Ales
Petrasek, Tomas
author_facet Vojtechova, Iveta
Machacek, Tomas
Kristofikova, Zdenka
Stuchlik, Ales
Petrasek, Tomas
author_sort Vojtechova, Iveta
collection PubMed
description The amyloid cascade hypothesis, focusing on pathological proteins aggregation, has so far failed to uncover the root cause of Alzheimer’s disease (AD), or to provide an effective therapy. This traditional paradigm essentially explains a mechanism involved in the development of sporadic AD rather than its cause. The failure of an overwhelming majority of clinical studies (99.6%) demonstrates that a breakthrough in therapy would be difficult if not impossible without understanding the etiology of AD. It becomes more and more apparent that the AD pathology might originate from brain infection. In this review, we discuss a potential role of bacteria, viruses, fungi, and eukaryotic parasites as triggers of AD pathology. We show evidence from the current literature that amyloid beta, traditionally viewed as pathological, actually acts as an antimicrobial peptide, protecting the brain against pathogens. However, in case of a prolonged or excessive activation of a senescent immune system, amyloid beta accumulation and aggregation becomes damaging and supports runaway neurodegenerative processes in AD. This is paralleled by the recent study by Alam and colleagues (2022) who showed that alpha-synuclein, the protein accumulating in synucleinopathies, also plays a critical physiological role in immune reactions and inflammation, showing an unforeseen link between the 2 unrelated classes of neurodegenerative disorders. The multiplication of the amyloid precursor protein gene, recently described by Lee and collegues (2018), and possible reactivation of human endogenous retroviruses by pathogens fits well into the same picture. We discuss these new findings from the viewpoint of the infection hypothesis of AD and offer suggestions for future research.
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spelling pubmed-96713272022-11-18 Infectious origin of Alzheimer’s disease: Amyloid beta as a component of brain antimicrobial immunity Vojtechova, Iveta Machacek, Tomas Kristofikova, Zdenka Stuchlik, Ales Petrasek, Tomas PLoS Pathog Review The amyloid cascade hypothesis, focusing on pathological proteins aggregation, has so far failed to uncover the root cause of Alzheimer’s disease (AD), or to provide an effective therapy. This traditional paradigm essentially explains a mechanism involved in the development of sporadic AD rather than its cause. The failure of an overwhelming majority of clinical studies (99.6%) demonstrates that a breakthrough in therapy would be difficult if not impossible without understanding the etiology of AD. It becomes more and more apparent that the AD pathology might originate from brain infection. In this review, we discuss a potential role of bacteria, viruses, fungi, and eukaryotic parasites as triggers of AD pathology. We show evidence from the current literature that amyloid beta, traditionally viewed as pathological, actually acts as an antimicrobial peptide, protecting the brain against pathogens. However, in case of a prolonged or excessive activation of a senescent immune system, amyloid beta accumulation and aggregation becomes damaging and supports runaway neurodegenerative processes in AD. This is paralleled by the recent study by Alam and colleagues (2022) who showed that alpha-synuclein, the protein accumulating in synucleinopathies, also plays a critical physiological role in immune reactions and inflammation, showing an unforeseen link between the 2 unrelated classes of neurodegenerative disorders. The multiplication of the amyloid precursor protein gene, recently described by Lee and collegues (2018), and possible reactivation of human endogenous retroviruses by pathogens fits well into the same picture. We discuss these new findings from the viewpoint of the infection hypothesis of AD and offer suggestions for future research. Public Library of Science 2022-11-17 /pmc/articles/PMC9671327/ /pubmed/36395147 http://dx.doi.org/10.1371/journal.ppat.1010929 Text en © 2022 Vojtechova et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Review
Vojtechova, Iveta
Machacek, Tomas
Kristofikova, Zdenka
Stuchlik, Ales
Petrasek, Tomas
Infectious origin of Alzheimer’s disease: Amyloid beta as a component of brain antimicrobial immunity
title Infectious origin of Alzheimer’s disease: Amyloid beta as a component of brain antimicrobial immunity
title_full Infectious origin of Alzheimer’s disease: Amyloid beta as a component of brain antimicrobial immunity
title_fullStr Infectious origin of Alzheimer’s disease: Amyloid beta as a component of brain antimicrobial immunity
title_full_unstemmed Infectious origin of Alzheimer’s disease: Amyloid beta as a component of brain antimicrobial immunity
title_short Infectious origin of Alzheimer’s disease: Amyloid beta as a component of brain antimicrobial immunity
title_sort infectious origin of alzheimer’s disease: amyloid beta as a component of brain antimicrobial immunity
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9671327/
https://www.ncbi.nlm.nih.gov/pubmed/36395147
http://dx.doi.org/10.1371/journal.ppat.1010929
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