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  Re-thinking the etiological framework of neurodegeneration

Castillo, X., Castro-Obregón, S., Gutiérrez-Becker, B., Gutiérrez-Ospina, G., Karalis, N., Khalil, A., et al. (2019). Re-thinking the etiological framework of neurodegeneration. Frontiers in Neuroscience, 13: 728. doi:10.3389/fnins.2019.00728.

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Castillo, Ximena1, 2, Author
Castro-Obregón, Susana3, Author
Gutiérrez-Becker, Benjamin4, Author
Gutiérrez-Ospina, Gabriel5, Author
Karalis, Nikolaos6, Author
Khalil, Ahmed7, 8, 9, Author           
Lopez-Noguerola, José Sócrates10, Author
Lozano Rodríguez, Liliana11, Author
Martínez-Martínez, Eduardo12, Author
Perez-Cruz, Claudia13, Author
Pérez-Velázquez, Judith14, 15, Author
Piña, Ana Luisa16, Author
Rubio, Karla17, Author
García, Héctor Pedro Salazar18, Author
Syeda, Tauqeerunnisa13, Author
Vanoye-Carlo, America19, Author
Villringer, Arno7, 8, 9, Author           
Winek, Katarzyna20, 21, Author
Zille, Marietta22, 23, 24, Author
1Institute of Neurobiology, National Autonomous University of Mexico, Mexico City, Mexico, ou_persistent22              
2Institute of Neurobiology, University of Puerto Rico, San Juan, PR, USA, ou_persistent22              
3Institute of Cellular Physiology, National Autonomous University of Mexico, Mexico City, Mexico, ou_persistent22              
4Laboratory for Artificial Intelligence in Medical Imaging (AI-Med), Ludwig Maximilians University Munich, Germany, ou_persistent22              
5Systems Biology Laboratory, Department of Cell Biology and Physiology, Institute of Biomedical Research and Coordination of Psychobiology and Neurosciences, National Autonomous University of Mexico, Mexico City, Mexico, ou_persistent22              
6Friedrich Miescher Institute for Biomedical Research FMI, Basel, Switzerland, ou_persistent22              
7Center for Stroke Research, Charité University Medicine Berlin, Germany, ou_persistent22              
8Berlin School of Mind and Brain, Humboldt University Berlin, Germany, ou_persistent22              
9Department Neurology, MPI for Human Cognitive and Brain Sciences, Max Planck Society, ou_634549              
10Department of Gerontology, School of Health Sciences, Autonomous University of Hidalgo State, Pachuca, Mexico, ou_persistent22              
11Department of Biochemistry, Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico, ou_persistent22              
12Cell Communication & Extracellular Vesicles Laboratory, National Institute of Genomic Medicine, Mexico City, Mexico, ou_persistent22              
13Center for Research and Advanced Studies of the National Polytechnic Institute (CINVESTAV), Mexico City, Mexico, ou_persistent22              
14Department of Mathematics and Mechanics, Research Institute in Applied Mathematics and Systems, National Autonomous University of Mexico, Mexico City, Mexico, ou_persistent22              
15Mathematical Modeling of Biological Systems, Faculty of Mathematics, TU Munich, Germany, ou_persistent22              
16Department of Neurosurgery, Charité University Medicine Berlin, Germany, ou_persistent22              
17Lung Cancer Epigenetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany, ou_persistent22              
18Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany, ou_persistent22              
19Laboratorio de Neurociencias, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City, Mexico, ou_persistent22              
20Edmond & Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Israel, ou_persistent22              
21Department of Experimental Neurology, Charité University Medicine Berlin, Germany, ou_persistent22              
22Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Germany, ou_persistent22              
23Institute for Medical and Marine Biotechnology, University of Lübeck, Germany, ou_persistent22              
24Fraunhofer Institute for Marine Biotechnology, Lübeck, Germany, ou_persistent22              


Free keywords: Body–brain trophism; Dysbiosis; Lifespan; Senescence; Vascular pathology
 Abstract: Neurodegenerative diseases are among the leading causes of disability and death worldwide. The disease-related socioeconomic burden is expected to increase with the steadily increasing life expectancy. In spite of decades of clinical and basic research, most strategies designed to manage degenerative brain diseases are palliative. This is not surprising as neurodegeneration progresses "silently" for decades before symptoms are noticed. Importantly, conceptual models with heuristic value used to study neurodegeneration have been constructed retrospectively, based on signs and symptoms already present in affected patients; a circumstance that may confound causes and consequences. Hence, innovative, paradigm-shifting views of the etiology of these diseases are necessary to enable their timely prevention and treatment. Here, we outline four alternative views, not mutually exclusive, on different etiological paths toward neurodegeneration. First, we propose neurodegeneration as being a secondary outcome of a primary cardiovascular cause with vascular pathology disrupting the vital homeostatic interactions between the vasculature and the brain, resulting in cognitive impairment, dementia, and cerebrovascular events such as stroke. Second, we suggest that the persistence of senescent cells in neuronal circuits may favor, together with systemic metabolic diseases, neurodegeneration to occur. Third, we argue that neurodegeneration may start in response to altered body and brain trophic interactions established via the hardwire that connects peripheral targets with central neuronal structures or by means of extracellular vesicle (EV)-mediated communication. Lastly, we elaborate on how lifespan body dysbiosis may be linked to the origin of neurodegeneration. We highlight the existence of bacterial products that modulate the gut-brain axis causing neuroinflammation and neuronal dysfunction. As a concluding section, we end by recommending research avenues to investigate these etiological paths in the future. We think that this requires an integrated, interdisciplinary conceptual research approach based on the investigation of the multimodal aspects of physiology and pathophysiology. It involves utilizing proper conceptual models, experimental animal units, and identifying currently unused opportunities derived from human data. Overall, the proposed etiological paths and experimental recommendations will be important guidelines for future cross-discipline research to overcome the translational roadblock and to develop causative treatments for neurodegenerative diseases.


Language(s): eng - English
 Dates: 2019-03-312019-06-282019-07-24
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.3389/fnins.2019.00728
PMID: 31396030
PMC: PMC6667555
Other: eCollection 2019
 Degree: -



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Project name : -
Grant ID : 01DN18054
Funding program : -
Funding organization : German Federal Ministry of Education and Research (BMBF)

Source 1

Title: Frontiers in Neuroscience
  Other : Front Neurosci
Source Genre: Journal
Publ. Info: Lausanne, Switzerland : Frontiers Research Foundation
Pages: - Volume / Issue: 13 Sequence Number: 728 Start / End Page: - Identifier: ISSN: 1662-4548
ISSN: 1662-453X
CoNE: https://pure.mpg.de/cone/journals/resource/1662-4548