Neurodegenerative Diseases: Looking Beyond the Boundaries of the Brai

Gutiérrez-Ospina, Gabriel

Perez-Cruz, Claudia

Zenaro, Elena

Zille, Marietta

English

PubMed

Gutiérrez-Ospina, Gabriel

Catalogo dei prodotti della ricerca

EDITORIALpublished: 23 June 2022doi: 10.3389/fnins.2022.929786Frontiers in Neuroscience | www.frontiersin.org 1 June 2022 | Volume 16 | Article 929786Edited and reviewed by:Wendy Noble,King’s College London,United Kingdom*Correspondence:Gabriel Gutiérrez-Ospinagabo@iibiomedicas.unam.mxClaudia Perez-Cruzcperezc@cinvestav.mxElena Zenaroelena.zenaro@univr.itMarietta Zillemarietta.zille@univie.ac.at†These authors have contributedequally to this workSpecialty section:This article was submitted toNeurodegeneration,a section of the journalFrontiers in NeuroscienceReceived: 27 April 2022Accepted: 16 May 2022Published: 23 June 2022Citation:Gutiérrez-Ospina G, Perez-Cruz C,Zenaro E and Zille M (2022) Editorial:Neurodegenerative Diseases: LookingBeyond the Boundaries of the Brain.Front. Neurosci. 16:929786.doi: 10.3389/fnins.2022.929786Editorial: NeurodegenerativeDiseases: Looking Beyond theBoundaries of the BrainGabriel Gutiérrez-Ospina 1*†, Claudia Perez-Cruz 2*†, Elena Zenaro 3*† and Marietta Zille 4*†1 Laboratorio de Biología de Sistemas, Departamento de Biología Celular y Fisiología, Instituto de Investigaciones Biomédicasy Coordinación de Psicobiología y Neurociencias, Facultad de Psicología, Universidad Nacional Autónoma de México,Mexico City, Mexico, 2Center of Research and Advanced Studies (Cinvestav) of the National Polytechnic Institute, MexicoCity, Mexico, 3 Section of General Pathology, Department of Medicine, University of Verona, Verona, Italy, 4Division ofPharmacology and Toxicology, Department of Pharmaceutical Sciences, University of Vienna, Vienna, AustriaKeywords: neurodegeneration, peripheral alterations, body-brain interactions, outside brain boundaries,neurodegenerative diseasesEditorial on the Research TopicNeurodegenerative Diseases: Looking Beyond the Boundaries of the BrainNeurobiological wisdom has long entertained the notion that the brain has functional primacyover the body. Under this presumption, the body serves as the “machine” through which thebrain manifests its “sublime workings” in the form of overt behavior. The body, nonetheless, doesmuch more than only being the brain’s marionette. Indeed, it “dialogues, cares, nourishes and mayeven condition” the brain so that its functional morphology stays operative throughout life until,eventually, with increasing age, the body-brain whole irreversibly decays as death approaches.As the saying outlines, “a healthy mind is a healthy body” and numerous instances supportthis simple yet profound notion. The occurrence of reciprocal altruistic/instructive trophicinterrelationships between the body and the brain has existed for decades (Purves, 1992). Scientificawareness about the overpowering influence the body’s inner sensing has on our consciouscognitive abilities and behavioral manifestations has also increased greatly. Indeed, embodiedcognition and emotions are no longer denied facts (Seth and Friston, 2016; Holzer, 2017;Nummenmaa et al., 2018).Despite this information, many scientists still believe that the origin of neurodegenerativeprocesses rests within the brain itself. However, this neurocentric view is confronted by relativelynew evidence suggesting that neuronal deterioration may be ignited, and its progression fosteredby processes ongoing outside the boundaries of the brain. These include, but are not limited to,an impaired cardiovascular system, infection, systemic inflammation, cellular senescence, alteredtrophic interactions, endocrine disruption, and gut dysbiosis (Preciados et al., 2016; Castillo et al.,2019; Limphaibool et al., 2019; Winek et al., 2022). “Neurodegenerative Diseases: Looking Beyondthe Boundaries of the Brain” is a volume that looks at brain diseases as consequences rather than asthe result of primary neurological causes.Gut microbiota, for instance, modulate the immune system in a variety of neurologicaldiseases (Cryan et al., 2020; Willyard, 2021). The imbalance of its composition, distribution,and metabolic activity may lead, as commented by Maiuolo et al., to anxiety, depression, autismspectrum disorder, and multiple sclerosis. Studying the crosstalk between neurons, mucosalimmunity, and gut microbiota may help us improve therapeutic measures aimed at lessening thesedisorders. Dumitrescu et al. evaluated the presence of biomarkers of intestinal inflammation andbarrier permeability in the peripheral circulation and stool samples obtained from Parkinson’sdisease subjects. The correlation observed supported a causal link between dysbiosis, enhancedGutiérrez-Ospina et al. Editorial: Looking Beyond Brain Boundariesinflammatory response, and the progression ofneurodegeneration. Rydbom et al. demonstrated that Tau iscapable of disrupting gut motility, microbiome composition,and innate immune response in Drosophila. This opensthe possibility that peripheral tauopathy may alter theavailability of the antimicrobial peptides that oversee theelimination of pathogenic microorganisms that mightpromote neurodegeneration. Lastly, sirtuins, a family ofhistone deacetylases, modulate genome stability, stress cellularresponse, and nutrient and hormone sensing in response tovarious metabolites that signal aging, obesity, and diabetes.Chandramowlishwaran et al. revised the novel role of sirtuins onenteric neuronal growth and survival, and propose sirtuins asnovel modulators of the gut-brain axis.In addition to dysbiosis, viral infections are presumed to causeneurodegeneration (Limphaibool et al., 2019; Shinjyo and Kita,2021). With the novel SARS-CoV-2 infection, growing evidencesupports infections as an etiological path to neurodegenerationand cerebrovascular disease (Wenzel et al., 2021; Douaud et al.,2022). Römer reviews the epidemiological and experimentalevidence that links viruses and endogenous retroviruses to neuro-immune degeneration.Lifestyle and metabolic alterations during midlife areconsidered important risk factors for developing Alzheimer’sDisease (AD) (Livingston et al., 2017). Memory dysfunctionin AD patients results from the brain and peripheral glucoseresistance (Arnold et al., 2018). Wei et al. revise the multiplepathogenic mechanisms induced by insulin resistance that areimplicated in AD and discuss the use of antidiabetic and anti-inflammatory drugs to delay the onset of neurodegeneration.Sim et al. offer a comprehensive overview of the potentialrole of dipeptidyl peptidase-4 inhibitor and sodium-glucosecotransporter 2 inhibitors, both used in type-2 diabetespatients, as repurposing drugs against AD based on theirantidiabetic effects.As already mentioned, several lifestyle factors during midlifeare important modulators of dementia onset later in life. Inparticular, unhealthy dietary habits influence neurodegenerativediseases through cellular inflammation and increased oxidation(Tan and Norhaizan, 2019; Winiarska-Mieczan et al., 2020).Nassir et al. provide a persuasive and plausible explanation thatsupports the role of cellular-derived circulating microparticlesreleased after consuming unhealthy diets in promotingthrombotic events throughout the microcirculation. Whenthinking about the etiology of neurodegeneration, thesemicroparticles must then be considered as risk factors andbiomarkers of the brain-heart-gut axis.The erythroid 2-related factor 2 (NRF2) forms part ofthe molecular machinery that supports the body’s antioxidantdefense system. Petrillo et al. performed a family study ofFriedreich’s ataxia, the most frequent autosomal recessiveataxia in Western societies. Although all family members wereaffected by frataxin depletion, those having activation of NRF2were asymptomatic. The authors propose that the constitutiveupregulation of NRF2 keeps the antioxidant defense abovethe threshold, a circumstance that protects against progressiveoxidative damage.The glymphatic circulation modulates neuroinflammatoryresponses in neurodegenerative diseases. Natale et al.argue that, besides waste elimination, the glymphaticsystem may also function to connect the brain with theperiphery. It then facilitates communication betweenthe immune system and the brain, thus modulating thebrain’s immune surveillance and neuroinflammation. Thefunctional disruption of the glymphatic system mustthen be considered when unrevealing the mechanismsof neurodegeneration.It becomes more and more clear that neurodegenerationprogresses silently for many years or even decades beforeit becomes diagnosed. Therefore, the identification of earlyclinical biomarkers is urgently needed. Zhang et al. suggestthat evaluating retinal degeneration may be a gateway tounderstanding, monitoring the progression, and diagnosingParkinson’s disease, as visual symptoms appear early inthe disease.Taken together, this Research Topic highlights the relevanceof studying the etiology of neurodegeneration beyond theboundaries of the brain. Notably, this compilation of articlesdescribes how peripheral alterations can impact brain functionand health. Further research is needed to better understandthese paths to develop more effective and early treatmentoptions to stop the growing number of patients suffering fromneurodegenerative diseases.AUTHOR CONTRIBUTIONSAll authors listed have made a substantial, direct, and intellectualcontribution to the work and approved it for publication.REFERENCESArnold, S. E., Arvanitakis, Z., Macauley-Rambach, S. L., Koenig, A. M., Wang, H.Y., Ahima, R. S., et al. (2018). Brain insulin resistance in type 2 diabetes andAlzheimer disease: concepts and conundrums. Nat. Rev. Neurol. 14, 168–181.doi: 10.1038/nrneurol.2017.185Castillo, X., Castro-Obregón, S., Gutiérrez-Becker, B., Gutiérrez-Ospina, G.,Karalis, N., Khalil, A. A., et al. (2019). Re-thinking the Etiological Frameworkof Neurodegeneration. Front. Neurosci. 13, 728. doi: 10.3389/fnins.2019.00728Cryan, J. F., ORiordan, K. J., Sandhu, K., Peterson, V., and Dinan, T. G. (2020).The gut microbiome in neurological disorders. Lancet Neurol. 19, 179–194.doi: 10.1016/S1474-4422(19)30356-4Douaud, G., Lee, S., Alfaro-Almagro, F., Arthofer, C., Wang, C., McCarthy, P.,et al. (2022). SARS-CoV-2 is associated with changes in brain structure in UKBiobank. Nature. 604, 697–707. doi: 10.1038/s41586-022-04569-5Holzer, P. (2017). “Interoception and Gut Feelings: Unconscious Body SignalsImpact on Brain Function, Behavior and Belief Processes,” in, Processesof Believing: The Acquisition, Maintenance, and Change in Creditions.doi: 10.1007/978-3-319-50924-2_31Limphaibool, N., Iwanowski, P., Holstad,M. J. V., Kobylarek, D., and Kozubski,W.(2019). Infectious Etiologies of Parkinsonism: Pathomechanisms and ClinicalImplications. Front. Neurol. 10, 652. doi: 10.3389/fneur.2019.00652Livingston, G., Sommerlad, A., Orgeta, V., Costafreda, S. G., Huntley,J., Ames, D., et al. (2017). Dementia prevention, intervention,Frontiers in Neuroscience | www.frontiersin.org 2 June 2022 | Volume 16 | Article 929786Gutiérrez-Ospina et al. Editorial: Looking Beyond Brain Boundariesand care. Lancet 390, 2673–2734. doi: 10.1016/S0140-6736(17)31363-6Nummenmaa, L., Hari, R., Hietanen, J. K., and Glerean, E. (2018). Mapsof subjective feelings. Proc. Natl. Acad Sci. U S A. 115, 9198–9203.doi: 10.1073/pnas.1807390115Preciados, M., Yoo, C., and Roy, D. (2016). Estrogenic endocrinedisrupting chemicals influencing NRF1 regulated gene networks in thedevelopment of complex human brain diseases. Int. J. Mol. Sci. 17, 2086.doi: 10.3390/ijms17122086Purves, D. (1992). Body and brain: a trophic theory of neural connections. Perspect.Biol. Med. 36, 158–158. doi: 10.1353/pbm.1993.0067Seth, A. K., and Friston, K. J. (2016). Active interoceptive inference and theemotional brain. Philos. Trans. R. Soc. Lond B Biol. Sci. 371, 20160007.doi: 10.1098/rstb.2016.0007Shinjyo, N., and Kita, K. (2021). Infection and immunometabolism in the centralnervous system: a possible mechanistic link between metabolic imbalance anddementia. Front. Cell Neurosci. 15, 765217. doi: 10.3389/fncel.2021.765217Tan, B. L., and Norhaizan, M. E. (2019). Effect of high-fat diets on oxidative stress,cellular inflammatory response and cognitive function. Nutrients 11, 2579.doi: 10.3390/nu11112579Wenzel, J., Lampe, J., Müller-Fielitz, H., Schuster, R., Zille, M., Müller, K., et al.(2021). The SARS-CoV-2 main protease M(pro) causes microvascular brainpathology by cleaving NEMO in brain endothelial cells. Nat. Neurosci. 24,1522–1533. doi: 10.1038/s41593-021-00926-1Willyard, C. (2021). How gut bacteria alter the brain. Nature 590, 22–25.doi: 10.1038/d41586-021-00260-3Winek, K., Zanatta, D. C., and Zille, M. (2022). Brain–body communication instroke. Neuroforum 28, 31–39. doi: 10.1515/nf-2021-0030Winiarska-Mieczan, A., Baranowska-Wojcik, E., Kwiecien, M., Grela, E. R.,Szwajgier, D., Kwiatkowska, K., et al. (2020). The role of dietary antioxidantsin the pathogenesis of neurodegenerative diseases and their impact oncerebral oxidoreductive balance. Nutrients 12, 435. doi: 10.3390/nu12020435Conflict of Interest: The authors declare that the research was conducted in theabsence of any commercial or financial relationships that could be construed as apotential conflict of interest.Publisher’s Note: All claims expressed in this article are solely those of the authorsand do not necessarily represent those of their affiliated organizations, or those ofthe publisher, the editors and the reviewers. Any product that may be evaluated inthis article, or claim that may be made by its manufacturer, is not guaranteed orendorsed by the publisher.Copyright © 2022 Gutiérrez-Ospina, Perez-Cruz, Zenaro and Zille. This is an open-access article distributed under the terms of the Creative Commons AttributionLicense (CC BY). The use, distribution or reproduction in other forums is permitted,provided the original author(s) and the copyright owner(s) are credited and that theoriginal publication in this journal is cited, in accordance with accepted academicpractice. No use, distribution or reproduction is permitted which does not complywith these terms.Frontiers in Neuroscience | www.frontiersin.org 3 June 2022 | Volume 16 | Article 929786

Editorial: Neurodegenerative Diseases: Looking Beyond the Boundaries of the Brain

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Editorial: Neurodegenerative Diseases: Looking Beyond the Boundaries of the Brain

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